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=Chapter X The Genesis of Function in the Nervous System=
=Chapter X The Genesis of Function in the Nervous System=


THE beginning of functional activity in the nervous system has
THE beginning of functional activity in the nervous system has been investigated most thoroughly in embryos of the rat,I-4 guinea pig,5- S sheepfs 8 and cat,9-13 and less completely in man14s 15 and other mammals.10-I7 studies in the lower vertebrates,18-22 especially amphibia, have influenced conceptions of behavioral de— velopment in mammals to a very considerable extent. A complete review of all articles on the subject of early fetal movements would require far more space than is available in the present chapter.
been investigated most thoroughly in embryos of the rat,I-4 guinea
pig,5- S sheepfs 8 and cat,9-13 and less completely in man14s 15 and
other mammals.10-I7 studies in the lower vertebrates,18-22 especially amphibia, have influenced conceptions of behavioral de—
velopment in mammals to a very considerable extent. A complete
review of all articles on the subject of early fetal movements
would require far more space than is available in the present chap—
tclc


A B C


Fig. 47.—Embryo.s of the (.-1) rat, (B) cat and (C) human at approximately
the stage in development at which simple rellexes are expected for the first time.
crownckump length: 12 mm. rat; 14 mm. cat; 18 mm. human (7 weeks) . Magni—
ficatiom X Z.


1t is impossible to say precisely when nerve cells attain the
ability to discharge or when kibers can conduct nervous impulses
for the first time. However, muscle contractions induced by
nervous activity can be elicited surprisingly early in prenatal life.
The stage at which nervous function is first observable in mammals varies to some extent, but in all species that have been in—


138
Fig. 47. Embryos of the (A) rat, (B) cat and (C) human at approximately the stage in development at which simple rellexes are expected for the first time. crownckump length: 12 mm. rat; 14 mm. cat; 18 mm. human (7 weeks). Magnificatiom X Z.
oENEs1s or FUNCTION IN NEnvoUs sYsTEM 139


vestigated it is before body form has talcen on the characteristic
appearance of the species. In other words, somatic movements
start before the close of the embryonic, rather than in the fetal
period. This is illustrated by the accompanying photographs of
rat, cat and human embryos talcen at about the time simple reHexes can first be induced (Fig. 47) .


The initiation of function in slceletal muscle cells was considered in the preceding chapten Myogenic xesponses precede
1t is impossible to say precisely when nerve cells attain the ability to discharge or when kibers can conduct nervous impulses for the first time. However, muscle contractions induced by nervous activity can be elicited surprisingly early in prenatal life. The stage at which nervous function is first observable in mammals varies to some extent, but in all species that have been investigated it is before body form has talcen on the characteristic appearance of the species. In other words, somatic movements start before the close of the embryonic, rather than in the fetal period. This is illustrated by the accompanying photographs of rat, cat and human embryos talcen at about the time simple reHexes can first be induced (Fig. 47) .
reiiexes by at least one day in most mamma1s. The development
of muscle iibers and of motor nerves with simple epilemmal motor
nerve endings goes hand -in hand, but there does not seem to be
an immediate correlation between the appearance of motor end—
ings and Csunctional reflexes as some have suggestedks From the
structural point of view it is possible that muscle contractions can
be induced by discharge of motor neurons before reflex arcs have
been completely formed. With the advent of conduction from
afferent to efkerent neurons through synaptic centers, reHex re—
sponses to stimulation are manifested. At this point in deve1opment behavior may be said to have its genesis.


MYOGENIC RESPONSES


Let us examine the antecedents of behavioral genesis in somewhat gyeater detail. spontaneous muscle twitching characterizes
The initiation of function in slceletal muscle cells was considered in the preceding chapten Myogenic xesponses precede reiiexes by at least one day in most mamma1s. The development of muscle iibers and of motor nerves with simple epilemmal motor nerve endings goes hand -in hand, but there does not seem to be an immediate correlation between the appearance of motor end— ings and Csunctional reflexes as some have suggestedks From the structural point of view it is possible that muscle contractions can be induced by discharge of motor neurons before reflex arcs have been completely formed. With the advent of conduction from afferent to efkerent neurons through synaptic centers, reHex re— sponses to stimulation are manifested. At this point in deve1opment behavior may be said to have its genesis.
embryos of certain lower vertebrates before reHex excitation becomes eifective. 0bservations in fishes are especially notable.I9
The similarity to spontaneous contractions of myob1asts and
muscle iibers in cultures of embryonic chiclc tissues is striking. It
is possible that some of the earliest spontaneous movements »observed in the intact living chick embryo1S-21-24-25 are of this natake. ·


No comparable phenomenon has been seen in .mammalian
==Myogenic Responses==
embryos studied under normal« physiologic conditions. However,
the movements which manifest themselves in ionically unbalanced
saline solutions probably are myogenic responsesKs Why spontaneous muscle twitching is not encountered normally in mammalian embryos has not been determined. Musculature is laid
down well in advance of- the time it can be activated reflexly in
the rat, guinea pig, sheep and cat.


Mechanical and electrical stimuli applied directly to muscle
Let us examine the antecedents of behavioral genesis in somewhat gyeater detail. spontaneous muscle twitching characterizes embryos of certain lower vertebrates before reHex excitation becomes eifective. 0bservations in fishes are especially notable.I9 The similarity to spontaneous contractions of myob1asts and muscle iibers in cultures of embryonic chiclc tissues is striking. It is possible that some of the earliest spontaneous movements »observed in the intact living chick embryo1S-21-24-25 are of this nature.
140 PHYSIOLOGY OF THE FETUs·


masses of intact embryoX efkect contractions readily. Microselecs
trodes constructed of Hne nichrome wires insulated except at the
tips serve admirably for deliveringdocalized faradic shoclcs. Contractions of the embryonic slceletal muscles induced in this manner possess certain characteristics which distinguish them from
other types of somatic movement. They are as follows: (a) a
minimal stimulus, just adequate to produce a response, gives rise
to a quiclc contraction followed by a slower relaxationx (b) each
succeeding stimulation produces a similar contraction, for there
is no noticeable interval of fatigue during which the muscle is re—
fractoryz (c) the contraction is remarlcably well localized in a
small region immediately around the tips of the electrodes and
consequently -movements in several planes can usually be brought
about by shifting the Position of the electrodes; (d) the embryonic muscle tissue retains a high degree of excitability irrespective of great changes in metabolic conditions. In fact, specimens which have been allowed to bleed until white, which have
cooled to room temperature and in which the heart has practically
stopped beating still respond to direct stimulation of the slceletal
musculature. «


All the muscles of an embryo do not simultaneously reach a
No comparable phenomenon has been seen in .mammalian embryos studied under normal physiologic conditions. However, the movements which manifest themselves in ionically unbalanced saline solutions probably are myogenic responsesKs Why spontaneous muscle twitching is not encountered normally in mammalian embryos has not been determined. Musculature is laid down well in advance of the time it can be activated reflexly in the rat, guinea pig, sheep and cat.
state of development in which contractions are possible. The
first in which such direct responses can be observed are those ok
the forelimbs at the attachment to the body. With advancement
of growth,.excitability spreads both rostrally and caudally as well
as distally from these po»ints.


NEUROMOTOR RESPONSES


The second step in development of behavior is thought to be
Mechanical and electrical stimuli applied directly to muscle masses of intact embryoX efkect contractions readily. Microselecs trodes constructed of Hne nichrome wires insulated except at the tips serve admirably for deliveringdocalized faradic shoclcs. Contractions of the embryonic slceletal muscles induced in this manner possess certain characteristics which distinguish them from other types of somatic movement. They are as follows: (a) a minimal stimulus, just adequate to produce a response, gives rise to a quiclc contraction followed by a slower relaxationx (b) each succeeding stimulation produces a similar contraction, for there is no noticeable interval of fatigue during which the muscle is re— fractoryz (c) the contraction is remarlcably well localized in a small region immediately around the tips of the electrodes and consequently -movements in several planes can usually be brought about by shifting the Position of the electrodes; (d) the embryonic muscle tissue retains a high degree of excitability irrespective of great changes in metabolic conditions. In fact, specimens which have been allowed to bleed until white, which have cooled to room temperature and in which the heart has practically stopped beating still respond to direct stimulation of the slceletal musculature.
the appearance of muscle contraction in response to. excitation of
motor neurons.27 Nerve endings of a primitive lcind (Fig. 45)
are present upon developing muscle übers at a time when the
only somatic movements are those which follow direct skimulation
of the muscleskss 29 Although it has been impossible to obtain
direct evidence in the youngest cat embryos that purely neuromuscular contractions precede rellexes, such contractions can be
demonstrated in specimens a little more advanced, in which reflex
responses are already obtainable. After the reflexes have died
away with deterioration of the· plsysiologic oonditions of the
cENEsIs OF kUNcTlcN IN NERVOUS sYsTEM 141


embryo, stimulation of motor centers produces movements. A
s1ender and sharp dental broach was used to pierce the tissues of
the back and the spinal cord of the embryos. It was found that
a baclcward movement of the forelimb followed when the instrument was passed into the spinal cord at the level between C.7
and T.1 and a forward movement resulted in the same specimens
when it was inserted at the level between c.4 and c.6. The true
reflexes which had been obtained previously were all baclcward
and outward movements of the 1imbs. Thus it is apparent that a
new forward movement of the arm had been induced by direct
stimulation of a motor center before such a movement occurred
as the result of retlex stimulation of afferent nerves. It is especially noteworthy that the responses were localized and that there
was no diffuse spreading of excitation through the center even
with this rather crude form of stimulation. The segmentaL nonintegrated character of the motor ce11 column of the embryonic
spinal cord, so clearly evident in silver-stained histologic preparations, is demonstrable by physiologic methods.


GENESIS OF REFLEX BEEAVIOR
All the muscles of an embryo do not simultaneously reach a state of development in which contractions are possible. The first in which such direct responses can be observed are those ok the forelimbs at the attachment to the body. With advancement of growth,.excitability spreads both rostrally and caudally as well as distally from these points.


The third step in behavioral development is characterized by
==Neuromotor Responses==
the appearance of reflexes. These do not manifest themselves
unti1 atkerent and efferent neurons, simple nerve endings in
peripheral tissues, connector neurons in the central nervous system and functional synaptic central mechanisms have been
formed. ·


There are essentially two conceptions of the development of
The second step in development of behavior is thought to be the appearance of muscle contraction in response to. excitation of motor neurons.27 Nerve endings of a primitive lcind (Fig. 45) are present upon developing muscle übers at a time when the only somatic movements are those which follow direct skimulation of the muscleskss 29 Although it has been impossible to obtain direct evidence in the youngest cat embryos that purely neuromuscular contractions precede rellexes, such contractions can be demonstrated in specimens a little more advanced, in which reflex responses are already obtainable. After the reflexes have died away with deterioration of the· physiologic oonditions of the embryo, stimulation of motor centers produces movements. A s1ender and sharp dental broach was used to pierce the tissues of the back and the spinal cord of the embryos. It was found that a backward movement of the forelimb followed when the instrument was passed into the spinal cord at the level between C.7 and T.1 and a forward movement resulted in the same specimens when it was inserted at the level between c.4 and c.6. The true reflexes which had been obtained previously were all baclcward and outward movements of the 1imbs. Thus it is apparent that a new forward movement of the arm had been induced by direct stimulation of a motor center before such a movement occurred as the result of retlex stimulation of afferent nerves. It is especially noteworthy that the responses were localized and that there was no diffuse spreading of excitation through the center even with this rather crude form of stimulation. The segmentaL nonintegrated character of the motor ce11 column of the embryonic spinal cord, so clearly evident in silver-stained histologic preparations, is demonstrable by physiologic methods.
behavior in mammalian embryos. 0ne group of investigatorsY
II· IS believe that they have demonstrated the genesis of reflexes
by a process of individuation from a fully integrated mass reaction or «total Patter·n." In other words, they believe that more
or less discrete movements are not the primary units of behavior
but that local reflexes difkerentiate from a more fundamental
baclcground of massive movement. Another group of investigatorsws 30 hold the opposjng view that the basic elements in the
genesis of mammalian behavior are relatively simple reliex re—
sponses. They lind that the more complex reactions of older
fetuses are formed by progressive neuronal integration of the less
complicated activities of the embryo. some other investigatorss
142 PHYSIOLOGY OF THE FETUS


maintain that both theories are partially true, but are inclined to
kavor the form-er.


THE CONCEPT OF Ä TOTAL PATTERN
==Genesis Of Reflex Behavior==


The doctrine of development of behavior from a total pattern
The third step in behavioral development is characterized by the appearance of reflexes. These do not manifest themselves unti1 atkerent and efferent neurons, simple nerve endings in peripheral tissues, connector neurons in the central nervous system and functional synaptic central mechanisms have been formed.
is based on a long series of correlated physiologic and histologic
studies by coghill in the urode1e amphibiam Amblystoma, ap—
pearing frequently since 1913 and summarized in his London lec
x Ifloor PMB cslls


Fig. 48.—Diagram of the sensoryimotor mechanism of the Salamander embryo


which acoounts for the cephalwcaudal progkession of movement away from the
There are essentially two conceptions of the development of behavior in mammalian embryos. 0ne group of investigatorsY II· IS believe that they have demonstrated the genesis of reflexes by a process of individuation from a fully integrated mass reaction or «total Patter·n." In other words, they believe that more or less discrete movements are not the primary units of behavior but that local reflexes difkerentiate from a more fundamental baclcground of massive movement. Another group of investigatorsws 30 hold the opposjng view that the basic elements in the genesis of mammalian behavior are relatively simple reliex re— sponses. They lind that the more complex reactions of older fetuses are formed by progressive neuronal integration of the less complicated activities of the embryo. some other investigators 2 maintain that both theories are partially true, but are inclined to kavor the former.
side stimulated Arrows indicate direction of conductiom (coghi11: «Anatomy and


the Problem of Behavior," Cambridge Unim Press.)
==The Concept of a Total Pattern==


turesEs It was found that a motor mechanism develops on either
The doctrine of development of behavior from a total pattern is based on a long series of correlated physiologic and histologic studies by coghill in the urode1e amphibiam Amblystoma, ap— pearing frequently since 1913 and summarized in his London lectures.  18 It was found that a motor mechanism develops on either side of the embryonic floor plate as a longitudinally conducting system of neurons. Each neuron extends a process caudally to the next one; from this Process branches run to the muscles of the baclc and later to the 1imbs. Thesseries of neurons constitutes an integrating motor system which is laid down before kunction appears. An integrating s«ensory system is kormed by temporary neurons, the Rohon-Beard ce11s in the dorsal portion ok the spinal cord. They too send out processes, but in a rostral direction, with branches running to the epithelium and the muscles. The motor and sensory systems become connected by commissural fioorplate neurons, appearing iirst near the rostral end ok the embryo. These relations are illustrated in Figs. 48 and 49.
side of the embryonic floor plate as a longitudinally conducting
system of neurons. Each neuron extends a process caudally to
the next one; from this Process branches run to the muscles of the
baclc and later to the 1imbs. Thesseries of neurons constitutes an
oENEsrs or FUNoHoN 1N NEnvoUs sYsTEM 143


integrating motor system which is laid down before kunction appears. An integrating s«ensory system is kormed by temporary
neurons, the Rohon-Beard ce11s in the dorsal portion ok the spinal
cord. They too send out processes, but in a rostral direction, with
branches running to the epithelium and the muscles. The motor
and sensory systems become connected by commissural fioovplate


Spinoi cord
-(-—«-’——


 


T Gkk Moses· Post)
· —0 s» Riqht mofor YOU«


Xsksoor Plds cell
'''Fig. 48.''' Diagram of the sensoryimotor mechanism of the Salamander embryo which acoounts for the cephalwcaudal progkession of movement away from the side stimulated Arrows indicate direction of conductiom (Coghi11: "Anatomy and the Problem of Behavior," Cambridge Univ. Press.)


Fig. 49.—Diagrarn ok the neuromotor mechanism ok the Salamander embryo
which allows an initial irnpulse (a, w) to be kollowed by a oontralatetal secondary
Impulse (c, X) through an intermediate connecting neuron (b) . This makes pos—
sible the swimming rnovernents like those in Fig. He. (coghi11: «Anatomy and the
Problem ok Behavior," cambridge Univ. Press.)


neurons, appearing iirst near the rostral end ok the embryo.
These relations are illustrated in Figs. 48 and 49.


A stimulus which is applied to one side of the embryonic
'''Fig. 49.''' Diagram of the neuromotor mechanism ok the Salamander embryo which allows an initial irnpulse (a, w) to be kollowed by a oontralatetal secondary Impulse (c, X) through an intermediate connecting neuron (b) . This makes pos— sible the swimming rnovernents like those in Fig. He. (coghi11: «Anatomy and the Problem ok Behavior," cambridge Univ. Press.)
salamander sets up impulses which are conducted rostra11y in the
sensory System, across the· kloopplate neurons near its rostral end,
and then caudally in the integrating motor System. contralateral flexion is thereupon the iirst true» behavioral responsez it«
144 Pktysxoxock oF THE FETUs


is a mass movement or fully integrated response ’from the very
start. This reaction is iliustrated in a series of drawings taken
from a motion-picture record« (Fig. Ho) . The single flexion
stage is followed shortly by bilateral ilexion and then by typical
swimming. The latter depends upon the appearance of collateral branches of motor neurons (Fig. 49) which allow the
caudal1y flowing impulses of one side ·to precede those of the


Fig. 5o.-seria1 tracings from motion pictures (frame numhers indicatety of
the earliest contralateral movement in response to stimulation of a Salamander
embryo. The neural mechanism involved is illustrated in Fig. 48. (coghill:


«Anatomy and the Problem of Behavior," cambridge Univ. Press.)
A stimulus which is applied to one side of the embryonic salamander sets up impulses which are conducted rostra11y in the sensory System, across the· kloopplate neurons near its rostral end, and then caudally in the integrating motor System. contralateral flexion is thereupon the iirst true» behavioral responsez it is a mass movement or fully integrated response ’from the very start. This reaction is iliustrated in a series of drawings taken from a motion-picture record« (Fig. Ho) . The single flexion stage is followed shortly by bilateral ilexion and then by typical swimming. The latter depends upon the appearance of collateral branches of motor neurons (Fig. 49) which allow the caudal1y flowing impulses of one side ·to precede those of the other. In this way two waves of movement can course down the trunlc as shown in Figs. 51 and 52. 0ne response coming upon another in this manner produces forward propulsion of the embryo, establishing aquatic locomotion.


other. In this way two waves of movement can course down the
trunlc as shown in Figs. 51 and 52. 0ne response coming upon


·another in this manner produces forward propulsion of the


embryo, establishing aquatic locomotion.


Later, as the 1imbs grow out they first move with the trunlc
Fig. 50. Serial tracings from motion pictures (frame numhers indicatety of the earliest contralateral movement in response to stimulation of a Salamander embryo. The neural mechanism involved is illustrated in Fig. 48. (Coghill: "Anatomy and the Problem of Behavior," cambridge Univ. Press.)
passively but ultimately acquire independence. Limb movements may thus be said to individuatefrdm the mass movement
oENEs1s oF FUNcTmN 1N NERvoUs sYsTEM 145


Fig. 51.—serial tracings from motion pictures of the early swimming stage of a
Salamander embryo. Resting position in 1 and to. (coghi11: «Anatomy and the
Problem of Behavior," cambridge Unim Press.)


Fig. Hex-Three diagrams to; show the development of the first and subsequent
waves of contraction which result in swimming in the Salamander embryo. (coghill: «Anatomy and the Problem of Behavior," cambridge Unim Press.)


of the trank. Terrestrial locomotion, the feeding reaction and
Later, as the 1imbs grow out they first move with the trunlc passively but ultimately acquire independence. Limb movements may thus be said to individuatefrdm the mass movement of the trank. Terrestrial locomotion, the feeding reaction and other activities are made possible by brealcing up of the original total pattern or by the formation of segondary patterns within it. 0ther more discrete reflexes individuate from these patterns as development proceeds. « An independent and integrated motor system is present in fishesfor some time before it is captured by developing sensory mechanisms. During this period of independence the motor system can respond to changes in the internal but not the external environment. 19
other activities are made possible by brealcing up of the original
total pattern or by the formation of segondary patterns within


10
146 Pnvssror.ocv oF THE FETUs


it. 0ther more discrete reflexes individuate from these patterns
as development proceeds. « An independent and integrated motor
system is present in fishesfor some time before it is captured by
developing sensory mechanisms. During this period of independence the motor system can respond to changes in the internal
but not the external environmenr.U


In 1929 Coghillsl lattempted to explain behavior in human
embryos studied by Minlcowslci32 and others in terms of the total
pattern of the Salamander. He concluded that behavior in man
follows a developmental plan of a similar type. Some of the
earlier systcespmatic studies on development of fetal movements in
other mammals2s 9 suggested very strongly that nearly all embryonic motility develops from mass reactions resembling total
patterns. The more recent interpretations of these observations
will be discussed in the latter part of the present chapter.


Human and other mammalian embryos are so very different
'''Fig. 51.''' Serial tracings from motion pictures of the early swimming stage of a Salamander embryo. Resting position in 1 and to. (Coghi11: "Anatomy and the Problem of Behavior," Cambridge Univ. Press.)
from Amblystoma at the time movements and reflexes first appear
that it is surptising to find any functional similarities. The larval
Salamander develops its total reaction and precisely integrated
side to side waves of movement within this integrated pattern
before limbs and mouth have been formed. Mammalian embryos
are far from having attained functional age at a comparable stage
in morphologic dilferentiation (compare Figs. 47 and Ho) .
Muscle is entirely l·aclcing. Within the embryonic central nervous
system of mammals no structures exist which are comparable
with the chains of transient afkerent Rohon-Beard cells of lower
forms. Furthermore, the motor neurons are arranged segmentally
rather than in longitudinal series and they do not appear to be
connected with one another. The ear1iest secondary neurons
of the spinal cord build tracts that are predominantly ascending
pathways. 1n the brain, the descending tracts send few übers into
the spinal cord until spinal behavioral responses have become
establishedkHs « In other word-s, there is no longitudinally integrating mechanism in the spinal cord of mammalian embryos at
the stage in development which corresponds to the early motile


« Recently Aug-Mo« has reported that the media1 longitudinal fascicle of the


spinal cord is the descending integrating tract for the mass reaction of the rat
'''Fig. 52.''' Three diagrams to; show the development of the first and subsequent waves of contraction which result in swimming in the Salamander embryo. (Coghill: "Anatomy and the Problem of Behavior," Cambridge Univ. Press.)
embryo and that its termination forms the ventral spinal commissure. This is at
variance with our own observations which show that the ventral commissure übers


arise in the spinal cord and ascend in the vgntraltuniculus
GENESIS OF FUNCTION IN NERVOUS sYsTEM 147


Amblystomaz nor is there until some time later. By the time
dikkerentiation of structure makes functional activities possible
the head and limbs have become prominent structures.


In the further course of development of mammalian embryos
these parts exert an ever increasing dominance over the trunk,
and growth in the nervous system responds to this dominance.
There is never a need for the type of aquatic locomotor total pattern which is found in the iishes and amphi«bians.


EARLY REFLEXES IN MÄMMALIAN BMBRYOS
In 1929 Coghillsl lattempted to explain behavior in human embryos studied by Minlcowski32 and others in terms of the total pattern of the Salamander. He concluded that behavior in man follows a developmental plan of a similar type. Some of the earlier systcespmatic studies on development of fetal movements in other mammals2s 9 suggested very strongly that nearly all embryonic motility develops from mass reactions resembling total patterns. The more recent interpretations of these observations will be discussed in the latter part of the present chapter.


True behavior makes its appearance about one ·««day after it
was Erst possible to elicit muscle contractions in embryos of the
rat, guinea pig, cat and sheep. It is essential to emp1oy experimental methods which do not impair the physiologic conditions of pregnant animals and their embryos to observe the tirst
reflexes. F urthermore, studies must be conducted immediately
upon opening the uterus because this operation invariably interferes with placental respiratory exchange, resulting in anoxemia.
The procedures used in such studies have been discussed in the
first chapter.


Although the description of early reflex responses which follows pertains primarily to cat embryos about 14 mm. crownrump lengthP similar results have been obtained in other mammals.3- «« C« «« When an embryo with placenta still attached to the
Human and other mammalian embryos are so very different from Amblystoma at the time movements and reflexes first appear that it is surptising to find any functional similarities. The larval Salamander develops its total reaction and precisely integrated side to side waves of movement within this integrated pattern before limbs and mouth have been formed. Mammalian embryos are far from having attained functional age at a comparable stage in morphologic dilferentiation (compare Figs. 47 and Ho) . Muscle is entirely l·aclcing. Within the embryonic central nervous system of mammals no structures exist which are comparable with the chains of transient afkerent Rohon-Beard cells of lower forms. Furthermore, the motor neurons are arranged segmentally rather than in longitudinal series and they do not appear to be connected with one another. The ear1iest secondary neurons of the spinal cord build tracts that are predominantly ascending pathways. 1n the brain, the descending tracts send few übers into the spinal cord until spinal behavioral responses have become established. 33-36 * In other words, there is no longitudinally integrating mechanism in the spinal cord of mammalian embryos at the stage in development which corresponds to the early motile Amblystoma; nor is there until some time later. By the time dikkerentiation of structure makes functional activities possible the head and limbs have become prominent structures.
uterine wall has been brought quickly into view and the intact
amniotic sac is percussed witli some blunt instrument, pressure
transmitted to the embryo through the amniotic fluid results in
quick outward and backward movement of the forelimb. The
movement may be called a twitch or jerk. similar responses are
obtainable in other ways. Flipping the limb gently with a needle
or a hair passed through the amnion serves equally well. In a
few instances it was even possible to elicit this reaction by lightly
touching certain points upon the forelimb. Furthermore, faradic
shocks applied to approximately the same points by means of
micro-electrodes gave rise to similar quick outward and backward
movements of the limb.


Another reaction is frequently elicitable in embryos 14 mm.
long. stimulation of the forward end of the head. especially the
snoutz results in extension of the head. When the stimulus is
148 PHYSIOLOGY or THE FETUs


applied to one side ok the midline the head moves toward the opposite side and baclcwardH When the tip ok the snout is stimu1ated
* Recently Angulo 37 has reported that the media1 longitudinal fascicle of the spinal cord is the descending integrating tract for the mass reaction of the rat embryo and that its termination forms the ventral spinal commissure. This is at variance with our own observations which show that the ventral commissure fibers arise in the spinal cord and ascend in the vgntral funiculus.
it moves baclcward. Because this head response is more resistant
to changing physiologic conditions than that of the korelimb it
usually persists a little longer. Under the best conditions it too
is a quiclc movementz It has been observed by all investigators,
although some have encountered it at an earlier stage than others.


The head and korelimb responses are entirely separate and
distinct from one another when they iirst appear. They difker
somewhat in respect to the types ok stimulation eliciting them but
both seem to require stronger stimuli at first than they do at a
slightly later stage in development. The head movements, being
contralateral and involving muscles some little distance away


from the site of stimulation, are certainly reflexes. All observers
agree on this point. However, some have doubted the reflex nature ok the korelimb reactions, holdingsthat they may be due to
stimulation ok the muscles directly. The evidence, which will be
reviewed brieilyy kavors the view that they too are simple spinaltype reHexes.


Although the limb muscles can be induced to contract by
direct stimulation in asphyxiated embryos, the response held to be
a reflex is (a) elicitable kor only a briek interval (okten only a
kew seconds) while« metabolic conditions ok the embryo are at
their best. states of anoxemia set up experimentally make it impossible to obtain the reactions. Akter adequate direct stimulation the new muscle tends to relax slowly, whereas the reHex-like
response (b) seems to be a quiclcer movement with more rapid relaxation. Embryonic muscle appears to respond instantaneously
to directly app1ied stimuli, but (c) there is an interval just per—
ceptible· between stimulus and response ok thexeiiex type. 0ne
muscle contraction after another can be induced by direct stimulation, but (d) a second reflezklilce reaction cannot be made to kollow the Erst one until a briek interval ok time, a rekractory or
katigue period, has elapsed. Finally, (e) the responses believed to
be reilexes are stereotyped and do not show the molding characterizing direct contractions when the position ok the stimulus is
varied.


0ther experimental evidence demonstrates that the korelimb
In the further course of development of mammalian embryos these parts exert an ever increasing dominance over the trunk, and growth in the nervous system responds to this dominance. There is never a need for the type of aquatic locomotor total pattern which is found in the iishes and amphi«bians.
movements are reflexes. When xtiicroelectrodes are used to stimGENEsIs OF FUNCTION IN NERVOUS sYsTEM 149


ulate an embryo over the spinal cord some distance caudal to the
==Early Reflexes in Mammalian Embryos==
forelimb, the same quiclc outward and baclcward twitch results.
This is due to conduction up the spinal cord; stimuIation of other
parts of the embryo, equally distant from the limbs, does not pro—
duce this movement. At least one synapse is involved as indicated in Fig. 53.


The conception of the refiex nature of the early forelimb response iinds further confirmation in histologic studies in the
True behavior makes its appearance about one day after it was Erst possible to elicit muscle contractions in embryos of the rat, guinea pig, cat and sheep. It is essential to emp1oy experimental methods which do not impair the physiologic conditions of pregnant animals and their embryos to observe the tirst reflexes. Furthermore, studies must be conducted immediately upon opening the uterus because this operation invariably interferes with placental respiratory exchange, resulting in anoxemia. The procedures used in such studies have been discussed in the [[Book - Physiology of the Fetus 1|first chapter]].
spinal cords and peripheral nerves of the very specimens which
showed the reaction and which were subsequently stained by the


Fig. zssdiagram illustrating the probable nervous elements involved in elicits
ing forelimb movement by faradic stimulation of the spinal cord of an early main
malian embryo.


Ranson pyridine-silver techniquekss THE All nervous elements
Although the description of early reflex responses which follows pertains primarily to cat embryos about 14 mm. crownrump lengthP similar results have been obtained in other mammals. 3,4,6,7 When an embryo with placenta still attached to the uterine wall has been brought quickly into view and the intact amniotic sac is percussed witli some blunt instrument, pressure transmitted to the embryo through the amniotic fluid results in quick outward and backward movement of the forelimb. The movement may be called a twitch or jerk. similar responses are obtainable in other ways. Flipping the limb gently with a needle or a hair passed through the amnion serves equally well. In a few instances it was even possible to elicit this reaction by lightly touching certain points upon the forelimb. Furthermore, faradic shocks applied to approximately the same points by means of micro-electrodes gave rise to similar quick outward and backward movements of the limb.
essential for reflex action are present in the embryonic spinal cord
but their intrinsic synaptic connections are incomplete at the
time muscles can be made to contract by stimulating them directly
and previous to the appearance of the reliexdilce responses. 0ne
iinds alferent neurons whose peripheral Ebers pass to the tissues
immediately beneath the' epithelium of the forelimb and whose
central branches constitute the dorsal roots and dorsal funiculus
of the spinal cord. The efkerent neurons are assembled in two
groups in the ventral gray matter of the spinal cord, a medial
150 PHYSIOLOGY OF THE« FETUS


nucleus for trunk innervation and a lateral nucleus for the arm.
The efferent axons courses into the muscles of the shoulder region
and end in simple terminations upon some of the muscle übers.
Commissural and associationa1 neurons are present in the dorsal
column. ,The former are numerous in the region just beneath the
dorsomedial border of the dorsa1 funiculus, while the latter tend
to accumulate nearer the ventrolateral border of this afferent
pathway. Commissural axons pursue a course ventrally through


J« « »F. - «. v · « ·s - fis, F; - »,«’-«»; J  l -,E"-Z««
Another reaction is frequently elicitable in embryos 14 mm. long. stimulation of the forward end of the head. especially the snoutz results in extension of the head. When the stimulus is applied to one side ok the midline the head moves toward the opposite side and baclcwardH When the tip ok the snout is stimu1ated it moves baclcward. Because this head response is more resistant to changing physiologic conditions than that of the korelimb it usually persists a little longer. Under the best conditions it too is a quiclc movementz It has been observed by all investigators, although some have encountered it at an earlier stage than others.


 


 
The head and forelimb responses are entirely separate and distinct from one another when they iirst appear. They difker somewhat in respect to the types of stimulation eliciting them but both seem to require stronger stimuli at first than they do at a slightly later stage in development. The head movements, being contralateral and involving muscles some little distance away from the site of stimulation, are certainly reflexes. All observers agree on this point. However, some have doubted the reflex nature ok the korelimb reactions, holdingsthat they may be due to stimulation ok the muscles directly. The evidence, which will be reviewed brieilyy kavors the view that they too are simple spinaltype reflexes.


-..-«. ·« JHJL J»
Fig. 54.-—Photo1nicrograph of the fifth cervical Segment of the spina1 cord of a
13 mm. cat embryo just before the time the Erst forelimb reflexes can be elicitedx
as» Ventral funiculus; tut» association neurons; c» cornmissurex ern» Commissural
neurons; ihn, dorsal root and ganglionx M» Iateral funiculusx m.l., motor nucleus
for the limb muscles; Max» motor nucleus for the trunlc musclesz p.f., dorsal funiculus. Compare with Fig. 56. Pyridinesjlver stainz X so.


- s « -. »«
Although the limb muscles can be induced to contract by direct stimulation in asphyxiated embryos, the response held to be a reflex is (a) elicitable kor only a briek interval (okten only a kew seconds) while« metabolic conditions ok the embryo are at their best. states of anoxemia set up experimentally make it impossible to obtain the reactions. Akter adequate direct stimulation the new muscle tends to relax slowly, whereas the reflex-like response (b) seems to be a quiclcer movement with more rapid relaxation. Embryonic muscle appears to respond instantaneously to directly app1ied stimuli, but (c) there is an interval just perceptible between stimulus and response ok thexeiiex type. 0ne muscle contraction after another can be induced by direct stimulation, but (d) a second reflezklilce reaction cannot be made to kollow the Erst one until a briek interval ok time, a rekractory or katigue period, has elapsed. Finally, (e) the responses believed to be reilexes are stereotyped and do not show the molding characterizing direct contractions when the position ok the stimulus is varied.
J» I ««


the gray matter and cross the kloor p1ate, to become an ascending
tract close to the motor nerve cells which supply the trank. Associational axons pass close to the motor nucleus for limb muscles
and enter the Iateral funicu1us. This relation of associational
neurons and primary motor forelimb neurons appears to be very
intimate, with axons of the former coursing parallel with dendrons
of the latter. However, up to the time of appearance of the forelimb response there is no close re1ationship between the primary
afferent and the secondary neurons (Fig. 54) . A few collatera1
CENESIS OF FUNCTION IN NERVOUS SYSTEM 151


branches of dorsal funiculus ftbers do pass for a very short distance
Other experimental evidence demonstrates that the korelimb movements are reflexes. When xtiicroelectrodes are used to stimulate an embryo over the spinal cord some distance caudal to the forelimb, the same quiclc outward and baclcward twitch results. This is due to conduction up the spinal cord; stimuIation of other parts of the embryo, equally distant from the limbs, does not produce this movement. At least one synapse is involved as indicated in Fig. 53.
toward the associational group, but not many have reached it.


In the early motile embryos in which reilezklike twitches of the
forelimb occurred when the limbs were flipped or when the
amniotic sac was percussed, connections have been comp1eted be—
tween the primary afkerent and the associati0na1 neurons. This is


.. 


« Z«
'''Fig. 53.''' Diagram illustrating the probable nervous elements involved in elicits ing forelimb movement by faradic stimulation of the spinal cord of an early mammalian embryo.


Fig. 55.-—Photoicrograph of the dorsal funiculus (zt).j.) f the spinal cord of:
a 13 mm. cat embryo showing the Erst collateral branches (col.) of primary aikerent
neuronsz these serve to complete the first spinal reflex arcs. Pyridinesilver stainx


X Hin.
The conception of the refiex nature of the early forelimb response iinds further confirmation in histologic studies in the spinal cords and peripheral nerves of the very specimens which showed the reaction and which were subsequently stained by the  Ranson pyridine-silver techniquekss THE All nervous elements essential for reflex action are present in the embryonic spinal cord but their intrinsic synaptic connections are incomplete at the time muscles can be made to contract by stimulating them directly and previous to the appearance of the reliexdilce responses. 0ne iinds alferent neurons whose peripheral Ebers pass to the tissues immediately beneath the' epithelium of the forelimb and whose central branches constitute the dorsal roots and dorsal funiculus of the spinal cord. The efkerent neurons are assembled in two groups in the ventral gray matter of the spinal cord, a medial nucleus for trunk innervation and a lateral nucleus for the arm. The efferent axons courses into the muscles of the shoulder region and end in simple terminations upon some of the muscle übers. Commissural and associationa1 neurons are present in the dorsal column. ,The former are numerous in the region just beneath the dorsomedial border of the dorsa1 funiculus, while the latter tend to accumulate nearer the ventrolateral border of this afferent pathway. Commissural axons pursue a course ventrally through the gray matter and cross the kloor p1ate, to become an ascending tract close to the motor nerve cells which supply the trank. Associational axons pass close to the motor nucleus for limb muscles and enter the Iateral funicu1us. This relation of associational neurons and primary motor forelimb neurons appears to be very intimate, with axons of the former coursing parallel with dendrons of the latter. However, up to the time of appearance of the forelimb response there is no close re1ationship between the primary afferent and the secondary neurons (Fig. 54) . A few collatera1 branches of dorsal funiculus fibers do pass for a very short distance toward the associational group, but not many have reached it.


accomplished when collateral branches grow in among the cells
of the dorsal gray horn from the sensory Hbers nearest the lateral
border of the dorsal funiculus Some of the longest collaterals
enter the nucleus of motor cells supplying the forelimb musc1es.
These relationships will be seen in accompanying photomicros
graphs (Figs. 54 and 55) and diagrams (Figs. 56 and 57) . The
organization of the first structural reflex mechanism is clearly such
152 PHYSIOLOGY OF THE FETUS


that when it begins to kunction the response will not only be
homolateraI but will be conlined to the segments at which the
impulses enter the spinal cordx The greatest number and the


Fig. 56.-camera lucida tracings ok the dorsal roots (d.s·.) and dorsal kuniculus
(d.f.) ok sheep embryos M) Do mai» (B) 23 kam» and (c) 24 nun. long. The
developrnent ok collaterals (col.) ok the dorsal kuniculus which curve rnedially
around the gelatinous substance (gel.) ok the gras matter is correlated with the
appearance ok the tirst korelitnb retiexes. Pyridinesilver stainz X 72.


Fig. 57.—Diagrammatic cross Section through the embryonic spinal cord just
'''Fig. 54.''' Photo1nicrograph of the fifth cervical Segment of the spina1 cord of a 13 mm. cat embryo just before the time the Erst forelimb reflexes can be elicitedx as» Ventral funiculus; tut» association neurons; c» cornmissurex ern» Commissural neurons; ihn, dorsal root and ganglionx M» Iateral funiculusx m.l., motor nucleus for the limb muscles; Max» motor nucleus for the trunlc musclesz p.f., dorsal funiculus. Compare with Fig. 56. Pyridinesjlver stainz x 80.
before (lekt side) and just after (right side) the completion ok reilex arcs malte
the earliest retiexes e1icitable. The earliest connections ok aiketent neurons (·a)
appear at the lateral end ok the dorsal kuniculus and complete unisegtnental reklex
arm. some ok these involve an interneuron but others (c) make direct connections
with the pritnary motor neurons kor the limb rnuscles. Only later do the dorsal
kuniculus übers krom lower segtnents ok the spinal c0rd connect with the Commissural interneurons by means ok collaterals O) and thus etkect contralateral trunk


tnovements.


longest new collateraIs lirst grow into the gray matter in the
In the early motile embryos in which reilezklike twitches of the forelimb occurred when the limbs were flipped or when the amniotic sac was percussed, connections have been comp1eted be— tween the primary afkerent and the associational neurons. This accomplished when collateral branches grow in among the cells of the dorsal gray horn from the sensory Hbers nearest the lateral border of the dorsal funiculus Some of the longest collaterals enter the nucleus of motor cells supplying the forelimb musc1es. These relationships will be seen in accompanying photomicros graphs (Figs. 54 and 55) and diagrams (Figs. 56 and 57) . The organization of the first structural reflex mechanism is clearly such that when it begins to kunction the response will not only be homolateraI but will be conlined to the segments at which the impulses enter the spinal cordx The greatest number and the longest new collaterals first grow into the gray matter in the brachial region and, correlatively, one linds the first reflex response involving the forelimbs.
brachial region and, correlatively, one linds the first reklex re—


sponse involving the korelimbs.
osksinsrs ori- FUNcUoN 1N NERvoUs sYsTEM 153


The correlation between completion of anatomical reflex
arcs in the spinal cords of cat embryos and the manifestation of
forelimb reiiex function has been confirmed in the chiclc, rat and
sheep. The stage of development reached in the spinal cord of
these four species at the time reiiexes appear varies to some extent,
but the responses occur in all at the time reflex arcs are ready
irrespective of other structural variations.


such evidence as has been disclosed by the correlated histologic and physiologic experiments reviewed here briefly leads to
'''Fig. 55.''' Photoicrograph of the dorsal funiculus (zt).j.) f the spinal cord of: a 13 mm. cat embryo showing the Erst collateral branches (col.) of primary aikerent neuronsz these serve to complete the first spinal reflex arcs. Pyridine-silver stain x 510.
the conclusion that the early foreIimb movements are local, uni—
segmentah homolateral two- and three—neuron reflexes. Mammalian behavior has its genesis, not in a mass reaction or total
pattern like that of lower vertebrates, but in these relatively Simple reilexes which are at first entirely nonintegrated.


OTHER SIUPLE REFLEXES AND TBZEIR MTEGRAT10N


During the course of development of cat embryos, many re—
flexes malte their appearance. Just as the first responses at the
shoulder can be elicited before the limbs move spontaneously and
before they move with the neclc and trank, local reilexes appear
at the elbow and wrist joints as separate entities before the distal
portions of the« limbs become integrated with other parts of the
body. Local liexion at the elbows occurs at about the 16—mm.
steige. It is often followed by other more distant movements,
such as bending at the shoulder or extension of the head and
Iiexion of the trank. However, these more proximal and cephalic
movements are not followed by rnovement at the elbow at this
time. similarly, local wrist movements seen in embryos about
17 mm. long, are at lirst unrelated to other movements.


Local movements at the proximal hind-leg joint, unintegrated
'''Fig. 56.''' Camera lucida tracings ok the dorsal roots (d.s·.) and dorsal kuniculus (d.f.) ok sheep embryos M) Do mai» (B) 23 kam» and (c) 24 nun. long. The developrnent ok collaterals (col.) ok the dorsal kuniculus which curve rnedially around the gelatinous substance (gel.) ok the gras matter is correlated with the appearance ok the tirst korelitnb retiexes. Pyridine-silver stainz X 72.
with trunlc responses, are encountered in specimens between 15
and 16 mm. long. Those at the lcnee appear at 17.5 mm. The
earliest independent motility of the tail is found at the same
steige.


Although the first head reilexes can be elicited by stimulating
only a small area near the tip of the snout in embryos 13—14 mm.
long, it is but a short time later that they occur in response to
stimulation of most of the facial area. In specimens 15—16 mm.
long, contralateral head flexion is obtainable from all parts of the
154 PHYSIOLOGY OF THE« FETUS


face except that supplied by the ophthalmic division of the trigem—
'''Fig. 57.''' Diagrammatic cross Section through the embryonic spinal cord just before (lekt side) and just after (right side) the completion ok reilex arcs malte the earliest retiexes e1icitable. The earliest connections ok aiketent neurons (·a) appear at the lateral end ok the dorsal kuniculus and complete unisegtnental reklex arm. some ok these involve an interneuron but others (c) make direct connections with the pritnary motor neurons kor the limb rnuscles. Only later do the dorsal kuniculus übers krom lower segtnents ok the spinal cord connect with the Commissural interneurons by means ok collaterals O) and thus etkect contralateral trunk movements.
inal nerve. From the ophthalrnic region, extension with flexion
to the same side occurs. With further developmenh stimulation
of more and more Portions of the face leads to the homolateral
response until, at about the 20 mm. stage, only the ear gives a contralateral head flexionk


These and other interesting reflex sactivities have been ob—
served in embryos. All possess an element of individuality at
 
first, but ultimately most of the local responses are brought together into more generalized movements. This comes about by
 
integration within the frameworlc of a growing central nervous
 
mechanism. Longitudinal tracts of nerve ftbers develop within
The correlation between completion of anatomical reflex arcs in the spinal cords of cat embryos and the manifestation of forelimb reiiex function has been confirmed in the chiclc, rat and sheep. The stage of development reached in the spinal cord of these four species at the time reiiexes appear varies to some extent, but the responses occur in all at the time reflex arcs are ready irrespective of other structural variations.
the spinal cord, and as they make connections with afkerent and
 
efkerent neurons they begin to exert an integrating function over
 
the local, isolated reactions.»
such evidence as has been disclosed by the correlated histologic and physiologic experiments reviewed here briefly leads to the conclusion that the early foreIimb movements are local, uni— segmentah homolateral two- and three—neuron reflexes. Mammalian behavior has its genesis, not in a mass reaction or total pattern like that of lower vertebrates, but in these relatively Simple reilexes which are at first entirely nonintegrated.
 
==Other Simple Reflexes and Their Integration==
 
During the course of development of cat embryos, many re— flexes malte their appearance. Just as the first responses at the shoulder can be elicited before the limbs move spontaneously and before they move with the neclc and trank, local reilexes appear at the elbow and wrist joints as separate entities before the distal portions of the« limbs become integrated with other parts of the body. Local flexion at the elbows occurs at about the 16—mm. steige. It is often followed by other more distant movements, such as bending at the shoulder or extension of the head and flexion of the trunk. However, these more proximal and cephalic movements are not followed by rnovement at the elbow at this time. similarly, local wrist movements seen in embryos about 17 mm. long, are at first unrelated to other movements.
 
 
Local movements at the proximal hind-leg joint, unintegrated with trunlc responses, are encountered in specimens between 15 and 16 mm. long. Those at the lcnee appear at 17.5 mm. The earliest independent motility of the tail is found at the same stage.
 
 
Although the first head reilexes can be elicited by stimulating only a small area near the tip of the snout in embryos 13—14 mm. long, it is but a short time later that they occur in response to stimulation of most of the facial area. In specimens 15—16 mm. long, contralateral head flexion is obtainable from all parts of the face except that supplied by the ophthalmic division of the trigeminal nerve. From the ophthalrnic region, extension with flexion to the same side occurs. With further developmenh stimulation of more and more Portions of the face leads to the homolateral response until, at about the 20 mm. stage, only the ear gives a contralateral head flexion.


The earliest secondary pathway in the spinal cord is a ventral
longitudinal bundle, primarily an ascending tract formed by the
axons of commissural neurons. Impulses carried by it apparently
are able to discharge motor neurons supplying trunlc and neck
musc1es at more rostral 1evels. Cel1 bodies of the commissural
neurons, lying near the medial border of the dorsal funiculus,
receive impulses from primary afferent neurons which have been
coursing rostrally for some distance in the dorsal funiculus. Consequently the local homo1ateral forelimb reflex is sometimes followed, at the 15 to 1 6 mm. stage, by a contraction of neclc muscles
similarly at a later period, hind-limb reflexes are followed progressively by responses of the forelimbs and the neck. A progressive discharge of neurons from caudal to rostral regions of the
spinal cord is broughtlabout through integration of ascending
neurons of the primary afferent dorsal funiculus with the commissural secondary tract.


Nerve Ebers grow caudally into the spinal cord from centers
These and other interesting reflex sactivities have been observed in embryos. All possess an element of individuality at first, but ultimately most of the local responses are brought together into more generalized movements. This comes about by integration within the frameworlc of a growing central nervous mechanism. Longitudinal tracts of nerve ftbers develop within the spinal cord, and as they make connections with afkerent and efkerent neurons they begin to exert an integrating function over the local, isolated reactions.
in the medulla oblongata and midbrain. Many of these occupy


»positions in the ventral funiculus but they do n’ot reach any given


point in the spinal cord until after ascending Ebers from a lower
The earliest secondary pathway in the spinal cord is a ventral longitudinal bundle, primarily an ascending tract formed by the axons of commissural neurons. Impulses carried by it apparently are able to discharge motor neurons supplying trunk and neck musc1es at more rostral 1evels. Cel1 bodies of the commissural neurons, lying near the medial border of the dorsal funiculus, receive impulses from primary afferent neurons which have been coursing rostrally for some distance in the dorsal funiculus. Consequently the local homo1ateral forelimb reflex is sometimes followed, at the 15 to 1 6 mm. stage, by a contraction of neclc muscles similarly at a later period, hind-limb reflexes are followed progressively by responses of the forelimbs and the neck. A progressive discharge of neurons from caudal to rostral regions of the spinal cord is broughtlabout through integration of ascending neurons of the primary afferent dorsal funiculus with the commissural secondary tract.
spinal segment have reached the medulla oblongata. consequently stimulation of structures near the caudal end of an
embryo of about 18 mm. (Fig. 58) can result sequentially in (a)
local reflexes, (b) reflexes of more rostral .parts, (c) head moves


GENESIS OF FUNCTION IN NERVOUS sYsTEM 155


ments and then (d) the trunk activities which are integrated with
Nerve fibers grow caudally into the spinal cord from centers in the medulla oblongata and midbrain. Many of these occupy positions in the ventral funiculus but they do n’ot reach any given point in the spinal cord until after ascending Ebers from a lower spinal segment have reached the medulla oblongata. consequently stimulation of structures near the caudal end of an embryo of about 18 mm. (Fig. 58) can result sequentially in (a) local reflexes, (b) reflexes of more rostral parts, (c) head movements and then (d) the trunk activities which are integrated with the head and which always fall just short of the most recently acquired local responses. The descending integrating tracts of nerve ftbers are so placed in the ventral portion of the spinal cord that when activated they can more eifectively bring about discharge of motor cells which supp1y the trunk muscles than neurons for the limb muscles. As a result of such an arrangement the limhs seem not to be completely integrated with the trunk during the early embryonic period. Later the association becomes more intimate. On the other hand, the trunlc movements become integrated with those of the neclc almost as soon as they begin to appear at the 15 mm. stage. With growth in size of the individual, more and more muscles of the back are added to the trunk activities in a caudal1y expanding Progression.
the head and which always fall just short of the most recently
acquired local responses. The descending integrating tracts of
nerve ftbers are so placed in the ventral portion of the spinal
cord that when activated they can more eifectively bring about
discharge of motor cells which supp1y the trunk muscles than
neurons for the limb muscles. As a result of such an arrangement
the limhs seem not to be completely integrated with the trunk
during the early embryonic period. Later the association be—
comes more intimate. 0n the other hand, the trunlc movements
become integrated with those of the neclc almost as soon as they


Fig. 58.-—Cat embryo 18.5 mm. C. R. 1ength, from which local reHexes as well
as early integrated movements could be elicited. Magniiication is the same as that


in Figs. 44 and 47.


begin to appear at the 15 mm. stage. With growth in size of the
'''Fig. 58.''' Cat embryo 18.5 mm. C. R. 1ength, from which local reHexes as well as early integrated movements could be elicited. Magniiication is the same as that in Figs. 44 and 47.
individual, more and more muscles of the back are added to the
trunk activities in a caudal1y expanding Progression.


Some recent experiments involving the production of states of
anoxemiaU have added important information to our conception
of the relation of simple reHexes to the more massive integrated
activities of cat embryos. When decerebrate cats were allowed to
breathe atmospheres low in oxygen before the uterus was opened
it was found that local reflexes became depressetd and the integrated head and trunk movements were exaggerated and more
sustained or tonic than normally. Irritability of the embryos wszas
is6 isiiYsiohocY or THE Fixsrus


diminished during anoxemia. Extended use ok the gas mixture
brought about more complete anoxemia and all responses ceased.
spontaneous movements and responses to stimulation ok embryos
studied under conditions ok partial anoxemia resemble mass reactions and might easily lead one to the conclusion that behavior
develops in mammalss in a manner very similar to that in the
Salamander. Only when such conditions are avoided can the


various simple reflexes be observed as separate elements.


REFERENCES CITED
Some recent experiments involving the production of states of anoxemiaU have added important information to our conception of the relation of simple reHexes to the more massive integrated activities of cat embryos. When decerebrate cats were allowed to breathe atmospheres low in oxygen before the uterus was opened it was found that local reflexes became depressetd and the integrated head and trunk movements were exaggerated and more sustained or tonic than normally. Irritability of the embryos wss diminished during anoxemia. Extended use ok the gas mixture brought about more complete anoxemia and all responses ceased. spontaneous movements and responses to stimulation ok embryos studied under conditions ok partial anoxemia resemble mass reactions and might easily lead one to the conclusion that behavior develops in mammalss in a manner very similar to that in the Salamander. Only when such conditions are avoided can the various simple reflexes be observed as separate elements.
 
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es. Windle, W. F. i937. 1bid., Zö- 64o.


e9. scharpenberg, L. G. sc W. F. Windle. ig3s. Anat» 7e: 344.
e9. scharpenberg, L. G. sc W. F. Windle. ig3s. Anat» 7e: 344.


so. carmichaeL L. i933. 1n C. Murchison’s I-Iandb. child Psychol» end ed»
so. carmichaeL L. i933. 1n C. Murchison’s I-Iandb. child Psychol» end ed»
Line 654: Line 244:


3i. coghilh G. E. i9e9. Arch. Neun sc Psychiat., ei: 989.
3i. coghilh G. E. i9e9. Arch. Neun sc Psychiat., ei: 989.
GENEsIs OF FUNCTION IN NERVOUS sYsTEM 157


ge. Minlcowslch M. 1922. Schweiz. mecL Woche-weht» He: 721, 751.
ge. Minlcowslch M. 1922. Schweiz. mecL Woche-weht» He: 721, 751.  
 
33. Windle, W. F. 1934. J. comp. Neun, 59: 487.
33. Windle, W. F. 1934. J. comp. Neun, 59: 487.


Line 666: Line 256:


37. Angulo y Gonzalez A. W. 1939. Ibic1., 71: 325.
37. Angulo y Gonzalez A. W. 1939. Ibic1., 71: 325.
CHAPTER x1
CONDPDIONS REQULATING FETAL NERVOUS ACTIVITY
THERE is no doubt that the progressive development of nervous function is related to difkerentiation of structure in the fetal
nervous System. 1t was hoped that many correlations like those
discussed in Chapter X could be drawn between specific responses
and the appearance histologically of new neura1 connections.
This is not an easy task because structural growth proceeds with
great rapidity and results in the establishment very early of complexities defying microscopic ana1ysis. 0n the other hand, function in the central nervous system of the fetus is not regulated
solely by structural factors. 0ne must not lose sight of metabolic
influencesz it is quite clear that variations in fetal activities are
closely related to changing respiratory conditions. The parts
played by the blood, the heart and vascular system and even the
endocrine glands have to be determinedh Many problems in
physiology of the fetal nervous system await solution, but it will
be well to view some of them, even though questions raised
thereby can not be given satisfactory answers.
THE PLAN OF STRIJCTURAL DEVELOPMENT OF« THE FETAL BRAM
lcnowledge of development of intrinsic brain structure is far
from complete, for it ha’s been within the past few years only that
systematic studies in specimens prepared by adequate methods
were undertaken. The« usual histologic procedures are unsatisfactory to demonstrate embryonic nerve übers, their terminations
and relations to one another inside the brain and spinal cord.
Cajal’s silver stains, especially the Ranson modification, bring out
details of this nature incomparably better than any other known
techniqueJ Procedures of this type are being used extensively
for studying the prenatal mammalian nervous system in this2-I2
and the Madrid13-I7 laboratories, as well as in a few other
places.18-22
By the time fetal movements can be elicited for the Hrst time in
any species, a surprisingly exfensive organization ok neuron groups
158
CONDITIONS REGULATING NERVOUS ACTIVITY 159
Fig. so.
Fig. St.
Fig-I. 59-61.-—I)iagrams ok the brains ok cat embryos 7 nun. (Fig. 59) , to nun.
Eis. so) and 15 sum. (Fig. Si) c. R. length showing the principal über tracts
present in each. crossing neurons are clotted Eines. Questionable courses: dash
lines.
160 rnrstotocr or THE: rrsrus
and fiber tracts has already formed within the central nervous
System. We have discussed certain correlations between intrinsic
spinal connections and the first· forelimb reilexes. In the brain
equally specific correlations have not been worlced out completely.
Most of the tracts and nuclei have been identilied in cat embryos
and those that are present at the time« behavior has its genesis are
Tznm 21
cusstrtcssrrou or N rnvr Prnnns or srnr Trnnncnrnznou AND Drndronrnznon or
Wanst. c« Bank-we Aoconnnco sro Arrnoxmsskr Onnrn or Arrrsnzuon
«·I · - size of smallest
Abbrevtations «
Name of Aber group used in figs. WJTDIYFHL
ZHT komd
Z
Hasses-Heda doch-H?
Medial Iongitudinal kaseiele . . . . . . . . . . . . . . . . .
supraoptie system- direct preoptie eomponenh
supraoptie System: eommissural eomponent.. .
Olkaetmhypothalamie Ebers . . . . . . . . . . . . . . . . .
Olfaetwsubthalamie fibers . . . . . . . . . . . . . . . . . .
striosisubthalnmie Ebers . . . . . . . . . . . . . . . . . . . . .
Direet snbthalamwtegjnental Ebers (dilXuse) . .
Crossed preteetotegmental and thalamw
tegmental fibers (ventral eomrnissure) . . . . . .
Lemniseus system . . . . . . . . . . . . . . . . . . . . . . . . . .
Terminal nerv·e libers . . . . . . . . . . . . . . . . . . . . . . .
Posterior eommissure Ebers . . . . . . . . . . . . . . . . .
Eabenulwpeduneular fibers . . . . . . . . . . . . . . . . .
Iateral olkaetory traet fibers . . . . . . . . . . . . . . . .
Mammillwtegmental traet Ebers . . . . . . . . . . . . .
Optie nerve Ebers . . . . . . . . . . . . . . . . . . . . . . . . . .
Thalamostrial and thalatnosseortieal übers. . .. .
Mammillosthalamie Ebers . . . . . . . . . . . . . . . . . . .
Olkactory nerve Ebers . . . . . . . . . ». . . . . . . . . . . .
s-«-«-«-«-«-«-«-«-« GOOHHHHPOOOO PAGA-todt
listed in Table 2 I. Figss 59 to 61 illustrate diagrammatically and
incomp1etely this extensive development of tracts ich the rostral
portions of the embryonic brain.
(a) ORDER or Dnvaormnr n( Ptmcnonu srsrrus
Within the growing tangle of nerve iibers it is possible to distinguish several systems of functionally related tracts. They appear to be growing in anticipation of the time they will conduct
impulses to distant elfector organs. such systems of tracts are laid
down economicallyz for the most part they pursue the shortest
possible courses from place to place. 0ne .of the most interesting
coNInrIoNs nEcULATINc NEnvous Acrrvrrr 161
features of growth of each System is the order in which its component tracts are formed. This is from motor toward SenSory
side.
The very Erst neurons which can be recognized in the embryo
are primary motor e1ements of the spinal and cranial nerveS, present in rat embryos only z mm. long and appearing in the other
species at comparable Stages. These are final common path
neurons over which impulses must ultimately pass to bring about
responses in the muscleS of. the body. They are the first, local
connecting neurons are second and the primary afferent tracts appear third.
The earliest secondary connecting neurons make their appearance in 17 day old cat embryos in the portion of the medulla
oblongata which will become the reticular formation. Growth
very soon spreads into the upper spinal cord segmentS. There,
nerve cells give rise to crossed and direct axons which make local
connections with primary motor elementS. Some in the medulla
oblongata form the earliest reticuloSpinal übers, but they do not
extend their procesSes far along the nerve axis. secondary elementS of the spinal cord enter into the formation of local conduction Systems, all components of which are not present how—
ever until primary afferent neurons begin to build the sensory
tracts. Even then, the local Systems do not become functional retlex mechanisms until Synaptic relations between the three elements-—motor, connector and sensory—have been eStablished on
the 24th day in the cat embryos. similar reflex arcs are completed during the 8th week in man.
Almost simu1taneously with the appearance of secondary
neurons in the medulla oblongata, another group begins to be
laid down in front of the mesencephalon. FiberS from this source
descend to the lower part of the brain stem without crossing and
form one component of- the medial longitudina1 kascicle. 1t seems
probable that the early secondary neurons are related to more
than one baSic rellex System. Just as the lower motor neurons are
not an exclusive component of any one System, so these interneurons may be shared by several.
secondary neurons malce their appearance in still another location in .the early embryo. crossing and direct ftbers arise
in the mesencephalic tectum and form the tectobulbar and tecto
II
162 PHYstoLooY or THE FETUS
spinal tracts. Thus we lind essential1y four groups of secondary
neurons undergoing developrnent in the Central nervous system
between the 18th and 2oth days-of gestation in the cat and during
the 5th weelc in man. These are (a) local intraseginental and
intersegmental elements, such as later constitute the ground
bundles of the spinal cord, (b) reticulospinal tracts, (c) medial
longitudinal fascic1es and (d) tectobulbar and tectospinal tracts.
Few übers course farther caudally than the lower end of the
medulla oblongata until a day or so after initiation of the first individual head and forelimb ref1exes· However, it can not be
doubted that one or more of these tracts play a part in the earliest
cephalocaudal integration of movements which occurs on the 25th
day in cat embryos.
secondary neurons of .the spinal cord, especially commissural,
course rostrally in the ventral and lateral funiculi. These are
present before a signiiicant number of descending iibers from the
brain reach the cord. They account for conduction of impulses
from caudal to rostral segments and explain the observation of
forelimb and head reflexes which sometimes follow stimulation
of more caudal structures.
(b) Gaovrn or Ort-Es: Crskcurrs For: Rmixxss AND Etext-n lnrsoaartos
Just as the intrasegmental neurons of the spinal cord enter
into the structure of basic short reflex circuits, reticulospinah
tectospinal and medial iongitudinal iibers constitute Iinlcs in
Ionger circuits which becotne functional much later than the local
ones. Examples of such- systems are the olfactory and optic reflex
mechanisms of the early embryo. Analysis of the growth of these
systems shows that theircomponent tracts too are laid down from
efferent to afkerent side. For example, during development of
the optioreflex conduction mechanism the primary spinal motor
and the oculomotor neurons begin to form Erst, secondary
neurons represented by the medial longitudinal and tectospinal
tracts are next, the posterior commissure follows, the optic tract
itseIf is fourth, and linally the retinal bipolar neurons and visua1
cells appear. similar sequential development seems to be the
rule in other reiiex conduction Systems.
Within any conduction system such as the optic or olfactory,
the simplest reflex pathways are« formt-d« before those which have
CONDITIONS REGULATING NERVOUS ACTIVITY 163
to do with perception and higher integrative activities. Neurofibrillar development is late in the cerebellum, corpus striatum
and cerebral cortex. A primitive secondary aiferent tract, medial
lemniscus in part, reaches the thalamus of cat embryos from spinal
and bulbar centers by the 2 ist day of gestation. Fibers begin to
pass from the thalamus to the cerebrum on the 22nd day, but not
until late in fetal life does the cerebral cortex exert any influence
over lower motor parts of the nervous System. The pyramidal
tracts are last to form.
correlated with the tardy development of cerebral cortex, it
has been determined that cerebral electric potentials are absent
throughout most of prenatal life. Even in the guinea pig, an
animal which is much more mature than the rat, cat or man at
the time of birth, they do not manifest themselves until about
2 or z weelcs before the end of the gestation periodks A cortical
control of the motor mechanism for forelimbs has been established
at the time of birth in the cat, but the hind limbs laclc it until 16
days later.24
(c) Amor-Erst! as RELATED ro koste-non m tm: Nmvous srsrm
Many neurologists adhere to the theory that the initiation and
maturation of function of the nervous system depends upon the
formation of myelin sheaths. FlechsigV called attention to the
fact that the progress of deposition of myelin is orderly and that
tracts having definite functions become myelinated at different
times in the human infant’s brain. Some investigatorsW who have
studied the course of development of behavior in lcittens and have
attempted to correlate it with myelin formation have suggested
functional relationships. 0thers24-27-31 have carried out similar
studies in pouch-young opossum, Icitten and human infant
brains as well as in the fetal nervous system of the cat and man.
In a general way it seemed that maturation of behavior and the
acquisition of myelin sheaths of certain fiber tracts were related,
but it was impossible to draw specific correlations in all cases. For
example, the corticospinal tract is still unmyelinated at birth but
cortical areas for control of forelimbs are electrically excitable.
They can be a great deal of well organized activity in the
brain before any nerve libers become myelinated« In the cat,
myelin is present neither in the peripheral nerve roots nor in the
164 Pnvsrohoev oF THE. FETUs
tracts of the spinal cord and brain before the 42nd day of fetal
life.33 But 30 day old cat· fetuses can execute rhythmical respiratory and other coordinated reflex movements similar to those employing myelinated tracts at a later time. The early behavioral
reactions of the rat are certainly executed in the absence of
myelinated nerve fibers.32- 34
An attempt was made to correlate specific righting reflexes of
cat fetuses with development of myelin sheaths on the nerve fibers
which were involvedks It was demonstrated that the vestibular
righting reaction appears coincidentally with sheaths upon the
iibers of the vestibular nerve and that conduction pathways used
in the reaction are partially myelinated when the reflex first occurs. However, the righting response to sensory impulses from
the slcin and deep tissuesof the body, i. e» a body righting reflex,
is manifested before that employing the labyrinthine apparatus.
Its neural mechanism is incompletely myelinated at the time.
It is possible that myelination is more closely related to the
order of development of tracts in the embryonic nervous system
than to specific functional activities. Thus we find parts of the
medial longitudinal and reticulospinal systems of neurons appearing early and receiving their myelin sheaths first. But the
correlation is not absolute and many discrepancies can be ob—
served. About all that one can say is that the first tracts to develop in the embryo are the first to begin to be myelinated and
the last to form in the late fetus are the last to receive sheaths.
Some tracts never develop signiftcant numbers of myelin sheaths.
It is quite probable that conduction of impulses may ,be improved
with the acquisition of» myelin, but myelination is certainly not
an essential corollary of function. With increasing fetal si2e,
distances between points in the nervous system become greaten
Perhaps myelin is laid down to compensate by increasing the conduction speed of the iibers.
FAOTORS OTHER TIIAN STRIJCTIIRAL GROWTE
(a) THE: QmEscENcE oF IIITUJJTERME Lan!
It is relatively easy to elicit nervous activities throughout the
greater part of prenatal life in the guinea pig, cat, sheep and man
under certain experimental conditions. But it should not be assumed that all responses which can— sbe induced occur spontaneCONDITIONS REGILLATING NBRVOUS ACTIVITY 165
eously within the uterus of the normal intact individual. As a
matter of fact, there is scanty evidence that any of them occur
normally during the early part of the gestation period.
Human fetal movements can be detected as early as the 14th
weelc by means of a stethoscope, but the mother is usually unable
to feel them before the 17th weelc of gestation. It is difhcult to
diagnose them accurately much before the latter time without
considerable experiencttz for they are often confused with the
sounds produced by movements of intestinal gases. Fetuses of
experimental animals appear to be singularly quiet until late in
prenatal life when occasional quiclc jerlcs or twitches can be ob—
served upon the maternal abdomen. surprisingly little fetal activity is seen even when the thin-wal1ed uterus is delivered under
local anesthesia.
Although the few fetal movements which are readily visib1e
in the intact individual seem to be purposeless, we know that some
well coordinated and useful activities do talce place normally during the second half of prenata1 life. For examplq intrauterine
swallowing has been proved to be a normal physiologic func—
tionks This is an activity engaged in with great regularity during the last third of gestation in the guinea pig. We do not lcnow
its cause (see Chapter VII) .
(b) AFFERENT srmuxanon m Urciio
The relative quiescence of the normal fetus in utero is somewhat surprising when one considers all the activities of which the
growing specixnen is capable when removed from the uterus. The
reason seems to be at least twofold: laclc of adequate stimulation
and high thresholds in the fetal central nervous System. The
fetus is adequately nourished and warmed in a medium laclcing
practically all the stimulating iniluences of the environment with
which it will have to cope later on. No signiftcant excitation of
the external receptors occurs.
Experimental evidence in the cat supports the view that there
is little spontaneous motor discharge in the absence of afferent
impulses. In several hundred embryos and young fetuses de1ivered under good physiologic conditions and without using
anesthesia. spontaneous movements have rarely been seen at the
moment of delivery. They make their appearance within a few
166 PHYSIOLOGY or THE: FErUs
seconds or minutes. apparently because placental exchange has
been jeopardized or becaIuse changes in the environment cause
stimulation. One can not avoid manipulation entirely, and even
though every effort is made to maintain the placental circulation
intact, incision of the uterus disturbs the relationship between
uterus and placenta. .The resulting anoxemia accounts partially
for the movements. .
If there were a true automaticity of embryonic motor neurons,
spontaneous movements should be observed in many instances at
the moment the specimens are brought into view. But there is
very little motor discharge without afkerent stimulation. Rhythmical movements have been seen in sheep embryos 40 to 5o days
old at the moment of delivery and it has been suggested that the
responses are automatic« Some are- defmitely initiated by mechanical stimulation in the younger embryos. It was proposed
that the automatic movements of the sheep fetus become inhibited
as soon as descending secondary tracts grow down into the spinal
cord from the brain stem. In the cat. no rhythmical movernents
can be obtained until after tracts have. grown down; responses
between 23 and 28 days of gestation are neither automatic nor
rhythmic.
(c) Kannst· Tkmssnoxvs ro srmvunorst
Later in prenatal life all fetuses become less responsive to
stimulation than they were at first. How much this may be due
to inhibition over newly developed descending pathways from
the brain we do not know. Guinea pig and cat fetuses near term
do not respond activeIy to ordinary manual palpation through
the intact abdomen but they can be aroused from their profound
«slu1nber« by priclcing or prodding them with a needle thrust
into the abdomen and uterus. It seems reasonable to conclude
that the fetal nervous system has developed high thresholds. At
« any rate, fetal motor centers are less excitable than they were
earlier in prenatal life and less excitable than those of newborn
individuals.
But the excitability of fetuses in utero can be enhanced ex—
perimentally. One way to do so is to reduce the oxygen available
in the fetal brain without creating complete asphyxia Partial
anoxemia at all times in prenatal life predisposes toward an in—
crease in fetal movementsz but- most activities are not actually
induced through the internal environment b"y chemical stimuli.
CONDITIONS REGULATING NBRVOUS AcTlVlTY 167
They follow mechanical stimuli which were subliminal before
the anoxemia was set up. This was demonstrated in experiments
like the following one.
At 63 days of gestation, fetuses of a decerebrated cat were
observed to be very quiet in uter0. When a needle was passed
through the abdominal wall and into the Uterus, the fetuses responded to proddingx they executed brief kicks on non-respira—
tory jerks of the head which stopped almost immediately after
stimulation ceased. With the needle still in place, the cat was allowed to rebreathe air in a rubber tube with wide bore. stimulation of the fetuses was repeatedz this time the responses were much
Fig. Sau-Three Portions of a crystograph record showing maternal respirations
(1arge was-es, 16 per minute) broken up by intrauterine fetal movementsh The
cat (63 days gestation) had been decerebrated by the anemia method; no anesthesia
was used during the experimentz the abdornen was not opened but a long needle
had been passed through the abdominal wa11 into one amniotic sac. At the heavy
solid lines, the fetus was stimulated with the needle and the irregular defiections
on the record at these points are due to this mechanical eikech Fetal rnovenients
were observed at the points indicated by the broken linesz these movements were
siight in records i and z, during which the cat was breathing air. In reoord e, the
cat was rebreathing to induce a partia1 anoxemiaz stimulation led to marked proionged fetal rnovements of a tonic squirming type (double broken 1ines) which
caused considerable interference in the maternal respiratory reoord.
H
more active, the fetuses kicked and squirmed for some time after
the cessation of the stimulus and the movements were tonic and
sustained. The rebreathing tube was then removed and as soon as
the mother’s breathing had become normal again the fetuses were
restimulated. Results were obtained like those before the
anoxemia. One experiment of this type is illustrated in the parts
of a continuous record reproduced in Fig. 62.
certain very rapid rhythmica1 movements of respiratory
muscles do appear to be elicited by endogenous chemical stimulation of the fetal respiratory center.37 They can be induced by
raising the carbon dioxide level in the blood during the early part
of active fetal life, but can not be called forth by this method in
the late fetal period unless a rather marked oxygen deiiciency is
168 Pknsstohooy oF THE FETus
brought on too. These observations suggest a rising threshold in
the fetal nervous system of the cat with advancing prenatal age.
Respiratory rhythms are quite independent of most other
somatic movements in the cat. At the time they are first obtain—
able, they involve only the muscles which are normally used by
the adult for breathing, i. e» the diaphrag·m, intercostals and abdominals A little later in fetal life, they can be made to involve
neclc and trunlc muscles if the degree of anoxemia used to elicit
them is increase-d. Respiratory rhythms often set off other somatic movements in cat fetuses but are themselves less frequently
started by some non-respiratory twitch. Indeed, the cat fetus
when stimulated in the intact uterus can be induced to lcick or
move its head vigorously without any movement of a respiratory
nature following.
(c1) Muse-DE Tonus AND Uass Movzminrs
Not only does anoxemia facilitate the efkectiveness of subliminal mechanical stimulation and induce automatic rhythmical
respirationdilce movements but it also brings about changes in the
character of motor responses when its severity is increased beyond
the point of facilitation. Early in the gestation period of the cat,
local reflexes of the limbs are abolished more readily than those of
the trunlc and neclc under anoxemia. Throughout the middle of
prenatal life, stimulation of anoxemic fetuses leads to responses
which resemble mass reactions, any adequate stimulus eliciting
not local movements but generalized activities such as squirmingÆs
Movements of anoxemic cat fetuses laclced the «jerlcy" quality
they had shown beforehand and became more sustained and tonic.
A single stimulus often results in repeated movements suggestive
of considerable aftepdischarge in motor centers. Under marked
anoxemia, such as that following ·occlusion of the umbilical cord,
fetal muscles sometimes become so hypertonic that the fetus resembles a decerebrate animaL similar postures have been ob—
served in lcittens and rabbits (see Fig. 64) decerebrated by sectioning the brain at the rostral border of the mesencephalon.39
The increase in muscle tonus under asphyxial conditions may be
interpreted as a protective mechanism. It acts to insure the ex—
pansion of the chest which is necessakyfor air breathingfo
codxvtrtodcs Kraut-Arme Nsnnous Acrtvtrv 169
To what extent anoxemia is normal and physiologic in prenatal life is not lcnownX 0bservations in early stages of several
species of animals suggest that it may follow experimental procedures more readily in some than in others. This may be due in
part to species variation in the placenta as an organ for oxygen
exchange in early fetal life. It is possible that embryos of animals
like the sheep, which have rather primitive syndesmochorial
p1acentas, may tolerate operative procedures involving sdme
manipulation of the uterus less well than other forms such as the
cat or guinea pig, which have their maternal and fetal blood
streams in more intimate contact (see Chapter I) . Theoretically,
an equal amount of trauma would be more disastrous in the
former than in the latter. The fact that it was more diilicult to
observe the very first reliexes in sheep than in cat and guinea pig
embryos and that there is more of a tendency for movements,
sekjningly automatic, to manifest themselves in sheep than in cat
embryos, would iit into such a conception.
(e) suscsisrxgnxrr Gut-Eins ro Ast-Inn«
The exact nature of changes which depress neural thresholds
under oxygen deliciency is unknown. They may be chemical or
physical. some investigators have suggested that certain fetal
movements result from stimulation of the nervous system by
accumulating metabolic end-products, principally carbon dioxide.41-44 Although it is true that automatiq rhythmicaL respiratory
movements can be initiated by increasing the carbon dioxide content of fetal blood experimentally, those induced by asphyxiation
may be related less to an increase in the chemical stimulus than
to a depression of thresholds (increase of neuron excitability) .
It has been postulatedWs 49 that endogenous (chemical) stimulation afkects the motor centers directly and acts first on the most
recently developed units, that the new neurons have the highest
physiologic gradient and are consequently stimulated first by accumulating metabolites in the blood. The evidence is open to
question because experimental conditions were not well controlled. The embryos were studied in unbalanced saline solutions. It has been demonstrated more recently« that the waving
of embryonic limbs and tail, which suggested the theory, occurs
«« see J. Barcrofh et a1., 194o, J. Physiol» 97: 338, 347.
17o PHYsmLooY oF THE: FETUS
only in embryos placed in solutions delicient in calcium and
potassium and is not necessarily related to accumulating metabo—
lites. ·
Under asphyxia, the behavior of fetal sheep tends to revert to
a type characterizing younger specimens but a clear cut recapitulation of development of reilex movements was not found« simple
reflexes most recently acquired apparently were not called forth
during asphyxia. In the catss it has been observed that asphyxia
abolishes activities in a rather orderly manner. It has a more
destructive action upon the appendicular motor mechanism than
upon that of the neclc ånd trunlc. The last activity to disappear
under asphyxia is a respiratory movement of the chest. This conlirms a previous observation in bird fetuses-S; it was found that
deep rhythmical gasping could be induced repeatedly by tying
and untying the allantoic vessels. It seems probable that motor
centers show gradients of susceptibility to asphyxia but there is
no evidence that the oldest reflexes, i. e» those of the neclc and
forelimb, are the last to be afkected by the asphyxia.
(k) Intmrrroa or Moroa Hammer-s n! mer-rast can-rats
It has been suggested that the changes ·in behavior of sheep
fetuses under asphyxia may result from the removal of inhibitory
inliuences of new descending nerve tracts of higher order upon
lower motor neurons« This view conforms to the conception of
a gradient of susceptibility to destruction by asphyxia, the new
higher order neurons being thrown out of function before the
older motor neurons. It also assumes some sort of automaticity
in the lower motor centers.
Transection of the fetal brain stem and spinal cord at various
levels below the mesencephalon was performed in ten fetuses zo to
76 days old without removing them from the uterusås 0ne to 13
days later the abdomens of the ewes were opened again and the
fetuses delivered by Caesarean Section. Fetal movements at that
time resembled those characterizing unoperated specimens at 40
to 50 days gestation. It was suggested that the operations had released lower motor mechanisms from inhibitory influences of
nervous centers above the transection level in the region of the
red nucleus. 0n the other hand one investigator49 encountered
no qualitative difference in behavior of newborn rats whose cerebrum (alone or with other parts of the brain above the medulla
CONDITIONS REGULATING NERVOUS ACTIVITY 171
oblongata) had been destroyed in utero and their normal litter
mate controls.
It is probably true that sheep as well as other mammalian
fetuses are endowed with relatively lower thresholds in early fetal
life than later on toward term, and that structural growth within
the brain plays an important part in determining the nature of
thresholds The theory that motor centers are held in checlc by
the descending tracts is a very attractive one and deserves careful
study, but more experiments in other species of animals must be
performed before it can be proved.
0ther studies have been made with rssults suggestive of the
phenomenon in question. Minlcowslciso observed a reversal of
the type of response in the human plantar reflezc During the
course of its development plantar iiexion preceded dorsal flexion
from stimulating the sole, and after the latter had become well
established it commonly changed baclc to plantar ilexion under
narcosis as well as progressive asphyxia. 0thers have disagreed
with his interpretationsJU and Personal experience has shown that
the Babinslci reflex (dorsal ilexion) of the human fetus is remarlcably resistant to asphyxia. When it does succumb, the plantar flexion which remains appears to result from direct stimulation
of the muscles in the sole of the foot.
The earliest head movemen of cat embryos are contralateral.
With further development theyschange to homolateral responses,
but under asphyxia they sometimes become contralateral again.
Extension of the head of the early sheep fetus usually accompanies the respiratory-lilce rhythms of movement, but after a time,
during which a partial anoxemia builds up, extension changes to
ilexionR These and other examples show how progressive
asphyxia exerts selective action upon the central nervous System.
similar results have been observed in adult animalssss
REFERENCES C1TED
. Davenport, I-I. A» W. F. Windle s: R. I-I. Beech. 1934. stain Tech., g: Z.
. Windle, W. F. 1931. J. comp. Neur., Zzx 71.
. Windle, W. F. 1932 Ibid., 55: gg.
. Winde, W. F. 1932 Ibi·d., 55: gis.
. Windla W. F. 1g33. Ibid., 58: 643.
. Windle, W. F. 1934. Ibid., 59: 487.
. Windle, W. F. 1g35. 1bid., 63: 139.
. Windle, W. F. s« R. F» Baxten 1936. Ibids Eis: 173.
ON! CAN-Poe v s—172
. Windle, W. F. sc R. E. Baxten
. Tello, J. F.
. Trillo,  F. i938.
. Lanyworthy, O. R.
. Langworthy, O. R. i933. contn Ernb» e4: Z.
. Angulo y Gonzalen A. W. i9e9. J. Cornp. Neur., 48: 459.
. Windle, W. F., M. W. Fish sc J. E. O’Donnell.
. Beclcen R. F., W. F. Windle, E. E. Barth sc M. D. Schule.
iskiYsionocY or· THE. Fisrus
i936. Ibid.- As: i89.
Windle, W. F. i937. Proc.· soc. Expen Biol. sc Med., 36: 64o.
. Windle, W. F. sc J. E. Fitzgeralch ·i937. J. Comp. Neur., 67: 493.
scharpenbergx L. G. sc W. F. Windle. i938. J. Anat» 7e: 344.
Tello, J. F. i934. Ztschn inilc.—anat. For-seh» 36: See.
Tello, J. F. i934. Trav. Lab. Rech. Biol., Univ. Madrid, e9: 339.
i935. Ibid» so: 447.
i936. Ibid» Si: 77.
Ibid., se: i. .
Bok, s. T. i9e8. in W. von Möllendorkks Handbuch mik. Anat. Mensch.,
4 (I)- 478—
shanen R. F. i93e. J. cotnp. Neun, H: 493.
shanen R. F. i934. Ibid» 6o: z.
Tello, J. F.
. shanen R. F. i934.  Anat» 68: 3i4.
. Eos-g, l. D. Cited by D. Hooken
i936. Yale J. Biol. sc Med., 8: 579.
Jaspen H. H» C. s. Bridgman sc L. catmichaeL i937.  Expen Psychol»
ei: 63.
Langworthy, O. R. i9e7. 'contr. Emb» i9: i77.
Flechsig, P. i876. Die Leitungsbahnen im Gehirn und Rüclcenmarlc
des Menschen auk Grund entwiclcelungsgeschichtlicher Untersuchungen. W. Engelmann, Leipzig.
Tilney, F. sc L. casainajon i9e4. Arch. Neun sc Psychiat» ie- i.
Lang-worthy, O. R. i9e6. Contn Kind» i7: ie5.
Langworthy, O. R. i9e8. J. Comp. Neun, 46: eoi.
Lang-worthy, O. R. i9e9. contn Emb., so: ie7.
Use. Arch. Neurol. sc Psychiat» es: i365.
i934. Ibid., 59: iZ9.
Watson, J. B. i9o3. Animal Education. Univ. chicago Press.
i94o. surg»
Gyn. sc Obst., 7o: sog.
Barcrokn J. sc D. H. Barron. i937. J. Physiol» 9i: 3e9.
Windle, W. F» M. Monnier sc A. G. steeles i93s. Physiol. Zool» it: 4e5.
. Windle, W. F. sc R. F. Becken i94o. Arch. Neun sc Psychiat, 43: 9o.
. Windle, W. F.
. Hendersom Y. i937. science, 85: 89.
. Zuntn N. i877. Pklügens Arch., i4: sog.
. Brown, T. G.
i9e9.  Cornp. Neun, 48: 2e7.
i9i5.  Physiol» 49: 2o8.
Grahain, E. A. i9i3-i9i5. Trans. Chicago Path. soc» g: ie3.
. Walz, W. i9ee. Monatschn Geburt. Gyn., 6o: zzn
. Angulo y Gonzalen A. W.
. Angulo y Gonzalen A. W. i934. Anat. Rec., 58: suppL 45.
i930. Proc. soc. Exp. Biol. sc Med., e7: 579.
Windle, W. F. i939. Physiol. Zool» re: 39.
. Windle, W. F. sc J. Barcrokn i938. Am. J. Physiol» iei: 684.
. corey, E. L.
. Minlcowskh M. i9e3. schweizer Arch. Neun Psychiat» i z: 475.
. Bolaklio, M. sc G. Artom. i9e6. Zeitschr. Neun Psychiat., io3: 3eo.
. Barcrokn J. sc D. H. Barron.
. Kaban H. sc c. Dennis.
i934. Proc. soc. Exp. Biol. sc Med., Zi- 95i.
ig36. J. Physiol» 88: 56.
Proc. soc. Exp. Biol. sc Med., 38: 864.
CHAPTER Xll
FETAL MOTOR REACTION s AND REFLBXES
MANY provisions are made during intrauterine like to assure
survival akter birth. A number ok these depend upon development of the ketal nervous system. 0ne function ok vital im—
portance to all species is respiration and this has been emphasized
by separate consideration in another chapter. 0ther kundamental
activities involving the somatic motor mechanisms ok the body
are sucking and swallowing which are well developed in all mammals at birth, crying which is encountered in most ok them, and
locomotion which occurs to a variable extent. ln addition to
these instinctive motor reactions, a number ok reflexes which some
have thought ok as purposekul or protective have their genesis
during prenatal like. The amount of kunctional independence at—
tained within the uterus depends upon the degree ok matssdtion
reached in the nervous system and varies within wide limits.
DEVELOPUENT OF FEEDING RBÄCTIONS
Coordinated movements ok suclcing and swallowing are kully
kormed in viable premature human inkants, and may be seen in
the common laboratory animals considerably before birth. In—
deed, suclcing appears to be one ok the kew reactions endowing
the tiny newborn opossumKs 2 Feeding reactions may be said to
begin with the iirst movements ok the jaw.3- 4 Opening and closing ok the mouth appear -in cat fetuses only about 25 mm. long,
roughly comparable with the 9 weelcs human. The tongue can be
protruded almost this early but its sides do not. curl until several
days later. similar observations have been made in guinea pigss
and sheepäs In the latter species, closure ok the jaws is the only
response obtained by touching the tongue between the 41st and
49th days ok gestation. Throat movements occurring in briek
rhythms follow jaw closure at 49 days. The tongue ok the fetal
sheep curls at about 70 days. These early simple activities are the
korerunners ok a number ok more complex movements whose
173
174 PHYSIOLOGY OF THE« FETUS
integration ultimately accomplish suclcing, chewing and biting
in the cat, sheep and guinea pig. The early components of the
feeding reacti0n have not been thoroughly studied in human
fetuses but lip movements which may be related to suclcing have
been seen at about 1o weelcs and later.7- Es 9
True suclcing is rhythmical in the cat and involves a coordins
ation or integration of tongue, lip, jaw and throat movements.
Furthermore, alternate forward thrusts of the limbs and side to side
head movements enter into the feeding reaction to a remarlcable
extent in the newborn kirren. However, the rhythrnical suclcing
of the fetus is accomplished without participation of the limbs until late in the fetal period. Coronios4 observed pursing of the lips
around the tip of a glass stimulator in specimens 43 mm. long,
and at 54 mm. the first deftnite sucking coordinated with head and
forelimb movements was encountered. The response continues
to improve and appears to be fully developed and vigorous at
least one weelc before birth of the lcitten.
The actual contractions of muscles which occur in swallowing
are diiIicult to observe and can be seen only in late fetuses. These
movements have been reported in sheep of so days gestation and
we have seen them in the human fetus at 14 weelcs. Undoubtedly
they occur even earlie»1·. When the abdominal wall of a cat fetus
25 to zo mm. long is opened the stomach may be seen to be well
lilled with iluid. In specimens a little larger, brought out into the
air, bubbles soon appear in this Organ. This early fetal swallowing of the cat is in no way remarlcable when a comparison is
made wich ehe aik-hkeekhihg, suekihz 23 day «emhkye" ek khe
opossum. »
swallowing of amniotic lluid does not seem to occur under
perfectly normal physio1ogic conditions in the fetal guinea pig
until about the 42nd day of gestation. This has been demonstrated by roentgenologic studiesso made after injecting thorotrast into the amniotic sac (see chapter VII) . The frequency of
swallowing and the amount of iluid talcen into the fetal stomach
increase with age. It may be concluded that the feeding mechan
—ism, lilce that for respiration, has its genesis in the early part of
the fetal period well in advance of the time it is normally called
into use.
FETAL MOTOR RBACTIONS AND REFLEXES 175
DEVELOPMENT OF POSTURE AN D PROGRESSION
Mammalian locomotion is a complicated act requiring cooperation of many groups of muscles and exquisite integrative development within the Central nervous System. Nevertheless, it too
has its genesis in ear1y prenatal life. Establishment of erect
posture is prerequisite for wallcing. It involves the coming into
action of righting reflexesz afkerent impulses for these arise in
the slcin and muscles of the neclc and body, in the labyrinths and,
for higher mammals including the cat, in the retina. Maintenance of erect posture requires the presence of static or postural
tonus to establish the proper neurologic balance between flexor
and extensor muscle groups in order that the force of gravity be
successfully opposed. After these conditions have been met, progression becomes possible by alternately and rhythmically changing the balance in such a way that flexion-extension stepping
movements of the limbs are performed. Developmentally, however, the various components of a locomotor reaction are not laid
down in utero in the sequence just stated.3
1t is evident that alternation of trunlc movements is fairly well
developed in the fetus before there is evidence of a postural
mechanism. At the time bilateral flexion of the neclc and upper
trunk can be induced in cat embryos less than 20 mm. long, the
forelimbs move at the shoulders with the contractions of the
trunlc muscles. No rhythmicity manifests itself in these bilateral
trunk movements before the 25 to 28 mm. stage. Active,
arrhythmic alternation of the forelimbs can be induced in 3o to
35 mm. fetuses with considerable regularityz in fact, crossed ex—
tension responses begin to appear at 25 mm.
The bilateral trunk flexions, synchronized more or less pas—
sively with the limbs, are forerunners of squirming movements.
Early in development the resemblance between squirming and
aquatic locomotion is rather strilcing At birth the lcitten utilizes
side to side movements in its crawling-search reaction. The reflex crossed extension following active flexopwithdrawal of one
forelimb foreshadows the act of steppi·ng. squirming and stepping
are distinct from one another until the cat fetus has reached a
length of about 50 mm., at which time the first integrated activity vaguely resembling the act of crawling can be seen. synchronized stepping movements of all fourjegs are not encountered
176 pnYsrohooY oF THE FETUs
before 8o mm.,I1 and even at birth the hind limbs are imperfectly
coordinated with the forelimbsU Rhythmicity of forelimb stepping movements improves as the time of birth approaches. Kittens 95 to ioo mm. long delivered two weelcs prematurely manage
to crawl very credibly.
Development of Progression difkers according to species in
respect to late stages of developmenh but there is a surprising
amount of similarity at Erst. 1t requires no great imagination to
see a resemblance between the side to side head movements and
coordinated forelimb activities by means of which the opossum
»· -«.
»« «.»» . « ih  ».·-  --». »» -»·-,», -  ·  s 1
»«"«·--:«-»«,-«·-s.cå4 ANY« ;-,4,!" «,««’ JdzpVsstwsJt «Q4.Ez7:-G« IN« «« «« «« Es« «« - "·««7 V H ««
Fig. 63.-Record of muscle tonus in a sheep fetus at 144 days gestation delivered
at caesarean Section with placental circulation intact. In the Erst, third and iifth
records, the fetus lay quietly in a warm saline bath. In the second and fourth
records it was lifted into the air and impulses began to flow to the muscle-s. (Bak
croft: Irish Joutx Med. sei» 1935.)
«embryo" reaches the mother’s pouch at birth and the side to side
necl(, trunlc and forelimb movements of the so mm. cat fetus.
similar reactions have been observed in rat13- «« and guinea pig
fetuses.5 The records are very incomplete in the human, but we
have seen Hexor withdrawal of one leg accompanied by crossed
extension of the opposite leg in 4o mm. specimens Rhythmicity
of stepping has not been reported until much later in fetal life
and even at birth behavior of a locomotor type is most ineffectuaL
Development of postural tonus has not been studied thorough1y.
1t is probable that muscle tone as we know it in the adult is not
present at all in utero under nor-mal physiologic conditions. The
FETAL Mosron KEACTIONS AND nEFLExEs 177
fact that rhythmical respiratory movements can occur toward the
end of gestation without aspiration of a signiftcant amount of
amniotic fluid demonstrates that the fetal chest is not held tonically in an elevated position which it must assume after birthLE
The absence of afferent stimulation in utero is unquestionably an
important factor in maintaining tonus at a low level. As illus—
trated in Fig. 63, it was found that action potentials from fetal
muscles appear when a fetus is lifted out of its warni saline bath
and disappear again when it is returned to the bathJC The relation of anoxemia to thresholds of nervous activity and to tonus
has been discussed in the preceding chapter.
How early in prenatal life postural tonus can be induced ex—
perimentally is not deiinitely known, but an indication of it may
be seen in cat fetuses about 50 mm. long. It was noticed that re
» lease from their membranes was followed by straightening of the
back and extension of all limbs in such a way that they appeared
to stretch. Full term birth posture, i.e., extension of the head
and forelimbs," seem to be induced in part by a similar release
of tension when the membranes burst. A factor in development
of muscle tonus may be observed in the sustained fetal movements
during anoxemia. sustained extensor movements are sometimes
so marked in cat fetuses only 30 mm. long that they resemble the
decerebrate condition.
Decerebration of cat fetuses results in hyperextension of the
limbs during the last three weeks of prenatal life.3- IS 0ne or two
weeks before birth deiinite decerebrate rigidity appears in the
forelegs of specimens in which the brain has been cut through
from the rostral border of the mesencephalon to the rostral border
of the pons. When the level of the transection passes farther for—
ward, leaving the region of the red« nucleus intact, decerebrate
rigidity fails to appearRss IV Postural tonus can be called forth in
the human fetus by decerebration20 and there too it seems to be
more especially related to the midbrain and lower centers than to
the higher parts of the nervous System. Decerebrate rigidity in
the rabbit after birth is illustrated in« Fig. 64.
The mechanism by which the righting reaction evolves likewise has its development in the early fetus, but the actual accomplishment of righting has not been observed until after postural
«tonus and alternate stepping movements can be induced« Cat
178 PHYs1oLooY OF THE FETUs
fetuses 75 to 1oo mm. long try to hold their heads up and turn
their jaws parallel to the ground when they are placed upon a Hat
surface. The general impression gained is that they could right
themselves save for the weakness of their muscles. Between 1oo
and 1 Io mm., they are actually able to right the head in respect
to the surface on which they 1ie, but they are completely disoriented when placed in warm water beyond their depth. No
evidence of vestibular function was obtained in cat fetuses less
than iio mm. in lengtlr Neither rotation of the specimens nor
destruction of one or both labyrinths experimentally had any
efkect before this time. It was concluded that the vestibular right
Fig. 64.———l)ecerebrate rigidity in a young rabbiL The midbrajn was sectioned through the rostral border of the superior colliculus and rostral third of
the pons.
ing reflex appears about the 54th day of prenata1 life in the cat
and that a body righting reklex precedes it by at least four days.
The latter is activated by akferent impulses from the skin and
deep tissues of the body and necl(. Visual impulses play no part
in righting reactions until Some time after birth of the kitten
whose eyes remain closed for several days. ln the newborn kitten
the vestibular righting reflex is still incompletely developed.22
Development of a body righting reaction before the vestibular
mechanism begins to function has been conHrmed in other species.
In the sheep, which is more mature than the cat at birth and has a
longer gestation period, righting is accomplished relatively ears
FETAL MOTOR REACTIONS AND RBFLBXES 179
lier.3 0rientation in respect to gravity, seen in the opossum
at the time of birth, which is long before the vestibular mechanism
is functional, is an interesting related phenomenonks
In all animals in which fetal studies have been made, three
components essential for locomotion—righting, postural tonus
and alternate synchronous limb movements—have been developed
by the time of birth. All three are present in some form well
before the end of the gestation in most species, thus providing a
factor of safety against the danger of premature interruption of
intrauterine life.
DEVELOPMENT OF EYE REFLEXES
We have considered the prenatal development of motor mechanisms for respiration, feeding, posture and locomotion in some
detail. 0ther equally interesting fetal activities could be studied
profttably, but at the present time little is known about them.
some observations on movements of the eyes and eyelids have
been made but they are incomplete.
The eyeballs move behind closed lids in the fetuses of several
species. such movements can be seen at the middle of the gesta—
tion period in guinea pigss when the face is stimulated in the
neighborhood of the eyes. somewhat later, postural changes
elicit eye movements. Reactions to light appear during the third
quarter of prenatal life. In the cat, eye movements in response to
vestibular stimulation were not obtained before birth.« Most
l(ittens 5 to 7 days old showed ocular nystagmus during and after
stimulation of the labyrinthine afferents by rotation.
Contraction of the orbicularis oculi muscle can be elicited
in cat and guinea pig fetuses at about the middle of the gestation
period. The palpebral reflexes for protection of the eye have
their genesis in these movements and are well developed in late
fetal life, as can be determined by opening the eye experimentally
and stimulating the cornea. Contraction of the human orbicularis oculi was seen at about 12 weelcs (4o mm.) when the eye
region was touched.
Very little is known about the early development of light reflexes. The iris of guinea pig fetuses contracts in response to light
early in the last third of prenatal life. The visual mechanism of
this animal is more advanced than that of the cat or man at birth.
180 pnvstohoov oF THE: Fnrus
DEVELOPMENT OF PALMAR AND PLANTAR REFLEXES
several investigatorsUss 28 have studied the movements of the
digits of the hand which ente·r into the prehension reaction of
the fetus. These constitute the palmar or grasp reflex. HoolcerV
observed Hexion of the iingers but not the thumb when the
palm of a human fetus of 11 weelcs was touched, and it may
occur even earlier. At 12 weelcs the. fetus formed a true list
by flexing the thumb and fingers. Later, around 16 weelcs, when
the iingers were held in a flexed posture stimulation of the palm
brought about tightening of the iingerss Thumb movements
were never as marked as those of the iingers and apposition of the
thumb did not occur until after birth. Eikective sustained gripping of objects with the lingers began to manifest itself around
18 weelcs but even at 25 weelcs it was not strong. The grasp reflex appears to have two componentst iinger closure and gripping
The genesis of the human plantar reflex has interested many
because of its practical importance in neurologic diagnosis. Although several have studied it in prenatal life,25-29 Minlcows
slci’s7s S« 30 observations have been the most complete. spontaneous
dorsal ilexion of the great toe characterized the early fetal period.
No responses to stimulating the sole of the foot were obtained
before Io weelcsz at this time one specimen exhibited a plantar
flexion of the foot right after delivery. This was of very brief
duration and when it was no longer elicitable, due to progressive
asphyxiation of the specimen, only direct muscle responses could
be obtained.
In fetuses of 1 1 to« 15 weelcs gestation, stimulating the sole of
the foot sometimes produced dorsal flexion of the foot or of the
great toe with spreading of the others. These responses, which
constitute the Babinski phenornenon, were obtainable only when
local anesthesia had been used and in the first few minutes of the
observations. General anesthesia and progkessive asphyxia led
to an inversion of the response, in which the same type of stimulus
brought about plantar instead of dorsal Hexion. section of the
cervica1 spinal cord or brain stem did not alter the plantar re—
flexesz they could be observed for longer periods before they
changed from the dorsal to the ventral type of response. There
was only slight indication that higher centers participated in the
dorsal form of plantar reflext before— 6 months gestation.
FETAL MOTOR REAcTIONs AND REFLEXES 181
Minlcowslcis named the earIy period up to i6o mm. C. H.
length the neuromuscular stagez the period between 160 and i8o
mm. he called the spinal stagez the period between 190 and 270
mm., the tegmento-spinal stagez and the remainder up to birth,
the pal1ido—cerebello-teg-inentosspinal stage. These divisions were»
set somewhat arbitrarily, for the number of observations was
limited and the physiologic conditions of specimens varied to a
great extent. The phenomenon of inversion of the response has
been discussed in chapter XI. The subject of plantar responses
of infants and young children has been thoroughly reviewed recemiy by Richakds and Ikwixxss «
OTHER REFLEXES
Throughout the literature, mention has been made of many
other reactions and reflexes not only in experimental animals but
also in human fetusesF For the most part, the course of development of the slcin, tendon, deep neclc and other reflexes has not
been followed completelsy and these activities do not Iend themselves to signiücant discussion for this reason. Here are Helds
which future investigations may be expected to explore very
proütably.
REFERENCES CJITED
i. Hartman, c. G. i9eo. Anat. Ren, i9: e5i.
e. Mccradzz E. i938. The Embryology of the Opossunn Wistar Press,
Philadelphia
. Windle, W. F. sc A. M. Griklin igzn J. comp. Neur., se: i49.
. Coronios, J. D. i933. Genetic PsychoL Monog., i4: e83.
. carmichaeh L. i934. Ibid., i6: 337.
. Barcrofn J. sc D. I-I. Bari-on. i93g. J. comp. Neur., 7o: 477.
Minlcowskh M. i9ee. sehr-v. med. Wchnschn, se: 7ei, 75i.
Minkowskh M. i938. Abderhaldecks I-Iandb. biol. Arbeitsmetlk Abt.
V, Teil 5 B: zu.
g. Hooken D. i936. Yale J. Biol. sc Med., s: 579.
o. Becken R. F., W. F. Windle, E. E. Barth sc M. D. Schule. i94o. sur-g.
Gyn. sc Obst., 7o: sog.
ii. Brown, T. G. i9i5. J. Physiol» 49: Los.
te. Tilney, F. sc L. casamajon i9e4. Arch. Neur. sc Psychjat., ie: i.
i Z. swenson, E. A. i9e6. Thesis, Unin Kam.
i4. Angulo y Gonzalen A. W. i93e. J. comp. Neur., 55: 395.
i z. I-Ienderson, Y. i938. Adventures in Respiration, Williams sc Willcins,
Baltimore.
is. Barcroln J. i935. Irish J. Med. sei» series 7, i: e89.
i7f Rudolpln L. sc A. c. 1vy. i933. Am. J. Obst. Gyn., es: 74.
Pf« EVEN«
l
182 PHYsmLooY oF THE. FETUs
18. Windle, W. F. 1929. J. comp. Neun, 48: 227.
19. Langworthzz 0. R. 19291 Contrilx Emb., so: 127.
so. Minlcowslcjs M. I921. Ren Neun, igsu I1o5, I235.
tu. Winde, W. F. Z: M. W. Fish. 1932 J. comp. Neun, 54: 85.
u. Gen-Michael, L. i934.  Genetic Psychoh 44: 453.
as. Larsell, 0., E. Mccrady s: A. A. Zimmermann. 1935. J. Comp. Neun,
632 os
24. Fish, M. W. s: W. F. Winde. 1932. J. Comp. Neun, 54: 1o3.
es. Bot-cito, M. sc G. Artom. 1924. Ast-eh. di sei. Bio1., z: 457.
es. I-Iool(et, D. i938. Proc. Am. PhiL soc» 79: 597.
27. Krabbe, K. «1912. Rest. Neuro1.. 24: 434.
as. Bersoh I-I. 192i. sehn« Arclx Neun Z: Psychiat., s: 47.
29. I-Ioo1:er, D. 1939. Atlas ok Early Human Fetal Behavior (Pkivate1y
Printed).
so. Minkowslch M. 1926. c. R. cong. Med. Alienistes Neurologistes
Geneve so: got.
31. Richards T. W. Z: O. c. Irwin. 1935. Unisn Iowa stud. child Welkare, u (No. 1): I. «
CHAPTER XIII
THE FETAL sENsEs
IN discussing sensory mechanisms before birth the be1ief is
not implied that the fetus is consciously aware of any sensation
either in utero or after removal. Interest lies solely in whether
or not the various endiorgans and afkerent neurons can function
before birth. This is determinable by observation of the reflex
motor effects of stimuli of different kinds applied to the fetus. It
is seldom possible to be certain of the nature of neurons stimu1ated. Whether they conduct painful or tactile atkerent impulses,
or even whether exteroceptive or proprioceptive, following a given
stimulus is usually undeterminable.
Almost everyone who has studied fetal movements has contributed information to this subject, but it is impossible to
evaluate and coordinate all the data. We are faced in most in—
stances with the task of trying to synthesize experiments performed
under good and bad conditions to arrive at some lmowledge of
the- subject. No one would thinlc of accepting results in adult
physiology of sense org-ans obtained in animals under narcosis
and asphyxia Yet that is the lcind of data predominating in
respect to the fetus.
It would seem that variations among species as well as in animals of the same species by different investigators are explainable
td a very great extent on the basis of experimental methods used
to study fetuses. When specimens are examined without using a
general anesthetic and when they are exposed very quickly it is
found that they are excitable by much milder forms of stimuli
than must be used a minute or so later when anoxemia has begun
to afkect them.I Furthermore, grossly undetectab1e deterioration
of the physio1ogic condition of fetuses after delivery, even when
the placental circulation remains intact, aEects some sensory
nerves more than others and appears to alter synaptic mechanisms
in such a way that motor responses change their Character. These
efkects are especially well illustrated in human fetuses at hyster
183
184 PHYsmLooY oF THE: FETUs
otomy performed under local anesthesia. The human fetus of the
third and fourth monthsslies quietly within its crystal clear amnion. A very little pressure, such as follows tapping the membrane lightly, causes it to malce quiclc jerlcy movements of arms,
legs and other parts. When the stimulus stops, the movements
stop. 0n the other hand, when the placenta is detached and the
fetus removed from its membranes it· executes «spontaneous"
squirming movements which are more sustained and tonic than
those seen at first. Fewer slcin regions are sensitive to the lighter
forms of stimulation than was the case in amnio. Excitability
diminishes rapidly. Most human fetuses have been studied after
removal from the uterus2s Z« 4 and it was only recently that the
opportunity arose to observe them at the moment of delivery
while the placenta was intact and before the amnion was rupturedP consequently our lcnowledge of sensation in human
fetuses is still very incomplete. ·
THE FETAL sKIN As A RECBPTOR ORGAN
(a) Pnsssunx Touckt Am) Pan(
Motor function precedes sensibility.·3—8 1n mammalian embryos it is always possible to obtain contractions of slceletal muscles by stimulating them directly before any of the sensory neurons
can be activated. spontaneous movements of the chick embryo
occur in advance of the reactions which follow stimulating the
surface of the body,9- 10 but this is not the case in mammals.
The superlicial epithelium with its underlying mesenchymal
connective tissue serves as a receptor organ in early fetal life.
Nerves course beneath the epithelium and end under it in primitive free terminations before any reflexes can be elicited in mammalian embryos.1I-I2 They appear in the face and forelimbs before they can be seen in the hind limbs and tail. Reflex responses
follow stimulating them in cat embryos about 14 mm. long, Ibut
the stimuli must be somewhat stronger at that time than later.
Mild faradic shoclcs call forth responses before it is possible to
obtain them by touching the epithelium with a single hair or a
soft brush. A little later, in specimens about 15 mm. or 16 mm.
long, touching with a single hair often serves adequately, providing the stimulus is placed directly over a spot supplied by
primitive afkerent nerve übers. stimulation with a little brush
THE FETAL sENsEs 185
made up of soft hairs is more often effective than a single punctate stimu1us,7-8-13-I4 because there is greater chance of pressing
upon one of the sparse endings with it.
It is relatively easier to lind reflexogenous spots upon the face
than upon the limbs. Furthermore, -responses to stimulating endings in the forelimb disappear before those from the face, under
the influence of progressive anoxemiaJ Consequently, the failure
to elicit fetal movements by punctate stimulation of the epithelium of a limb does not prove the absence of a response-producing mechanism in the limb unless careful consideration is given
to experimental conditions.
With further growth the number of nerve endings in the con—
nective tissue beneath the epithelium increases and the Ebers
begin to penetrate the epithelium itself. It becomes progressively
easier to lind points whose stimulation elicits motor responses.
Development proceeds in a cephalo-caudal direction in the body
and proximodistally in the limbs. 0n the other band, rising
thresholds, either in the endings themselves or in the central nervous System, soon bring about a condition of diminishing excitability of many cutaneous surfacesJs
0ne is scarcely justiiied in classifying the early sensory func·
tions as touch or pain. strictly spealcing, the fetus experiences no
sensation whatsoever; it simply responds automatically, reflexly,
in the early part of prenatal life. It is true that the neurons are
activated by external environmental changes and may be considered exteroceptive, but there is nothing about their structure
and nothing about the response itself which would indicate that
some subserve pain and others touch or cutaneous pressure.
It is the opinion of some investigators that both pain and touch
are difkerentiated in late fetal life. Very little difkerence could
be observed in cat fetuses between responses elicited by coarse
but innocuous stimuli and ones which produced demonstrable
trauma until after the 45th day of gestationJ Even at full term,
pain, touch and pressure are not well differentiated Raney and
carmichaels have dealt with the question of localization to tactual
stimuli in relation to the genesis of space perception in the rat.
They found greater speciiicity of response as the time of birth
approached.
186 PHYsIoLooY or THE FETUS
(b) Tauf-www ssnsmvrrr
Only one attempt has been made to study the eifect of tempera—
ture stimulation systematically throughout the entire fetal
periodss Physiological saIine solutions of different temperatures
were applied in drops upon six representative cutaneous areas of
guinea pig fetuses and the motor responses were recorded with a
motion—picture camera. The parts stimulated were vibrissae
area, ear, shoulder, rump, forepaw and hind paw. Control tests
were made with the solution at body temperature. Responses
were obtained throughout most of the fetal period but the warmer
or cooler the solution the greater their number. Cold solutions
 
kraus-o mous- ussde am)
Ein-o sum» tsssas now
Usoio eng-«- (so-s3 Im)
   
95
o; Tom. «
Its-sonstcticireo
m net( I
se! est-up
lIlIIIIIllllllIlt(lIIIIlIllIllllllI
Illllllllsltlllllltl
lllIllIllll
Illcsllllllllislllk
IIIIIIIIIIIIIIIIIIIIIIIIIIIII
tlttttIttlIlitt«lIItIsIItIIstIItIItstIists
s s n« II« «« es« as« c
senken-nun:
Essen-Ists o- cvinekpsc kkrusks w meinst. STZIUIII
Fiz 65.—Temperature sensitivity in guinea pig fetuses. (carmichae1 s: Lehnen
J. Genetic Psycholsp Vol. so, 1g37.)
IIIlIlIlIIIIIlIllllIIIIIIllIIIIlllIlIlIIIIII
appeared to be a little nsore effective than warm during the early
part of the motile period. sensitivity increased with age to some
extent but the growth of hair modified the effectiveness of stimuIation in the older specimens Furthermore, there »was evidence
of sensitivity spreading from cephalic to caudal and from pro-c—
imal to distaI parts as development progressed. Fig. 65 illustrates
the relative eEectiveness of solutions of Various temperatures used
in three age groups of fetuses.
PROPRIOCEPTIVE FUNCTION IN THE PETUS
It is quite possible that afferent nerves of the deeper fetal cis—
sues such as muscles and joints become functionaI very early.
Some of the first responses of mammglian embryos may resu1t
THE FETAL sENsEs 187
krom their activation. Movements ok the primitive limbs can be
induced by bending the limbs or by tapping on them. They can
lilcewise be obtained without touching the embryos at all by
tapping lightly upon the fluid filled amniotic sac containing a
specimen, but one does not know what nerves are being stimulated. since akkerent neurons are present in the connective tissue
just underneath the epithelium, it is just as likely that the response is due to exteroceptive as to proprioceptive stimulation.
Nevertheless there are many observations suggesting that
primitive endings in the muscle are capable ok being stimulated
by the middle ok the gestation period or a little latet. The stretch—
ing ok the ketus upon opening the amniotic vesicle and thus
changing the pressure upon the specimen is a case in point. 0ther
observations on the development ok muscle tonus and the tonic
neclc and body righting rellexes leave no doubt that proprioception is present, and well kormed, considerably bekore birth.
1n newborn rats whose spinal cords were sectioned completely
during intrauterine like it was often very diklicult to determine
by physiologic tests that nerve pathways had been interr"upted.
The animals responded to stimulation ok points below the level
ok section much as did their unoperated litter mates.I7 It was
suggested that in these very immature animals reflex movements
below the lesion were responsible kor stimulating proprioceptive
endings in muscles above, setting up proprioceptive reilex movements ok which the rats were aware and in this way acquainting
«the rats, as it were, with what was happening in a part ok the body
from which no direct messages could be received. The spread ok
activity krequently seen in much less mature mammalian ketuses
ok other species suggests a mechanism ok a similar sort. Ik proprioceptive kunction plays a part in the responses ok the early human
ketus it is certain that it does not require highly specialized
neuromuscular spindles because these structures do not appear
until about the third monthÄs
Function ok the vestibular mechanism begins rather late in
ketal like ok the can« In other species it may be present relatively
earlier, as seems to« be thes case in the sheepJs However, caution
must be exercised in attempting to determine its presence, kor
righting reflexes and eye movements can be induced by stimulat188 PHYsmLoeY oF THE FETUs
ing other receptors such as those of the neck and body. The
righting reiiexes have beens discussed in the preceding chapter.
OLPACTORL GUSTATORY AND VISCERAL sENsEs
The olfactory apparatus is made ready during prenatal life,
but it is doubtful if adequate stimuli are ever present in utero
where no air comes into contact with the nasal recept0rs. In the
newborn and prematurely born human infant, various observers
have obtained evidence of olfactory function.20s 21 It has been
pointed out, however, that common chemical receptors of the
trigeminal nerve are readily stimulated by strongly aromatic materials and they must not be confused with true olfactory
phenomena.
Taste has been demonstrated at birth in man as well as in
lower animals, but it is doubtful if dikkerentiation between sour,
salt and bitter is very well formed. The day old lcitten can distinguish between millc and a mixture of millc and sodium chloride.22 The experiments of De snooks who injected saccharin
solution into the amniotic sac of women sukkering from polyhydramnios, seem to indicate that the fetus responded to the sweet
taste and swallowed unusually large quantities of the amniotic
fluid.
Regarding other visceral aiferent stimulation, nothing is
known. 0ne can speculate that the normally occurring intestinal
movements stimulate afkerent neurons. Perhaps the active swallowing of amniotic Auid by fetuses in the last months of gestation
is reflexly controlled by» such a mechanism. Vigorous «hunger"
contractions of the stomach are found in prematurely delivered
mammals.24 .
IIEARING AND VISION
Hearing has been considered to be imperfect «at birth but
seems to improve within a short time after the amniotic fluid and
secretions drain from the middle ear.25 — Prematurely delivered
infants show evidence of audition a little while after birth. Some
investigators hold that the respiratory changes observed in the
human infant concomitant with the production of sounds signify
a functional auditory mechanism. «
Attempts were made by PeiperW to observe changes in intra—
uterine activity associated with Hund. »Alt.hough it was diflicult
THE FETAL sENsEs 189
to rule out stimulation of the fetus by the mother’s own responses,
the evidence suggests that strong sounds may have initiated reflex
movements of the fetus near term. 0thers have confirmed these
results« We have found that very slight tapping upon the amnion at the time of hysterotomy under local anesthesia results in
similar quiclc fetal movements even at a much earlier time in
prenatal life) such stimuli need not be thought of as sound producing. It is possible that the strong sounds, especially in the
case of tapping upon a metal bath tub in which the pregnant
woman 1ay, were not in themselves the cause of the fetal responses,
but that pressure was transmitted to the fetus as in our own ex—
periments. 0n the other hand, sontag and Wallace have presented good evidence that the human fetus does react in utero
to sound producing stimuli app1ied externally to the mother’s
abdomen. The fetal responses (movements) became more
marked as term approachedks Electrical responses have been re—
corded from the fetal cochlea after auditory stimulation in guinea
pigs of 52 days gestation.29 This was the earliest period at which
this species reHd overtly to such stimuli.
Although there can be no stimulation by 1ight before birtln
it is probable that the visual mechanism is functional t«o an imperfect degree in late prenatal life. 0bservations in premature
infants indicate that some sort of differentiation of light and dark
is present. Pupillary responses to strong light can be obtained
in late fetal life.
REFERENCES cITED
r. Windle, W. F. sc R. F. Becken 194o. Arch. Neur. sc Psychiat., 43: ge.
. Minkowslci. M. 1938. Abderhaldecks Handb. biol. Arbeitsmeth., Abt.
V, Teil 5 B: Zu.
. Bolaflio, M. sc G. Artom. 1924. Arch. di sei. Biol., H: 457.
. Hoolcen D. 1936. Yale  biol. sc Med., s: 579.
. Fit2gerald,  E. sc W. F. Windle, unpublished observations
. Preyer, W. 1885. spedielle Physiologie des Embryo. Gnaden, Leipzig.
. Windle, W. F. sc A. M. Griiiiw xgsn J. comp. Neun, se: 149.
. Raney, E. T. sc L. carrnichaeL 1934. J. Genetic Psychol., 45: Z.
g. 0rr, D. W. sc W. F. Windle. 1934. J. comp. Neur., 6o: 271.
to. lcuo, Z. Y. 1932 J. Exp. Zool» Hi: 395.
u. Windle, W. F. 1937. Proc. soc. Exp. Ziel. sc. Med., 36: 64o.
is. Windle, W. F. sc E. Fitzgerald. 1937.  comp. Neun, 67: 493.
is. coronios, J. D. 1933. Genetic PsychoL Monog., I4: 283.
i4. carmichaeh L. 1933. In c. Murchisocks Handb. child Psychol., and
ed., clarlc Univ. Press, Worcester.
U
IN! GIVE-Abs
190
IOIAIOIOIIIAIOU Obschon-HiYPOVPSOPEVP PPYPOJTSIWI
PHYSIOLOGY OF THE FETUS
. Bat-Gott, J. s- D. H. Bau-on. 1939. J. comp. Neun, 7o: 477.
cartnichaeh L. s- G. F. J. Lehnen 1937. J. Genetic Psychol., so: 217.
Hoolten D. s- J. s. Nicholas 193o. J. Comp. Neun, so: 413.
. cuajunco, F. 1927. contn Emb., 19: 45.
Winde, W. F. s- M. W. Fish. Igzn J. comp. Neun, 54: 85.
Peipetx A. 1928. Ergebw inn. Med. Kinderhlh 33: 5o4.
Frau, K. c» A. K. Nelson s- K. H. sun. 193o. The Behavior of the
Newborn Inkanr. Ohio state Univ. studies, No. to.
Pkalkmanm C. 1936. J. Genetic Psychol., 49: Si.
De snoo, K. 1937. Monatschtz Geburtsh. Gyn., 1o5: As.
carlson, A. J. s- I-I. Ginsburg. Ists. Am. J. Physiol» 38: 29.
Peterson, F. s- I.. I-I. Rainezu 191o. Bu11. N. Y. Lyingsin I-Iosp., 7: 99.
Peipen A. 1925. Monatschtn Kind-Ethik» sey: 236.
. Fort-es, H. s. s- I-l. B. Fort-es. 1927. J. Gott-F. Psychol., 7: 353.
. sontag, L. W. and R. Wallacn
child Developmeny 6: 253.
1938.  Exp.
I935Rawdonismith A. F» L. carmichael and B. We1Iman.
Psychol., es: zzn
CHAPTER XIV
THE FETAL ENDOCRINE GLANDS
Qui: lcnowledge of endocrine functions during prenatal life is
fragmentary as may be expected from the fact that adult glands of
internal secretion are still incompletely understood and their
relationship to one another only partly determine-d. There
seems to be little doubt that a few of the maternal hormones do
influence embryonic deve1opment, but not all can pass the pla—
cental barriers The present deftciency of information concem—
ing placental transmission of hormones is a factor limiting any
discussion of their activities in the fetus. Perhaps the secretions
of the fetus itself are equally or more important than those of the
mother for the well being and normal metabolism of the new
individual. It is with their functions that we shall be especially
concerned.
THE SUPRARENAL OORTBX
Among all the endocrine glands of the humazfetus the
suprarenals manifest the most remarlcable peculiaritiesks 3 Exam—
ination of them in the still—born infant reveals that they are proportionately very much larger than at any time after birthx in fact
they form o.2 per cent of the entire body weight. Those of the
adult constitute only o.o1 per cent.4 The reason for their great
size is found in an hypertrophy of the innermost cortical cells
sforming a layer to which the names, X-zone, fetal cortex and
androgenic zone have been applied. Only the outer rim of the
embryonic gland difkerentiates into the characteristic suprarenal
cortex of the adult, and it does not come into prominence until
after prenatal life.
The androgenic zone of the fetal suprarenal undergoes involution rapidly after birthF and as it disappears the size of the gland
becomes actually -as well as relatively smaller. The growth curve
of the human suprarenal gland is reproduced in Fig. 66.C The
gland loses one—third of its birth weight during the first postnatal
week, one-half in the first three months and fouplifths by the
191
192 PHYSIOLOGY OF THE FETUS
» end of the first year. Thereafter, a slow growth takes place and at
puberty the suprarenal again attains the weight it had at the end
of the fetal life ; but the androgenic Zone is no longer recognizable. This characteristically fetal part of the suprarenal gland
has been identiiied in the cat,7 Inouse,8 rabbit9 and in one strain of
rats.10 It seems to be absent, or at least not present as a comparable distinct layer of cells, in the albino rat and some other
anitnals.
The physiologic signiHcance of the hypertrophiecl fetal cortex
of the suprarenal gland is not understood. That it is closely re—
c« B «? 4 6 F J« ZZ « 36 II ZU
. Ase f« Yes-·.
Fig. 66.-—Growth of the human suprarenal glands (weight) during fetal like (c—B)
and after birth. (scammon: «The Measurement of Maus« Und: dünn. Press.)
lated to other endocrine organs is quite certain. A possible influence of Inaternal sex hormones upon the growing feta1 suprarenal is suggestecl by the closely parallel growth curve of the
uterus in prenatal and early postnatal life (Fig. 67) . Involution
of the X-2one of young male Ihice is accomplished under the in—
fluence of testicular horrnoneU
It has been suggested that the fetal suprarenaLgland elaborates an anclromirnetic substance.I2- I« Its ability to maintain the
prostates of the castrated immature mouse and rat, which degenerate when gonads and suprarenals are removed, demonstrates
THE FETAL ENDOCRINE GLANDS lgs
an andromimetic property quite clearly-P«- 15 «« Recentlzy however,
evidence has been advanced which indicates that carefully prepared extracts of fetal and of other X—2one—bearing glands do not
have androgenic propertiesss but it is possible that the amount
of suprarenal tissue extracted was too small to produce eifects.
should it prove that androgens are laclcingx one would have to
discard the attractive hypothesis that the androgenic cortex serves
directly to protect the fetus against an excessive iniluence of maternal estrogens reaching it through the placental barrier.
a---»»!
OF« Z Z 4 6 J« E) «? ««- Jö X r«AXJD Bär-«.
Fig. 67.-Growth of the hutnan Uterus (length) during ketal like (c-—B) and after
birth. (scammon: «The Measurement of Man," Univ. Minn. Press.)
75
 
The possibility that cortin or a cortin-like hormone is forrned
by the feta1 suprarenal gland has received attention. Some
investigators have reported that the survival times of adrenalectomized cats and dogs are prolonged during advanced pr«eg—
nancy.I7szI9 Others failed to substantiate this at the end of gestation,20 but even if it is true there is no proof that a fetal secretion
protected the mother. Progesterone maintains life and growth
in ferrets and rats in the absence of suprarenal glands,2I-««’3 and
the functional corpus luteum of pregnant adrenalectomized anirnals does the Same« Adrenalectomy of pregnant rats during
gestation results in an increase in weight of the fetal glandsW as
will be seen in Table ge.
IZ
194 Pnrsxoroor or THE: rETUs
Tanm 22
Tun Bringe-IS or Aussicht-Demut Denn-ro Pagen-mer III-on kur- Wntenks or rat;
Fast-Hi« sur-Hauptn- Gunvs
Time of adrenaleetomy No. of Average Ist. Ave. set. of suprarenal
of mothek litters of fetuses (gm.) glands of fetuses (mg.)
« d« 9 o« 9
Unoperated eontrols . . . . . . 18 5 .84 5.t»)8 0.90 0.82
14th day of FeSUItIOIL . . . . 15 4 .96 4.78 LLZ I .l8
7th day of Feste-tion . . . . . . 10 4 .70 4.51 1.17 Lls
Attempts have been made to destroy the suprarenal g1ands by
means of intrauterine surgery to observe effects on other fetal
endocrine organskk but it proved impossible to obtain clear—cut
results because of the magnitude of technical difkiculties
THE SUPRARENAL MEDULLA
The medulla of the suprarena1 gland has an embryonic origin
very different from that of the cortex. It is formed by cells which
arise from the primordia of sympathetic ganglia and which begin
to migrate into the already prominent cortical bodies at about
seven weeks gestation in man. cells ok the suprarena1 medulla
as well as of certain other small glandular bodies of similar embryonic origin (e.g., the aortic paraganglia) possess a retnarld
able afkinity for chrome compounds with which they take on a
brown color. This chromafkin reaction has been demonstrated
to be elicitable iirst at about the time extracts of embryonic suprarenal tissue begin to produce pharmacologic responses characteristic of epinephrink749
Many have investigated the activities ok the embryonic -and
fetal suprarenal medulla by this histochemical method as well
as by other chemical and sensitive physiologic techniques Epinephrindilce reactions are obtainable from suprarenal extracts pre—
pared from chiclc embryos as early as the eighth day of incubation although similar extracts of other embryonic tissues give
negative resultsFHI Epinephrin is formed, or at least stored,
in the medulla of the glands in many fetal mammals before the
middle of gestation.32-39 The medullary cells show the chromaliin reaction at the 17th to 18th day in the pig and both physiologic and histochemical tests reveal the presence of an epinephrins
lilce substance at the time migration of. iznedullary cells into the
THE« FETAL ENDOCRINE GLANDS 195
cortical bodies is first observablekssfs The epinephrin content
of fetal glands has been reported to be greater than in the adult;
more was found in female than in rnale fetusesPs A correlation
between appearance of. epinephrin in the suprarena1 of th«e rat
and the origin of fetal movements has been suggestedxm but this
seems to be coincidental.
In sharp contrast with results obtained in most rnamma1s,
human fetal suprarenal extracts give negative or only very
slightly positive tests for epinephrinJHss 4144 However, in- full
term infants as well as prematures which lived for a short time
somewhat more definite reactions were obtained. The near fai1—
ure to obtain epinephrin-lilce responses from human fetal suprarenal extracts may be contrasted with the observation that the
paraganglia yielded definite amounts of epinephrin in one in—
stance:43
kluman suprarenal at birth - 0.0I arg. epinephrin per OR? Hm. Flur-d.
Etunan paraganglion at birth - 0.24 rag- epinephria per 0.1I Hm. sind.
Any relationship between low content of epinephrin and the
presence of a very prominent androgenic cortical zone in man is
undetermined
Im: sEx Blond-muss
An excellent consideration of embryologic development of
sex with a review of all but the latest literature has appeared
recentlyxss We are limited here to only a small part of this interesting subject.
The male gonads produce substances with androgenic properties in prenatal life. 1t was demonstrated that extracts prepared
from the testes of fetal calves are similar to those from the adult
and the hormonal yield per unit weight of tissue is greaterKS It
is probable that the male sex glands begin to elaborate secretions
about as soon as their sex can be differentiated, which is the sixth
day in the incubating chiclc and the seventh weelc in man. The
ovary is recognizable as such about a weelc later than the testes.
The best indication we have that fetal androgens are active
in early prenatal life is that forthcoming from a study of freemartins in cattle.47s 48 The freemartin is an intersexed or mascu—
linized female calf which deve1ops under conditions of chorionic
fusion in which vascu1ar anastomoses are estab1ished between the
196 PHYSIOLOGY oF THE. FETus
placentas of adjacent male and female fetuses. The male is always a normal individual: It is believed that the hormone elab—
orated by the fetal male gonadscirculates in the conjoined blood
streams, acting upon the female twin’s Miillerian or female duct
derivatives to inhibit their normal development and upon its
Wolllian or masculine duct derivatives to stimulate their abnormal
dilferentiatiom When vascular connections are not established
between adjacent fetuses of opposite sex no freemartin results,
but the calves are normal male and female.
A. similar freemartin condition has been described in swine.49
It should be noted that the placentas of both cattle and swine are
relatively ineflicient from the standpoint of permeabi1ity. A high
degree of placental fusion, apparently with vascular union, was
observed in one instance of synchorial twinning in the cat.50 The
fetuses were of opposite sexes, were sexually normal in every way,
and were sulliciently advanced in development to make it appear
certain that the female twin would not have become a freemartin.
similarly synchorial twins of opposite sexes are encountered in
other animals and man,51- 32 but freemartins have not been re—
ported. It will probably be prolitable to- learn how the transmission of fetal male sex hormones across the placental barrier
is related to the phenomenon in question. It is diflicult to see how
the freemartin condition can be so limited unless the diffusibility
of embryonic testicular hormones is greater in the deciduate types
of placentas which therefore never allow hormones to accumulate in suilicient amounts to stimulate the Wolflian derivatives of
the genetically female twin.
It would carry us too far alield to inquire deeply into the ex—
tensive experimental studies on production of pseudohermaphrodism in the lower animals« success has been attained in mams
mals at several laboratories recentlyks Injections of pregnant rats
with large doses of testosterone and related preparations bring
about abnormal development of the potentially male ducts of
genetically female young. It is necessary to administer the hormone before the 16th day of gestation to obtain the most marked
effects.54 This is about one day before the WolHian ducts begin
to regress The intersexed individuals produced experimentally
resemble the naturally occurring freemartins in certain particu
lars.
THE! FETAL ENDOCRINB GLANDS 197
Male ofkspring of rats receiving large doses of estrogens before
the Izth day of gestation have been markedly feminizedPs Thus
a converse of nature’s freemartin has been induced with excessive
female sex hormones. The extent to which the mother’s own
hormones may inliuence normal development of sex in the fetus
is not understood. It is known that the fetal uterus exhibits a
marked hypertrophy and diminishes in size after intimate contact with the mother is abolished by birth. The mammary glands
of newborn infants of both sexes show enlargement and may
secrete transientlys It is possible that this production of «witch
milk" is stimulated by the same maternal hormonal mechanism
that leads to the preparation of the mother’s breasts for lactation.
THE TEYROID GLAND
The ability of the fetal thyroid to secrete at an early period
seems to have been established. Iodine has been identilied in the
gland at the 2nd or zrd month of gestation in cattle, sheep and
swiness and in man at least as early as the 6th month» The
amount is said to increase toward the end of prenatal life but to
be low as compared with the adult gland, perhaps because storage
of colloid is not so marked in the fetus« There is no close correlation between the maternal and fetal blood content of hormone
iodine, a fact which suggests that the fetus is secreting its own
hormoneIs The presence of thyreoglobulin in the human fetus at
the zrd and 4th months has been established by means of an
immunologic precipitin reaction.59
Amphibian metamorphosis and growth can be inlluenced by
extracts and transplants of avian and mammalian fetal thyroid
glands. In several, it may be said that the thyroid« becomes active
at about the time its structure begins to resemble that of the
adult. This is on the iith day of incubation in the chickW In
calves colloid is present as early as the end« and differentiation is
comp1eted between the 4th and 6th prenatal monthsz at this time
extracts serve to bring about metamorphosis in the axolotl, a
salamander which normally retains the larval state throughout
life.30 Extracts prepared from the glands of pig fetuses 7 cm.
long proved to be inactive, but those from 9 cm. pig fetuses produced reactions comparable with adult thyroids; correlatively,
the adult structure was nearly attained at 9 cm.» When bits of
198 PHYsmLooY oF THE: FETUS
the thyroid gland from a 3-months-old human fetus (1o cm. C. R.
length) were transplanted into larvae of a toad, accelerated development took place, and trarisplants from 5-months-old human
fetuses had more marked efkectsYs Control experiments with bits
of fetal muscle gave negative results. It was found that the thyroid
gland of the youngenfetus had already deve1oped col1oid Iilled
vesicles.
Little is known about placenta! transmission of the thyroid
secretions. In swine, horses, cattle and sheep, animals with
adeciduate placentas, it appears that there is no transmission. In
geographical regions where iodine deliciency is prevalent the offspring of these animals are born in a state of athyreosis while the
mothers show little or no evidence of the iodine lack.C4- S« It
seems sthat the fetal requirements of iodine are greater than those
of the mother and that the fetus cannot draw upon the mother’s
hormone but must manufacture its own. Iodine feeding during
pregnancy corrects this deliciency, and the newborn pigs are then
normal. In man, on the other hand, it seems probable that the
mother’s hormone is available to the fetus because it can traverse
the placental barrier. Human infants born without or with
atrophic thyroid glands exhibit none of the symptoms of myxe—
dema, but a latent athyreosis soon manifests itself.S3-71
THE PARATIIYROID GLANDS
Practically nothing is known of function of fetal parathyroid
glands. Injections of parathyroid hormone into dog fetuses bring
on an elevation of the calcium level of the fetal, but not the maternal blood. This suggests that the parathyroid secretion does
not pass the placenta in the species studied.72 Attempts have been
made to determine the effects of fetal glands of dogs after thyroparathyroidectomy of the mothers. It was found that tetany de—
veloped just as soon as it did in nonpregnant animalsJss ««
THE TIIYMUS
Although the thymus is usually considered with the glands of
internal secretion, it is doubtful if it logically belongs there. By
3 months in man, the thymus has the appearance of a lymphoid
organ with cortex and medulla already in evidence. There is no
anatomical basis for the belie,f that the sgland elaborates a hormone
THE« FBTAL BNDOCRINE GLANDS 199
and few attempts have been made to study the fetal thymus from
the standpoint ·of its endocrine function.30s «« ««
Extracts of thymus seem to exert no elfects when fed to tadPoles, although opinion has been divided on this questions«- ««
An extract of calf thymus, to which the name «thymocrescin" was
given, has been reported to produce marked acceleration of
growth in young rats when injected in daily doses as small as
1 .mg.79
Another extract prepared in an entirely different way resulted
in even more marked effects in the hands of Rowntree and his
colleaguesko This material was injected intraperitoneally in i cc.
doses into rats over long periods including gestation and lactation; the young of succeeding generations were similarly treated.
Elfects on the olkspring of the first animals were not signijicant
but the second and subsequent generations showed remarkable
changes. They were larger at birth, more of them survived and
their postnatal development was delinitely speeded. The young
rats became sexually mature precociously. Maximum effects
were found in the eighth and tenth generations. It was necessary to keep giving the treatments and not miss a generation or
the effects were promptly dissipated. From the more recent re—
ports it seems that it was necessary to inject the extracts into
females onlyFI
0ther investigators have attempted to reproduce these very
interesting results. but so far no adequate confirmation has been
reported» The biologic effects of certain iodine-reducing sub—
stances (glutathione, ascorbic acid, cysteine) have been found to
simulate those of the thymus extracts in certain particularsPI
Im; nrpopkkrsxs
A few studies have been made on placental transmission of
hypophyseal extracts but we know Iittle about hormone elaboration by the fetus itself. When pituitrin was injected into rabbit
fetuses no muscular contractions were observed in the mother.83
This suggests, but does not prove, that the substance failed to
pass the placenta. Anterior lobe extract did not produce any
evidence of its usual gonadotropic activity in the mother when
it was introduced into the fetuses« Furthermore, this hormone
failed to appear in the fetal fluids after it had been injected into
200 PHYSIOLOGY OF THE FETUS
the «mother; at least, the administration of these fluids to other
adult rabbits fai1ed to bring about ovulatory changesss These
experiments seem to show that there is very Iittle if any transmission of the large molecules of the anterior lobe gonadotropic
factor even in the hemosendothelial type of p1acenta.
The fetal hypophysis seems to be capable of elaborating several active principlesPss VHV A pressor substance has been found
at 6 months in man. similar studies have been made in fetuses
of cattle, sheep and swine in which the response was found relatively earlier. The guinea pig uterine strip method served to
demonstrate the oxytocic princip1e about as early as the pituitary
glarid can be recognized macroscopicallzn It was found in appreciable amounts in pigs and sheep at term.
The melanophoreexpanding hormone has been identified in
the fetal hypophysis It was found in the glands from calf fetuses
of 3 months gestation but was not there at 2 months. It was present in pigs of only Zo mm. c. R. length.30- 88
Gonadotropic and growth promoting factors of the anterior
lobe seem to make their appearance rather late in fetal life, and
the former is later than the latter.90 In fetal pigs the gonadotropic
response was obtained from glands at the 2o to 21 ern. stage, a
short time before the end of gestation but was not found earlier.
The general body growth response could be obtained at the 9 to
13 cm. stage which was just about the same time the thyroid hormone made its appearancesEs 90
SECRETIN
Extracts of the proximal portion of the fetal small intestine
have been found to cause secretion of pancreatic juice when in—
jected into adult animals with pancreatic Hstu1as.9I·9f The earliest
period at which secretin has been obtained from the human fetus
is 414 months. The exact source of the hormone is unknown
and attempts to ascribe it to the chromalkn cells of the duodenum93 seem to be entirely unjustiöed
THE ENDOCRINE PANCREAS
The endocrine function of the pancreas is vested in the cells
of the islands of Langerhans These make their appearance in the
third month of human gestation but— it-.is not known how early
THE FETAL ENDOCRINE GLANDS 201
they become capable of secreting. The acinar portion of the
gland does not begin to produce its proteolytic ferment before
about the 5th month,93 and Banting and Best took advantage of
the fact that island tissue is functional earlier when they chose the
pancreas of the fetal calf as a source of antidiabetic principle in
their early search for insulin.97 Many have discussed the possibility that fetal insulin plays an important röle in carbohydrate
metabolism of the fetus and have pointed to a correlation between
the appearance of glycogen in the liver and the development of
island tissue in the pancreassss 99 but the relationship is still somewhat unsatisfactorily established because the influence of maternal
secretion acting through the placenta is diflicult to evaluate. It is
said not to pass the placenta from fetal to maternal sides.83 Administration of insulin to pregnant cats failed to reduce the blood
sugar level of the fetuses near term. This suggests that the pla—
centa is impervious at the time, but at earlier stages similar results
were not obtainedEoo Further discussion of this question will be
found in Chapter XVI »
In birds, where all metabolic processes must be managed by
the fetus itself, an insulin-like substance has been found in the
unincubated eggJOI However, it is not present in the tissues of
the early chick embryo until after the pancreatic islets are formed.
The ofkspring of diabetic animals are not diabetic and as a ruIe
seem to possess healthy glandsW This is not always true in man
where hypertrophy and hyperplasia of islands and postpartum
hypoglycemic deaths are encountered in infants born of diabetic
womenJos Although hyperplastic pancreatic islands are not.
found in all instances, careful searching might show the condition
to be more prevalent.
The possibility that during prenatal life fetal insulin can
protect the diabetic mother has been discussed by several investigators. It was discovered by Carlson and his colleaguesIM W
that the urine of completely pancreatectomized dogs remained
free from sugar when the .operation was performed in late stages
of pregnancy. This suggested that fetal island tissue had, supported both the mother and fetuses, for after parturition the
mother exhibited glycosuria. These experiments have been adequately confirmedW and similar conditions app«arently occur
in the human.I07 Completely depancreatized dogs maintained in
202 PHYSIOLOGY OF THE FETUs
good hea1th by diet and insu1in therapy can conceive and give
birth to normal pups. They show an increased carbohydrate tolerance kor only about two weeks prior to labor. However, an even
greater tolerance appears after birth during lactationz it would
seem that the results previously ascribed entirely to ketal insulin
are more probab1y due largely to increased utilization ok carbohydrates by the fetuses and, after birth, by the nursing puppies.
We cannot be sure that the ketal insulin plays any part in protecting the diabetic mother. It is quite reasonable to suppose that
it is more important kor the utilization ok sugar received by the
ketus krom the mother.
Glycogen appears in the liver ok the deve1oping chick at 7 days
ok incubation. This is about three days before delinitive islands
ok Langerhans make their appearance. Between the tenth and
thirteenth days the glycogen content ok liver cells diminishes and
the metabolic rate and respiratory quotient increase, although
there is no rise in the blood sugar concentration. Thus it appears that an increased utilization ok carbohydrate by the embryo
is correlated with the advent ok kunction in suprarenal medulla.
pancreatic islands and thyroid glandsÄss «
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PHYSIOLOGY OF THE« FETUs
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THE FETAL ENDOCRINE GLANDS 205
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CHAPTER XV
FETAL NUTRITION AN D METABOLISM
PARAPLACENTAL NUTRITION
THE maternal organism not only breathes and excretes for the
ketus but it also digests kood and kurnishes nutriments needed kor
the growth ok the new individual. In early stages ok development
the intimacy between embryo and mother is slight, and until a
close approximation to the endometrium is ekkected nutrition can
not be accomplished by direct processes which characterize the
older and more advanced types ok placental circulatory Systems.
An intermediate substance ok transient nutritional value to the
early embryo is provided by secretion ok the uterine glands, by
transudation and especially by erosion ok the endometrium and
production ok tissue detritus in response to implantation ok the
newly arrived blastocyst. To this paraplacental nutriment, the
name histotrophe may be applied.I-4
In mammals with relatively simple epithelio-chorial and syn—
desmo-chorial p1acentas, such as the horse and sheep, quite a
different histotrophic material bathes the chorionic surkace
throughout gestation. This, the «uterine mi11c," is composed predominantly ok secretions and transudates from the intact uterine
epithelium. Its high kat- content gives it the appearance ok dilute
millc.
It is doubtkul ik histotrophic nutrition can be ok real signikicance in man and other primates for more than a kew days during
implantation) A yollc-sac placenta develops early in the rat, and
with it a more eiiicient mechanism kor nutrition. The passage
ok substances through the yollcssac epithelium ok the rat has been
demonstrated very clearly.0- 7 0ne can not consider that the processes involved are entirely histotrophic in those animals in which
uterine millc is laclcing.
With the kormation ok endothelio-chorial, hemo—chorial and
hemo-endothelial (deciduate) placentas in carnivores, primates
and rodents, histotrophe plays only a. Jninor and transient part
206
FETAL NUTRITION AND MBTABOLISM 207
and nutrition becomes possible largely by processes similar to
those occurring in the tissues ok the body itseltl The substances
which pass more directly from one blood stream to the other have
been designated hemotrophe. Thus Bonet’s term «embryotrophe" has given way to a more usekul classiiicatiom
Bmbryofrophe
Eistotrophe klemotrophe
l . I . I . I « I
Ikansient Uterme milk. Diikusible Nitrogenous substances
endometrial Nutrition substances substances (e.y., lipids)
detritus, etc. throughout (gases, ok high truly
Nutrition kor gestation in dextrose and molecular absorbed b)implanting ungulatea inorganic weight which trophoblast
blastoeyssz eompounds) are diikuss and yolkssac
requiring no ible but epitheliunh
resynthesia require
resynthesia
PLACENTAL PERMEABEITY
N utrition ok the fetus is closely dependent upon the manner
and ekkiciency with which materials are transmitted across the
placental barrier. It must be born in mind that the physiologic
characteristics ok the placenta are not constant throughout development, nor are they the same in all species ok mammals. Furthermore, the chorio-allantoic attachment is not the only means
ok contact between the ketus and motherz in some species, e.g.,
the rat, a yollosac placenta ok very dilkerent structure is known
to serve concomitantly throughout gestationsk The term «the
placenta« rekers as a rule to the combined ectoplacenta and yollc—
sac placenta when used in rekerence to kunctioxx Density and
number ok tissue layers separating maternal and fetal blood
streams vary, as was pointed out in Chapter I. For these reasons
one must exercise caution in attempting to draw conclusions regarding the permeability ok one type of placenta based upon experiments with a different type.
The subject ok placental permeability is much too extensive ito
be discussed in detail, but a few signiiicant observations can be
considered such observations inquire into the characteristics ok
materials which make their way across the living membranes, and
into the nature ok the processes involved in their passage.
Particulate matten even when microscopic in size, kails to pass
208 PHYSIOLOGY oF THE: FETUs
the most advanced hemo-endothelial placentas. Formerly there
was much discussion of this, but the fact is now well establishedF
certain ultræmicroscopic particles in colloidal solutions do pass,
and the dye trypan blue seems to be one lying on the borderline
between the transmissible and non—transmissible substances in the
hemo-endothelial placentas. This dye does not traverse the
endothelio-chorial type found in the cat.?
That a relationship exists between the molecular weight of
substances and their ability to pass through placentas can scarcely
be doubted. 0xygen, carbon dioxide and many chemical com—
pounds of low molecular weight traverse membranes of all placentas. Tabulation of data available ·up to 1931 will be found
in N eedham’s10 «Chemical Embryology" (Table 227) . From this
it appears that the thinner the barrier, the more permeable it is
to materials of large molecular size. 0n the other hand, it has
been demonstrated that the thin chorionic trophoblast plates of
the early rat placenta are actually less permeable than the much
thiclcer yoll(-sac epithelium to the dye, toluidin blue.
A very close parallelism exists between the ability of colloidal
dye solutions to diffuse in iilms of 2o to 30 per cent gelatin and the
efliciency of their transmission from the mother to the fetuses of
rats and mice.U These and other observationsW have frequently
been cited as evidence that the placenta acts largely in the capacity of an ultra-iilter. There is ample evidence, however, that the
fat solubility of materials in the blood streams, their pH and
ionic charges at the membrane play important röles in governing
placental permeability. "Furthermore, one can not tell whether
the experiments with colloidal dyes demonstrate passage through
the ectoplacenta, the yolldsac placenta or a combination of both.
Although a number of investigations have led» to the conclusion that species differences exist at term in respect to permes
ability of dye solutions,9 other chemical solutions« and antibodiesss few experiments have been concerned with the changes
talcing place throughout the course of development of any one
species. Recently, however, it was demonstrated that the permeability of the rabbit’s placenta to agglutinins and hemolysins in—
creases during the course of gestation.14 The ratio of the titre of
the fetuses to that of the mother plotted against the gestation-age
forms a sigmoid curve (Fig. 68)'. Permeability is clearly related
FETAL NUTRITION AND METABOLISM 209
to the changing histologic structure of the placenta during gestationss «
The two principal theories concerning the nature of the placental barrier merit further study. Many recent observers have
favored the view that it is essentially an inert semipermeable
membrane, but advocates of the concept of a vital function are
not lacking. A preformed rcgulatory mechanism, inferring a
secretory process, has been suggcstedJs
Those who favor the ultra-iilter theory believe that substances
pass from mother to fetus, or in the reverse direction, by diffusion
and filtration, that physical processes alone govern the transmis
tIIIII--I
tIIIIgIII
ssIIZIIIs
tgtZIIIIs
I-IssUII
II Z( 2
 
O
G
Z
 
Rotte-Pers! Fuss-Hofstaat Tit-se
 
Period of Gestaden-days
Fig. 68.—Permeability of the rabbit placenta to antibodies at different times during
prenatal life. (Rodo1fo: J. Exp. Zool» Vol. 68, 1934.)
sion and that molecular size plays an important part in determining which shall and which shall not cross the barrier.10-U-17- 18
This seems to be well established for gases, dextrose and a number
of chemical compounds of relatively low molecular weight, including some of the products of fetal metabolism. The subject
has been reviewed by schlossmanW who concludes that, aside from
endocrine activities, there is not the slightest reason to believe that
the placenta and its chorionic epithelium has a truly secretory
function. He believes that even in the instances of seemingly
vitalistic activities, physical principles in the last analysis can ex—
plain transmission. Nevertheless it is reasonable to adhere to the
concept of absorption in the trophoblast.. The recent studies on
14
210 PHYSIOLOGY OF THE FETUs
metabolism of lipids provide strong circumstantial evidence for
the vitalistic theoryäs
With the recognition of functional properties of the yollc-sac
in some animals, the question of secretory function talces on re—
newed interest. In structure as well as in physiologic reaction to
perfusion of the maternal blood vessels with various chemical and
dye solutions, the yollcssac placenta of the rat appears to be an
organ for absorptionks 7 When more attention has been paid to
the functions of this organ, as well as to factors of age and species
differences, our lcnowledge of the passage of the nutriment from
mother to fetus will undoubtedly be advanced far beyond its
present state.
UETAZOLISM oF cumoknmmrns
The body of the fetus is bui-It from chemical substances which
are available in the mother’s blood. Energy needed by the fetus
is derived from the same source. Indeed, all the prenatal require·
ments are met by processes of intermediary metabolism. The
most readily available substance is carbohydrate in the form of
dextrose which serves as the important energy source for the fetus.
Dextrose can pass from mother to fetus across the placental
barrier in all mammalskHs Human fetal bloodssugar concentration is always a little lower than that of the mother near term.
For example, Morriss found averages of 1 15 mg. per cent in the
fetus and 132 Ins. per cent in the motherkl indicating that there
is a gradient of flow towards the fetus. A similar condition pre—
vails in most mammalssks 23 but not in the pig and cow in which
the concentration is lower in maternal than in fetal blood.23- 24
The reason for these species differences is not clear, but they may
be related to placental structural variations and to histotrophe as
an intermediate nutriment. Much of our information has been
obtained at the end of gestation or is based on averaged data of
different prenatal ages. A more complete study is available in the
incubating chiclc.25 The blood-sugar concentration maintains a
reasonably constant level up. to the 16th day; thereafter it rises
and surpasses the adult level at about hatching time, which is the
21st day. Fetal blood—sugar concentration varies with gestation
age in mammals too. For example, it decreases toward term in
the cow but increases marlcedly in the spguinea pig and rabbitkss 27
FETAL NUTRITION AND METABOLISM 211
It is apparent that a simple filtration across the placental barrier is
not the only mechanism governing the blood-sugar level in the
fetus.
The placenta and liver are important depots for carbohydrate
storage in prenatal life. As early as 1858, Claude Bernard demonstrated that the placenta contains glycogen and serves as a «transitory liver« for the embryoks It has been clearly shown that the
glycogen content of the placenta is high in the early part of fetal
life whenlittle or none is in the liver. Only the maternal portion of the placenta contains it.29 A time is reached, however,
when glycogen storage becomes active in the fetal liver; when this
occurs there is a corresponding reduction of storage in the placenta. This crossing over takes place after the elapse of 75 per
cent of the total gestation time in the rat, 82 per cent in the chiclc
and 91 per cent in the rabbitPHI The glycogen content of the
fetal liver rises rapidly toward the end of gestation and is especially high a few days before birth.22 Nevertheless, the amount of
liver glycogen is inconstant at any given period in the fetus and.
varies with the food intalce of the mother. Following 24 hours
of fasting in the rat at full term, the pealc of maternal liver glycogen was reached about four hours sooner than that of the fetuses«
When the average glycogen content in the mother’s liver was o.29
per cent of the total liver weight (fasting1eve1) , that of the fetuses
was 4.95 per cent. At the pealc of storage after feeding, average
values of 3.1 per cent and 1o.6 per cent were found in the mothers
and fetuses respectively. These differences are truly remarlcable.
Glycogenic function begins after secretion of bile has startedFs
It has been thought to begin at almost precisely the time the is—
lands of Langerhans differentiate and begin to supply insulin to
the fetal bloodZss ZHC However, it has been demonstrated re—
cently that the livers of incubating chiclcs contain glycogen at
Ieast as early as the 7th day of incubation, although the pancreatic
islands do not appear until the Iith day.3·3 In livers of pig and
sheep fetuses, likewise, glycogen has been observed before the
pancreatic islands are formed. Glycogen is distributed evenly
throughout the chiclc liver after island tissue makes its appearance, but is conlined to the cells around large veins in earlier
embryos. Nearly all livers show glycogen on the seventh, eighth
and ninth days and again after thirteen days, but in the interven212 PHYSIOLOGY oF THE. FETUs
ing period fewer contain it. There is no detectable change in the
blood-sugar concentration at this time of rapid glycolysis, even
though the metabolic rate increases and the respiratory quotient
approaches unity. These facts suggest very strongly a relative increase in utilization of carbohydrates as an energy source between
the Ioth and izth days of incubation, and they indicate that the
fetal liver supplies some of this material at this period during
which endocrine functions of thyroid, suprarenal and pancreas
are just becoming established. «
The passage of carbohydrate from mother to fetus is a s1ow
process under normal conditions, but it can be accelerated greatly
by injecting insulin into the fetus.37 When this was done it was
found that the glycogen or total carbohydrate content of livers
and muscles of dog fetuses was not infiuenced significantly However, the lactic acid concentration of the fetal blood was raised
a few hours after insulin injection and the difference between its
level in the umbilical artery and vein was increased many times
above the normal. About three-fourths of the dextrose which
passed from the dog to its fetuses to compensate for the experimental fetal insulin hypoglycemia returned to the mother as lactic
acid.22 "
The fetal dog is reported to be highly resistant to insulin and
the fetal sheep and goat scarcely respond at all to doses as great
as 415 units per lcilogram. An insulin antagonistic substance
seems to be present in their blood.22- 23 Although insulin fails to
deplete the fetal liver glycogen in dogs, sheep and goats when
given to the fetuses, it·has been observed to do so in rats when
injected into the mother-PS Adrenalectomy of pregnant rats simii
lar1y leads to depletion of the fetal liver glycogenks Apparently
the fetus practices a rigid glycogen economy at theexpense of its
mother’s dextrose, drawing upon its own liver store only in einer—
gencies.
METABOLISM 017 LIPIDs
Well nourished fetuses are supplied with good stores of fat.
Do they acquire this by transfer through the placenta or must it
be synthesized from simpler materials? Perhaps the fetus is able
to synthesize some from carbohydrates or amino acids, but these
are not the only sources. Certaimlipids are passed from the
FETAL NUTRITION AND METABOLISM 213
mother’s blood to that of the fetus by poorly understood mechanisms and thus become available for construction of fat. To what
extent lipids are oxidized by the mammalian fetus for energy is
not known. They form the principal source of energy in birds
during the greater part of the period of incubationKo
It has been quite deiinitely determined that the fat which is
fed to a pregnant animah and which is absorbed and stored in its
tissues, does not pass through the placenta unchanged When
stained by sudan III or some other similar dye before feeding,
the body fat becomes intensely colored, but there is not the least
color in the fetuses.39-4I Regardless of the degree of saturation
of the fatty acids available from material fed to the mother, the
fetal fat has an almost unalterable degree of saturation.42 It is
quite different from that of the mother in respect to melting point
and chemical composition, in that it contains much more palmitic
and less oleic and stearic acids.43
0ther lines of evidence suggest that there is no direct passage
of lipids across the placenta! membranes. A marked dilkerence
«in fatty acid content of maternal and fetal blood has been found.
The lipid content of red blood corpuscles is about the same in
infant and adult. However, the blood plasma contained on the
average 948 mg. per cent in the former and 737 mg. per cent in
the latter in one series of estimations.44 Average values in another
series of human newborn infants appear in Table 23345
Tut-D 23
Lusrv couposrrron or Gut-arm) Fuss«
kapu- Nswkom Isgsggskezkszks
mg.Xl00 ce. mg.Xl00 Oe. »Ja« value«
Tom! lipids ........... .. 589 -i- 87 198 -s- 80 84
Neutral fat . . . . . . . . . . . . . 154 - 42 90 - 50 58
Tom! kam— acids ...... .. 353 -i- 56 140 - 57 40
Totul eholesteroL . . . : . . . 162 -I- 32 84 -l- 15 2l»
Bster eholesterol . . . . . . . . 115 -I- 27 A) -s- 12 l7
Iüsee eholesterol . . . . . . . . . 47 -I- 7 14 -s- 7 80
Phospholipid . . . . . . . . . . . . 196 -l- 23 6l- -I- 32 31
0n the other band, the blood passing to the fetus from the
placenta is richer in certain lipids than that returning from the
fetusKC The difference must represent lipids used or stored by
214 PITYSIOLOCLIY OF THE FETUS
the growing fetus. Averages of 15 analyses are given in Table
24310
Tut-n 24
Lan) contes-im« or« Ema-m Unten-Iehr- conv Bnoov
Artery Vein
Ins! 100 Oe. mgjlllll ee.
Phospholipid . . . . . . . . . . . . . . . . . . . . . . . . 16«0 204
Free cholesterol . . . . . . . . . . . . . . . . . . . . . . 55 64
Ester cholesterol . . . . . . . . . . . . . . . . . . . . . 8 18
Neutral kat . . . . . . . . . . . . . . . . · . . . . . . . . 116 121
Phospholipids are always talcen up in large amounts, and
smaller amounts of free cholesterol may be absorbed by the human placenta. cholesterol esters pass to the fetus when they are
present in sulficient quantities in the mother’s blood. Neutral
fats have been thought to pass in both directions. Lipids continue to be added to the static placental blood by the placenta
after birth of the child. Without malcing a positive statement
concerning the mechanism involved, it may be said that a significant passage of lipids across the placental barrier takes place in
the human near term. It has been estimated that a well nourished
fetus takes up about 50 grams of lipids a day at full term, 40 grams
of which are in the form of phospholipidsås
The iipid eempesikieh ek khe pieeehkä and kekus ek the kahhik
at various stages in gestation has been reported« The phospho—
lipid and free cholesterol concentration increase rapidly in the
fetus up to the middle of gestation and then more slowly until
about the final weelc at which time the rate increases again. Up
to the middle of gestation, the placental concentration of« phos—
pholipid decreases while that of ester cholesterol increases. Beyond the midpoint in gestation, the reverse was found. slight increases in neutral fat and free cholesterol were encountered in
the placenta throughout gestation. The results suggest that there
is a greater demand for phospholipid by the fetus than can be met
by the placenta in the middle of gestation. and a late secondary
demand which is compensated near term by increased placental
ability to supply it.
Large amounts of fatty acids are accumulated in the liver by
the guinea pig fetus.48 Early irxgestation the liver contains about
FETAL NUTRITION AND METABOLISM 215
the same proportion as that of the adult, which is approximately
2 to 4 gramsx its liver fatty acid concentration is already increasing,
and at a few days before birth (8o grams weight) the value reaches
15 grams per cent, while the mother’s liver shows no change. It
drops again to the adult level within 3 or 4 days after birth.
The lipids of the fetal liver are much more unsaturated than
those in other fetal tissues and less so than those of the mother’s
liverfs 0ne wonders whether the fetal liver is endowed with
greater ability to desaturate fatty acids than is the mother’s liver
or if it simply receives already desaturated acids from the plaöenta.
The latter seems the more likely, and for the following reasons.
When the pregnant animals were fasted and then given
phloridzin it was found that the fetal liver storage of fatty acids
was increased in the early period of gestation (fetuses weighing
30 grams and less) , but no signiticant change occurred in the maternal liver with the dosage used. Furthermore, the fatty acid was
less unsaturated than normal, as would be expected under influence of phloridzin with Inobilization of the connective tissue
fat to the liver. Evidently the fatty acid in the fetal liver, norma1ly encountered, is not transported from the other fetal tissues
but comes from the placenta.
Evidence has been presented recently that esterification of
cholesterol by fatty acids takes place in the liver cells of the chick
embryofk Histochemical tests indicated the presence of free
cholesterol, ester cholesteroland cholesterol-fatty acid mixtures in
the liver on the e1eventh day; but in chorio-allantoic grafts of the
liver, in which the host was several days older than the graft, these
substances appeared during the latter part of the seventh day. It
is evident, therefore, that the fetal liver is prepared for its röle
in lipid metabolism some time in advance of the day it actually
begins to work.
METABOLISM OF PROTEIN«
A great deal of information has been obtained in recent years
regarding the metabolism of proteins in bird fetusesEo but we
still know little about this process in mammals. There are three
principal methods for approaching the question. The chemical
composition of maternal and fetal blood can be compared, the
composition of the embryo itself at different stages of development can be determined, and Hnally the initrogenous waste prod216 Ptivsxotocv oF THE FErUs
ucts of combustion in the fetus can be analyzed. We shall ex—
amine evidence obtained in these ways.
Food proteins are digested and brolcen down into amino acids
which are absorbed into the mother’s blood. These are used, not
only for tissue metabolism of the mother’s own body, but they
serve as a readily available material out of which the fetus builds
its tissues. Some of the nitrogenous food material together with
nitrogenous waste products can be determined analytically as the
non-protein nitrogen of the fetal blood. It has been found that
non-protein nitrogen concentration of maternal and fetal blood is
practically identicaIZU This suggests that the compounds in question pass through the placenta by simple diffusion.
Amino acids of use to the fetus are relatively simple nitrogi
enous compounds which are soluble in the blood p1asma, and it
is known that they are highly ditkusible The human fetal plasma
at term contains about 2 mg. of amino-acid nitrogen per Ioo cc.
more than does that of its mother. In one 8 month premature infant the dilkerence was greater. This makes it seem probable that
simple physical processes are not the only mechanisms involved
in the passage of amino acids through the« placenta.
In the case of the nitrogenous waste products, ammonia, urea,
uric acid and creatinine, the concentration in the two blood
streams is almost identical and they probably pass from fetus to
mother by purely physical processes.44 Table 25 summarizes some
of the data on human subjects.
, TAVLD 25
Armut-n cost-knister- ops Ntstsnoonuovs coupounvs m sum« Bnoov or« IIUUAN Mosknmis
AND Fsskusns ask Fuhr« Tut-tu«
Motheks blood Fetal blood No. of
mg.XI00 cc. mgJ 100 cc.« cases
Nonsprotein nitrogen . . . . . . . . . . . . . 25.2 24 . 9 85
Amino-acid nitrogen (plqsma) . . . . . . 5.5 7.4 10
7 . 2 II .9 I premature
Urea and ammonia . . . . . . . . . . . . . . . 10.5 I0. 4 16
Uric acid . . . . . . . . . . . . . . . . . . . . . . .. s. 8 8.7 IT
creatinine (plasma) . . . . . . . . . . . . . .« I .67 I .75 I8
- I . 70 I . 78 12
Results of analysis of embryonic tissues throughout the course
of gestation demonstrate that the pig. builds very largely with
FETAL NUTRlTlcN AND METABOLISM 217
nitrogenous compounds during its early prenatal like. The total
nitrogen content ok the body per unit of dry weight decreases
gradually from the 6 mm. to the so mm. stage and then remains
constant throughout the remaining portion ok the gestation
period. The decrease may be related to an increase ok other nonnitrogenous solids such as carbohydrates, lipids and inorganic
salts. At the so mm. stage, when total nitrogen becomes constant,
the embryo may be said to have attained chemical maturityFo
Tut-ti- 26
Aventin Witten-r am) Pvacnivsrhen contain« or· Wann, Ast! am) Nrsraoonu n: PreKarosse«
l
Embryo Ash Nitrogen
Weiter«
Lenglzh Weight P« com; Wes; Dry Wet Dry Ashckree
mm. ging. per cent per eent per eent per eent per eent
24 . . . . . . . . . . . . . . 97 .4 . . . . . . . . . . . . . . . . . . . . . . . . .
647 . . . . . . .. 0 81 94.07 . . . . . . . . ·. 0 699 18 18
l0 . . . . . . . . 0 50 98.87 0 558 8.48 0 861 12 99 14 18
15 . . . . . . . . 0 98 91.88 0 775 9.00 l 061 12 81 18 52
R) . . . . . . . . 2 21 91.14 0 708 8.00 l 108 12 45 18 58
50 . . . . . . . . 6 55 91.65 l 086 12.41 0 910 10 91 12 45
60 . . . . . . .. 014 85 91.05 . . . . . . . . .. 0 966 l0 80
80 . . . . . . .. 26 00 91.59 . . . . . . . . .. 0 915 10 88
100 . . . . . . ·. 722 t 91.l8 . . . . . . . . .. 095 1078
110 . . . . . . .. 82 2 91.02 l so 14.50 0 972 10 82 12 65
120 . . . . . . .. 962 91.26 . . . . . . . . .. 0950 1087
160 . . . . . . .. 288 57 91.71 l 849 i 16.28 0 891 l0 75 12 84
200 . . . . . . .. 488 0 90.84 . . . . . . . . .. l 014 10 50
240 . . . . . . . . 725 0 88.7 2 58 2309 l 288 11 01 14 29
Interesting changes in the various kractions ok the total nitrogen have been observed. No signiiicant variation was apparent in
amide, humin and cystine nitrogen but amino nitrogen concentration was increased and that ok the non-amino nitrogen decreased correspondingly during the early stages. There was a kall
in arginine and histidine nitrogen and a deiinite rise in lysine
nitrogen before the 30 mm. steige. Tyrosine showed a gradual
decline throughout development. Glutathione, which is thought
to aid in synthesis ok proteins, increased sharply until 30 mm.
had been reached, after which it gradually decreased. Reciprocal
ontogenetic variations in the nitrogenous substances arginine,
histidine and lysine have been compared with somewhat similar
218 PHYsIoLocY oF THE FETUS
phylogenetic variationsPfs E! They may be correlated to some ex—
tent with observations on tumor tissues, from which it appears
that the younger types of neoplasms have the greater content of
arg1n1ne.
Many attempts to study nitrogenous excretion in 1namma1ian
fetuses have been made without notable success. It is impossible
to account for all the nitrogen excretion because the greater part
is passed through the placenta, dissipated in the mother’s blood
and removed by her lcidneys. some, but only a small part, is
excreted by the fetal mesonephros and metanephros (see Chapter
VI1l) and passed into the allantoic and amniotic fluids which can
be recovered for analysis.
The urea content, in milligrams per ioo grams of human embryo, has been estimated to decrease as the gestation period advancesLo The amount of nitrogen per gram of fetus which is
excreted into the fetal fluid of the ruminating mammals is lilcewise
high in ear1y prenatal life, but decreases sharply and then remains
at a low level throughout the greater part of gestationFfs I» A much
clearer picture of nitrogenous metabolism of the embryo has been
obtained from studies in the chiclc. There. a closed system makes
it possible to obtain all the nitrogenous wastes which- accumulate
in the allantoic sac.59-10 Uric acid begins to collect in the allantois on the iifth day of incubation. The chiclc makes eflicient
use of the available protein, for about 96 per cent of that absorbed
from the egg by the embryo during the first 13 days of incubation
is retained in the embryonic tissues. Some protein is burned by
the chiclcz in fact about« 6 per cent of all organic matter used for
energy during the first two weelcs of incubation is protein.
0ne of the most interesting aspects of fetal protein metabolism
is its comparative embryologysw Protein materials are used for
energy in much greater amounts by embryos with an aquatic
habitat than by those which are terrestrial. We may classify
mammalian embryos in the aquatic group with those of ftshes,
amphibians and many invertebrates, for they pour out their ex—
cretions through the placenta into the limitless aqueous environment of the mother’s blood stream and l(idneys. The terrestrial
group includes birds, some reptiles (e.g., lizards, snakes) , arthro—
pods (e.g., insects) and molluslcs (e.g., land snails) . Aquatic
embryos excrete nitrogen principally in« the— forth of ammonia and
FETAL NUTRITION AND METABOLISM 219
urea which are very so1ub1e and diffusible end-products and require excessive use of water for their e1imination. From a teleo1ogical viewpoint, one may say that the terrestrial forms must conserve water and consequently have had to devise other methods
of excreting nitrogen. Uric acid is the end-product in these
embryos. If birds had retained urea excretion instead of resorting
to uric acid, and if they had to store it all, their tissues would soon
become high1y saturated with urea because this substance can
dilfuse through the allantois into the body whereas uric acid is
retained, concentrated and precipitated within the allantoic sac
as the water is being absorbed and utilized. In their early development birds recapitulate aquatic stages in respect to their
protein metabolism. During the first 5 days of incubation ammonia and urea are excreted, but on the lifth day a shift is made
to uric acid and the embryo is thus spared a uremic fate.
IN ORGANIO IVIETABOLISM
It is lcnown that copper is stored in the human Iiver and its
concentration and absolute amount is higher there at birth than
at any subsequent time. Its concentration is greater at birth than
at earlier prenata1 periods.34 copper is essential for hemoglobin
synthesis and its mobilization in the fetal liver is thought to assure
normal blood formation in the postnata1 nursing period during
which the diet is delicient in this element. In contrast to conditions in man it has been reported that the late fetal pig liver
shows no increase in percentage of copper as growth proceedsPsH
The copper reserve of the liver is unusually low in the goat at
birthFS In the incubating chick too the percentage of copper
in the liver declines from the izth day to hatching, although
there is an increase in the actual amount present in the liver
throughout» The difference between pig, goat and chick on the
one hand and man on the other may be explained ,on the basis
of placental permeability. The chiclc must utilize what store it
has in the egg, the pig and goat get their copper from the histotrophe, but man, having a true placenta in which contact between
maternal and fetal blood streams is intimate, may be able to draw
heavily upon maternal stores.
It has been suggested that catabolism of maternal hemoglobin
talces place in the human placenta to supply the pigment fraction
220 PHYSIOLOGY OF THE FETUS
of the hemoglobin molecule intact to the fetal circulationKs The
iron content of the human placenta gradually increases during development.59 Iron is stored in« the liver during fetal life and for
about two months after birth during which time there is an active physiologic postnatal hemolysis. Thereafter it declines in
amount until the nursing period has passed.s4 Iron is excreted in
the bile but is absorbed again in the fetal intestines.«4 As is true
of copper, the iron reserve of the goat is low at birth," and the percentage concentration of iron declines in the liver of the incubating chicl(.37 The ratio of copper to iron in the chiclc’s tissues,
other than the liver, stays constant throughout incubation. Nonhematin iron in the tissues is small. The metals are utilized and
not stored in such large quantities in the liver for postnatal use
as they are in the human fetus.
The efkect on fetal rats of iron deficient diets fed to the
mothers has been investigated recently.·3«0- S! The first pregnancy
brought on marked depletion of maternal liver iron but there
was no anemia; with the advent of a second pregnancy an anemia
did appear. The first litter of rat pups had normal hemoglobin
values, but a reduction in total iron content of the entire body
by about one-half the normal was evident. The second litter
exhibited a reduction of the hemoglobin of the blood and the
total iron content was only one-fourth normal. studies in the
human« reveal that iron deficiency of the fetus may be related
to that of the mother. Infants which are born of anemic mothers
may exhibit hypochromic anemia during the first year. The normal full term infant has a good reserve of liver iron which is
probably fully as important to it as the iron it may salvage from
catabolism of its excess hemoglobin during the early postnatal
period. If it were not for this fact, the human infant would probably exhibit more symptoms than it does when deprived of placental blood by the commonly practiced prompt c1amping of the
umbilical cord at birth.
A large series of chemical analyses of human fetuses has been
summarized recently by swanson and Iob.02 content of nitrogen,
calcium, iron and phosphorus throughout the greater part of prenatal life is illustrated in Fig. 69. The retention of these materials
shows a similar pattern of gradually increasing quantities. The
results indicate that there, can— be lit·kle··demand upon the mother’s
FETAL NUTRITION AND METABOLISM 221
« zoo
M
 
PHOSPHORUS
2»L
   
s o
34587690345670910
Dom-r« »oui«-ZFig. 69.- tent ok nitrogen, iu1n,iron and phospho ok the hutnan ketus
between the « c! th and bitt . (swanson sc lob: Am. . bst. sc. cyn., Vol. 38,
1939. c. V. Mosby .
Fig. 7o.-E.tk ok changes in the cliet ok pregnant rats on calciu ncl phoss
phorus content o eolksprinz (swanson Z: lob: Arn. J. Obs . sc Gynsp . 38, 1939,
c. V. Mosby co.)
222 PHYSIOLOGY OF THE« FETUS
reserve of the elements in question during the first halk ok presnancy. In kact it is not Juntil the last two or three months ok
gestation that the ketal requirements become large.
calcium and phosphorus are concerned in building skeletal
structures. Their content in the ketus is iniiuenced by vitamin D
in the mother’s diet and apparently by the amount ok exposure to
sunlight.s«4 The eEects ok changing the diet ok pregnant rats
in respect to vitamin D are illustrated in Fig. 7o. When the
mother’s diet, fortiiied by vitamin D, is low in the required
minerals the calcium and phosphorus content ok the ketal body
approaches the normal level, but when the diet has in it the required amounts ok the minerals plus the vitamins the ketal calcium
and phosphorus content exceeds the normal. Thus the ketal
metabolism ok calcium and phosphorus is dependent upon that
ok the mother and the transmission 'ok these substances to the ketus
can be increased by vitamin D adminis·tration. In the human
subject occurrence ok early congenital riclcets is illustrative ok
maternal deiicienciesXE
Metabolism ok inorganic substances other than those we have
already considered has been studied less eictensively. The most.
marked changes in all inorganic compounds are encountered in
the kourth lunar month in man. Bekore that time the ketus contains relatively little chlorine, potassium, sodium and magnesium,
but these elements show a marked increase at the kourth monthFs
ENERGY METÄBOLISM
Oxygen consumption in the ketus has been studied in various
species and by various methods. The most signikicant data relative to amount and rateok utilization have been obtained in the
incubating chiclc and in the sheep ketus. The amounts ok oxygen
used and ok carbon dioxide given oE by the incubating chicl(·increase in proportion to growth in size ok the embryo. At six days
ok incubation oxygen is consumed by the embryo (exclusive ok
its membranes) at the rate ok o.o2 cc.Jgrn.Jmin. This rate de—
clines as growth proceeds and by the nineteenth day reaches
o.oi34 ccJgrnJminFC Barcrokt and his colleagueswi have estimated the rate ok oxygen consumption in the sheep ketus recently
by a direct method. They obtained samples ok ketal blood at
timed intervals akter occludingthei umbilica1 cord and determined
FETAL NUTRITION AND METABOLISM 223
its oxygen content. In this way they observed the loss of oxygen
in respect to time and could calculate its utilization per gram ok
the ketal tissue without the complicating kactors ok the placenta
and ketal rnembranes. Their data appear in Table 27. It will
Tat-m 27
Oxford: conswrrtorc m sauer« Ferner-s
Oxygen eonsumption
Fetal age Fetal weight
days grams
cc.-mirs. cc.Xgm.Xtain.
III . . . . . . . . . . . . . . . . . . ·. I,200 4.6 0.0038
126 . . . . . . . . . . . . . . . . . . . .I 8,000 I2·s 0.004I
127 . . . . . . . . . . . . . . . . . . . . 2850 II .2 0. 0089
129 . . . . . . . . . . . . . . . . . . 2750 SZL 0.008I·«
Is7 . . . . . . . . . . . . . . . . . . . . 8,850 20.0 00052
138 . . . . . . . . . . . . . . . . . . . .k FOR) I5.5 0.0042
152 . . . . . . . . . . . . . . . . . . . . 2800 I6.4s 0.0048·«
’«'Authors’ values; errors present but souree unless-wo.
be seen that, although the total amount ok oxygen consumed
each minute rises sharply at the beginning ok the last quarter
ok gestation, the rate ok utilization remains nearly constant
throughout the period studied and averages o.oo43 cc.xgrn.jmin.
(excepting the 129 day ketus) . This is a higher value than was
obtained in earlier less satiskactory experiments in the Cambridge
laboratoryss and by other investigators who have used indirect
methods o»k estimation. The oxygen consumption ok human
ketuses at terms bekore labor starts has been estimated to be
1.25 ccJkiloJminO
The ratio ok the amount ok carbon dioxide given olk to that ok
cc. carbon dioxide
cc. oxygen
embryos ok several species. This, the respiratory quotient, varies
signiHcantly in the chiclc. Most deterrninations during the Hrst
tive days ok incubation have given values in excess ok o.7, some
ok them approaching unity. In vitro experiments on the iive
day chiclc have demonstrated that the quotient is 1.o at this
time« Between the sixth and ninth days ok incubation the respiratory quotient declines to approximately o.7, but it rises again
toward unity between the tenth and thirteenth days. These fluc
oxygen consumed ( ) has been determined in
224 PHYSIOLOGY OF THE« FETUs
tuations have been talcen to signify that the embryo utilizes carbohydrates almost exclusively for combustion up to five days, burns
proteins very largely for the next few days and after the tenth
day of incubation resorts to combustion of fat supplemented by
rather large quantities of carbohydrateJo It should .be pointed
out that in the chiclc, which excretes uric acid instead of urea after
the lifth day, a respiratory quotient of o.7 rather than o.8 should
be expected during combustion of proteins. For more detailed information, the reader should refer to original articlesJos W- ««
The respiratory quotient of guinea pig fetuses has been determined74 by direct measurement of the oxygen consumption and
carbon dioxide evolution of the mother and her fetuses in utero
before and after occluding the umbilical cords. Quotients of o.9
to 1.2 were obtained for the fetuses in most instances, and o.7 to
o.9 in the mother. Coniirmatory results have been obtained by
others« in experiments using whole rat embryos in vitro (mean
R. O. .—.—. I.o4) . Respiratory quotients of this nature indicate that
mammalian fetuses consume carbohydrates almost exclusively in
their energy metabolism.
Many investigators have studied metabolism during pregnancy.
especially in man, by indirect calorimetric methods.10 Mur1in75
observed a dog during two consecutive pregnancies, one pup being
produced at the lirst and live pups at the second birth. An in—
crease in caloric energy production due to the single fetus could
be detected at the sixth weelcz it amounted to 9 per cent between
the sixth and eighth weelcs. The total energy produced at full
term was proportional to’ the weight of the offspring and was about
equal to that required by the newborn pups (when calculated according to the law of slcin area·) . It amounted to 16.4 gm. cal.J1oo
gar. in the single pregnancy and 16.8 gm. cahxioo gar. in the
multiple pregnancy. The curve of total energy production of the
dog and her pups showed no deflection at birth. The number of
calories formed by the resting pregnant dog plus fetuses, placentas
and membranes was very much the same as the sum of that produced after delivery by the lactating dog and her resting pups.
In the human not all investigators have found relationships
quite so simple as those occurring in Mur1in’s experiments in the
dog. some« have reported that excessive heat production in
pregnancy results from some factors other than those of fetal
FBTAL NUTRITION AND METABOLISM 225
growth. 0thers"- 78 have been able to account for all of the ex—
cess on the basis of fetal heat production, fmding that the energy
produced by the woman plus her fetus and its accessory structures
at full term is equal to that produced by the lactating woman
and the infant after birth. Recently, Enright and her associatessp
reported that a greater post-partum drop in energy metabolism
than is accountable on the basis of that produced by the fetus
alone occurs in i 5-year-old females, amounting to about three
times the probable basal energy requirements of infants. They
concluded that in pregnant adolescents there appears to be some
factor stimulating metabolism which results in a greater rise than
occurs in more mature women. They suggested that this excessive energy production of immature -girls may be related to thyroid
function, and have presented some evidence that feeding iodized
salt diminished the rise in metabolism during pregnancy.
One point which has not been emphasized is worth consideration. The fetus in utero is quiescent and hypotonic whereas the
newborn infant is active and its muscles possess good tonus. If
the energy produced by the newborn is commensurately greater
than that of the full term apneic, hypotonic, quiescent fetus use
will have to conclude that more energy is produced by the woman
(plus the accessory fetal structures but minus the fetus) than is
produced by the post—partum lactating woman. The alternative
assumption is that basal requirements of the hypotonic fetus are
fully as great as in the newborn infant, and this seems unreason—
able.
The various calorimetric studies suggest that the fetal metabolic rate remains fairly constant throughout the latter part of
gestation, but during the early period while the embryo is very
small no data are available« Postnatally the rate rises and reaches
a pealc at about the Erst or second year in the human. similar
postnatal pealcs have been observed in other animals such as the
rabbit, mouse and some breeds of pigz others, notably the guinea
pig, show an already declining metabolic rate at birth. These
facts may be related to the maturity of the heat regulating mechanisms in the different species (see chapter VIII) . They suggest
«« Oxygen consumption of mammalian eggs during the one— to eightscell stages
ainounts to o.ooo7z c.mm. per egg per hour. When gkowth in size begins the oxygen
oonsumption increasesz on the eighth day of gestation in the rat it amounts to about
«o.o1 c.mm. per hour. This increases to about o.2 drum. in the next two days«
Is
226
PHYSIOLOGY OF THE FETUS
that the metabo1ic rate may in rea1ity be increasing to some ex—
tent throughout prenatal like in man and in the other animals
with a postnatal pealc ok heat production and may have begun to
decline in the others before birth.
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{{Footer}}
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Windle WF. Physiology of the Fetus. (1940) Saunders, Philadelphia.

1940 Physiology of the Fetus: 1 Introduction | 2 Heart | 3 Circulation | 4 Blood | 5 Respiration | 6 Respiratory Movements | 7 Digestive | 8 Renal - Skin | 9 Muscles | 10 Neural Genesis | 11 Neural Activity | 12 Motor Reactions and Reflexes | 13 Senses | 14 Endocrine | 15 Nutrition and Metabolism | Figures

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Chapter X The Genesis of Function in the Nervous System

THE beginning of functional activity in the nervous system has been investigated most thoroughly in embryos of the rat,I-4 guinea pig,5- S sheepfs 8 and cat,9-13 and less completely in man14s 15 and other mammals.10-I7 studies in the lower vertebrates,18-22 especially amphibia, have influenced conceptions of behavioral de— velopment in mammals to a very considerable extent. A complete review of all articles on the subject of early fetal movements would require far more space than is available in the present chapter.



Fig. 47. Embryos of the (A) rat, (B) cat and (C) human at approximately the stage in development at which simple rellexes are expected for the first time. crownckump length: 12 mm. rat; 14 mm. cat; 18 mm. human (7 weeks). Magnificatiom X Z.


1t is impossible to say precisely when nerve cells attain the ability to discharge or when kibers can conduct nervous impulses for the first time. However, muscle contractions induced by nervous activity can be elicited surprisingly early in prenatal life. The stage at which nervous function is first observable in mammals varies to some extent, but in all species that have been investigated it is before body form has talcen on the characteristic appearance of the species. In other words, somatic movements start before the close of the embryonic, rather than in the fetal period. This is illustrated by the accompanying photographs of rat, cat and human embryos talcen at about the time simple reHexes can first be induced (Fig. 47) .


The initiation of function in slceletal muscle cells was considered in the preceding chapten Myogenic xesponses precede reiiexes by at least one day in most mamma1s. The development of muscle iibers and of motor nerves with simple epilemmal motor nerve endings goes hand -in hand, but there does not seem to be an immediate correlation between the appearance of motor end— ings and Csunctional reflexes as some have suggestedks From the structural point of view it is possible that muscle contractions can be induced by discharge of motor neurons before reflex arcs have been completely formed. With the advent of conduction from afferent to efkerent neurons through synaptic centers, reHex re— sponses to stimulation are manifested. At this point in deve1opment behavior may be said to have its genesis.

Myogenic Responses

Let us examine the antecedents of behavioral genesis in somewhat gyeater detail. spontaneous muscle twitching characterizes embryos of certain lower vertebrates before reHex excitation becomes eifective. 0bservations in fishes are especially notable.I9 The similarity to spontaneous contractions of myob1asts and muscle iibers in cultures of embryonic chiclc tissues is striking. It is possible that some of the earliest spontaneous movements »observed in the intact living chick embryo1S-21-24-25 are of this nature.


No comparable phenomenon has been seen in .mammalian embryos studied under normal physiologic conditions. However, the movements which manifest themselves in ionically unbalanced saline solutions probably are myogenic responsesKs Why spontaneous muscle twitching is not encountered normally in mammalian embryos has not been determined. Musculature is laid down well in advance of the time it can be activated reflexly in the rat, guinea pig, sheep and cat.


Mechanical and electrical stimuli applied directly to muscle masses of intact embryoX efkect contractions readily. Microselecs trodes constructed of Hne nichrome wires insulated except at the tips serve admirably for deliveringdocalized faradic shoclcs. Contractions of the embryonic slceletal muscles induced in this manner possess certain characteristics which distinguish them from other types of somatic movement. They are as follows: (a) a minimal stimulus, just adequate to produce a response, gives rise to a quiclc contraction followed by a slower relaxationx (b) each succeeding stimulation produces a similar contraction, for there is no noticeable interval of fatigue during which the muscle is re— fractoryz (c) the contraction is remarlcably well localized in a small region immediately around the tips of the electrodes and consequently -movements in several planes can usually be brought about by shifting the Position of the electrodes; (d) the embryonic muscle tissue retains a high degree of excitability irrespective of great changes in metabolic conditions. In fact, specimens which have been allowed to bleed until white, which have cooled to room temperature and in which the heart has practically stopped beating still respond to direct stimulation of the slceletal musculature.


All the muscles of an embryo do not simultaneously reach a state of development in which contractions are possible. The first in which such direct responses can be observed are those ok the forelimbs at the attachment to the body. With advancement of growth,.excitability spreads both rostrally and caudally as well as distally from these points.

Neuromotor Responses

The second step in development of behavior is thought to be the appearance of muscle contraction in response to. excitation of motor neurons.27 Nerve endings of a primitive lcind (Fig. 45) are present upon developing muscle übers at a time when the only somatic movements are those which follow direct skimulation of the muscleskss 29 Although it has been impossible to obtain direct evidence in the youngest cat embryos that purely neuromuscular contractions precede rellexes, such contractions can be demonstrated in specimens a little more advanced, in which reflex responses are already obtainable. After the reflexes have died away with deterioration of the· physiologic oonditions of the embryo, stimulation of motor centers produces movements. A s1ender and sharp dental broach was used to pierce the tissues of the back and the spinal cord of the embryos. It was found that a backward movement of the forelimb followed when the instrument was passed into the spinal cord at the level between C.7 and T.1 and a forward movement resulted in the same specimens when it was inserted at the level between c.4 and c.6. The true reflexes which had been obtained previously were all baclcward and outward movements of the 1imbs. Thus it is apparent that a new forward movement of the arm had been induced by direct stimulation of a motor center before such a movement occurred as the result of retlex stimulation of afferent nerves. It is especially noteworthy that the responses were localized and that there was no diffuse spreading of excitation through the center even with this rather crude form of stimulation. The segmentaL nonintegrated character of the motor ce11 column of the embryonic spinal cord, so clearly evident in silver-stained histologic preparations, is demonstrable by physiologic methods.


Genesis Of Reflex Behavior

The third step in behavioral development is characterized by the appearance of reflexes. These do not manifest themselves unti1 atkerent and efferent neurons, simple nerve endings in peripheral tissues, connector neurons in the central nervous system and functional synaptic central mechanisms have been formed.


There are essentially two conceptions of the development of behavior in mammalian embryos. 0ne group of investigatorsY II· IS believe that they have demonstrated the genesis of reflexes by a process of individuation from a fully integrated mass reaction or «total Patter·n." In other words, they believe that more or less discrete movements are not the primary units of behavior but that local reflexes difkerentiate from a more fundamental baclcground of massive movement. Another group of investigatorsws 30 hold the opposjng view that the basic elements in the genesis of mammalian behavior are relatively simple reliex re— sponses. They lind that the more complex reactions of older fetuses are formed by progressive neuronal integration of the less complicated activities of the embryo. some other investigators 2 maintain that both theories are partially true, but are inclined to kavor the former.

The Concept of a Total Pattern

The doctrine of development of behavior from a total pattern is based on a long series of correlated physiologic and histologic studies by coghill in the urode1e amphibiam Amblystoma, ap— pearing frequently since 1913 and summarized in his London lectures. 18 It was found that a motor mechanism develops on either side of the embryonic floor plate as a longitudinally conducting system of neurons. Each neuron extends a process caudally to the next one; from this Process branches run to the muscles of the baclc and later to the 1imbs. Thesseries of neurons constitutes an integrating motor system which is laid down before kunction appears. An integrating s«ensory system is kormed by temporary neurons, the Rohon-Beard ce11s in the dorsal portion ok the spinal cord. They too send out processes, but in a rostral direction, with branches running to the epithelium and the muscles. The motor and sensory systems become connected by commissural fioorplate neurons, appearing iirst near the rostral end ok the embryo. These relations are illustrated in Figs. 48 and 49.



Fig. 48. Diagram of the sensoryimotor mechanism of the Salamander embryo which acoounts for the cephalwcaudal progkession of movement away from the side stimulated Arrows indicate direction of conductiom (Coghi11: "Anatomy and the Problem of Behavior," Cambridge Univ. Press.)


Fig. 49. Diagram of the neuromotor mechanism ok the Salamander embryo which allows an initial irnpulse (a, w) to be kollowed by a oontralatetal secondary Impulse (c, X) through an intermediate connecting neuron (b) . This makes pos— sible the swimming rnovernents like those in Fig. He. (coghi11: «Anatomy and the Problem ok Behavior," cambridge Univ. Press.)


A stimulus which is applied to one side of the embryonic salamander sets up impulses which are conducted rostra11y in the sensory System, across the· kloopplate neurons near its rostral end, and then caudally in the integrating motor System. contralateral flexion is thereupon the iirst true» behavioral responsez it is a mass movement or fully integrated response ’from the very start. This reaction is iliustrated in a series of drawings taken from a motion-picture record« (Fig. Ho) . The single flexion stage is followed shortly by bilateral ilexion and then by typical swimming. The latter depends upon the appearance of collateral branches of motor neurons (Fig. 49) which allow the caudal1y flowing impulses of one side ·to precede those of the other. In this way two waves of movement can course down the trunlc as shown in Figs. 51 and 52. 0ne response coming upon another in this manner produces forward propulsion of the embryo, establishing aquatic locomotion.



Fig. 50. Serial tracings from motion pictures (frame numhers indicatety of the earliest contralateral movement in response to stimulation of a Salamander embryo. The neural mechanism involved is illustrated in Fig. 48. (Coghill: "Anatomy and the Problem of Behavior," cambridge Univ. Press.)


Later, as the 1imbs grow out they first move with the trunlc passively but ultimately acquire independence. Limb movements may thus be said to individuatefrdm the mass movement of the trank. Terrestrial locomotion, the feeding reaction and other activities are made possible by brealcing up of the original total pattern or by the formation of segondary patterns within it. 0ther more discrete reflexes individuate from these patterns as development proceeds. « An independent and integrated motor system is present in fishesfor some time before it is captured by developing sensory mechanisms. During this period of independence the motor system can respond to changes in the internal but not the external environment. 19



Fig. 51. Serial tracings from motion pictures of the early swimming stage of a Salamander embryo. Resting position in 1 and to. (Coghi11: "Anatomy and the Problem of Behavior," Cambridge Univ. Press.)


Fig. 52. Three diagrams to; show the development of the first and subsequent waves of contraction which result in swimming in the Salamander embryo. (Coghill: "Anatomy and the Problem of Behavior," Cambridge Univ. Press.)



In 1929 Coghillsl lattempted to explain behavior in human embryos studied by Minlcowski32 and others in terms of the total pattern of the Salamander. He concluded that behavior in man follows a developmental plan of a similar type. Some of the earlier systcespmatic studies on development of fetal movements in other mammals2s 9 suggested very strongly that nearly all embryonic motility develops from mass reactions resembling total patterns. The more recent interpretations of these observations will be discussed in the latter part of the present chapter.


Human and other mammalian embryos are so very different from Amblystoma at the time movements and reflexes first appear that it is surptising to find any functional similarities. The larval Salamander develops its total reaction and precisely integrated side to side waves of movement within this integrated pattern before limbs and mouth have been formed. Mammalian embryos are far from having attained functional age at a comparable stage in morphologic dilferentiation (compare Figs. 47 and Ho) . Muscle is entirely l·aclcing. Within the embryonic central nervous system of mammals no structures exist which are comparable with the chains of transient afkerent Rohon-Beard cells of lower forms. Furthermore, the motor neurons are arranged segmentally rather than in longitudinal series and they do not appear to be connected with one another. The ear1iest secondary neurons of the spinal cord build tracts that are predominantly ascending pathways. 1n the brain, the descending tracts send few übers into the spinal cord until spinal behavioral responses have become established. 33-36 * In other words, there is no longitudinally integrating mechanism in the spinal cord of mammalian embryos at the stage in development which corresponds to the early motile Amblystoma; nor is there until some time later. By the time dikkerentiation of structure makes functional activities possible the head and limbs have become prominent structures.


  • Recently Angulo 37 has reported that the media1 longitudinal fascicle of the spinal cord is the descending integrating tract for the mass reaction of the rat embryo and that its termination forms the ventral spinal commissure. This is at variance with our own observations which show that the ventral commissure fibers arise in the spinal cord and ascend in the vgntral funiculus.



In the further course of development of mammalian embryos these parts exert an ever increasing dominance over the trunk, and growth in the nervous system responds to this dominance. There is never a need for the type of aquatic locomotor total pattern which is found in the iishes and amphi«bians.

Early Reflexes in Mammalian Embryos

True behavior makes its appearance about one day after it was Erst possible to elicit muscle contractions in embryos of the rat, guinea pig, cat and sheep. It is essential to emp1oy experimental methods which do not impair the physiologic conditions of pregnant animals and their embryos to observe the tirst reflexes. Furthermore, studies must be conducted immediately upon opening the uterus because this operation invariably interferes with placental respiratory exchange, resulting in anoxemia. The procedures used in such studies have been discussed in the first chapter.


Although the description of early reflex responses which follows pertains primarily to cat embryos about 14 mm. crownrump lengthP similar results have been obtained in other mammals. 3,4,6,7 When an embryo with placenta still attached to the uterine wall has been brought quickly into view and the intact amniotic sac is percussed witli some blunt instrument, pressure transmitted to the embryo through the amniotic fluid results in quick outward and backward movement of the forelimb. The movement may be called a twitch or jerk. similar responses are obtainable in other ways. Flipping the limb gently with a needle or a hair passed through the amnion serves equally well. In a few instances it was even possible to elicit this reaction by lightly touching certain points upon the forelimb. Furthermore, faradic shocks applied to approximately the same points by means of micro-electrodes gave rise to similar quick outward and backward movements of the limb.


Another reaction is frequently elicitable in embryos 14 mm. long. stimulation of the forward end of the head. especially the snoutz results in extension of the head. When the stimulus is applied to one side ok the midline the head moves toward the opposite side and baclcwardH When the tip ok the snout is stimu1ated it moves baclcward. Because this head response is more resistant to changing physiologic conditions than that of the korelimb it usually persists a little longer. Under the best conditions it too is a quiclc movementz It has been observed by all investigators, although some have encountered it at an earlier stage than others.


The head and forelimb responses are entirely separate and distinct from one another when they iirst appear. They difker somewhat in respect to the types of stimulation eliciting them but both seem to require stronger stimuli at first than they do at a slightly later stage in development. The head movements, being contralateral and involving muscles some little distance away from the site of stimulation, are certainly reflexes. All observers agree on this point. However, some have doubted the reflex nature ok the korelimb reactions, holdingsthat they may be due to stimulation ok the muscles directly. The evidence, which will be reviewed brieilyy kavors the view that they too are simple spinaltype reflexes.


Although the limb muscles can be induced to contract by direct stimulation in asphyxiated embryos, the response held to be a reflex is (a) elicitable kor only a briek interval (okten only a kew seconds) while« metabolic conditions ok the embryo are at their best. states of anoxemia set up experimentally make it impossible to obtain the reactions. Akter adequate direct stimulation the new muscle tends to relax slowly, whereas the reflex-like response (b) seems to be a quiclcer movement with more rapid relaxation. Embryonic muscle appears to respond instantaneously to directly app1ied stimuli, but (c) there is an interval just perceptible between stimulus and response ok thexeiiex type. 0ne muscle contraction after another can be induced by direct stimulation, but (d) a second reflezklilce reaction cannot be made to kollow the Erst one until a briek interval ok time, a rekractory or katigue period, has elapsed. Finally, (e) the responses believed to be reilexes are stereotyped and do not show the molding characterizing direct contractions when the position ok the stimulus is varied.


Other experimental evidence demonstrates that the korelimb movements are reflexes. When xtiicroelectrodes are used to stimulate an embryo over the spinal cord some distance caudal to the forelimb, the same quiclc outward and baclcward twitch results. This is due to conduction up the spinal cord; stimuIation of other parts of the embryo, equally distant from the limbs, does not produce this movement. At least one synapse is involved as indicated in Fig. 53.


Fig. 53. Diagram illustrating the probable nervous elements involved in elicits ing forelimb movement by faradic stimulation of the spinal cord of an early mammalian embryo.


The conception of the refiex nature of the early forelimb response iinds further confirmation in histologic studies in the spinal cords and peripheral nerves of the very specimens which showed the reaction and which were subsequently stained by the Ranson pyridine-silver techniquekss THE All nervous elements essential for reflex action are present in the embryonic spinal cord but their intrinsic synaptic connections are incomplete at the time muscles can be made to contract by stimulating them directly and previous to the appearance of the reliexdilce responses. 0ne iinds alferent neurons whose peripheral Ebers pass to the tissues immediately beneath the' epithelium of the forelimb and whose central branches constitute the dorsal roots and dorsal funiculus of the spinal cord. The efkerent neurons are assembled in two groups in the ventral gray matter of the spinal cord, a medial nucleus for trunk innervation and a lateral nucleus for the arm. The efferent axons courses into the muscles of the shoulder region and end in simple terminations upon some of the muscle übers. Commissural and associationa1 neurons are present in the dorsal column. ,The former are numerous in the region just beneath the dorsomedial border of the dorsa1 funiculus, while the latter tend to accumulate nearer the ventrolateral border of this afferent pathway. Commissural axons pursue a course ventrally through the gray matter and cross the kloor p1ate, to become an ascending tract close to the motor nerve cells which supply the trank. Associational axons pass close to the motor nucleus for limb muscles and enter the Iateral funicu1us. This relation of associational neurons and primary motor forelimb neurons appears to be very intimate, with axons of the former coursing parallel with dendrons of the latter. However, up to the time of appearance of the forelimb response there is no close re1ationship between the primary afferent and the secondary neurons (Fig. 54) . A few collatera1 branches of dorsal funiculus fibers do pass for a very short distance toward the associational group, but not many have reached it.



Fig. 54. Photo1nicrograph of the fifth cervical Segment of the spina1 cord of a 13 mm. cat embryo just before the time the Erst forelimb reflexes can be elicitedx as» Ventral funiculus; tut» association neurons; c» cornmissurex ern» Commissural neurons; ihn, dorsal root and ganglionx M» Iateral funiculusx m.l., motor nucleus for the limb muscles; Max» motor nucleus for the trunlc musclesz p.f., dorsal funiculus. Compare with Fig. 56. Pyridinesjlver stainz x 80.


In the early motile embryos in which reilezklike twitches of the forelimb occurred when the limbs were flipped or when the amniotic sac was percussed, connections have been comp1eted be— tween the primary afkerent and the associational neurons. This accomplished when collateral branches grow in among the cells of the dorsal gray horn from the sensory Hbers nearest the lateral border of the dorsal funiculus Some of the longest collaterals enter the nucleus of motor cells supplying the forelimb musc1es. These relationships will be seen in accompanying photomicros graphs (Figs. 54 and 55) and diagrams (Figs. 56 and 57) . The organization of the first structural reflex mechanism is clearly such that when it begins to kunction the response will not only be homolateraI but will be conlined to the segments at which the impulses enter the spinal cordx The greatest number and the longest new collaterals first grow into the gray matter in the brachial region and, correlatively, one linds the first reflex response involving the forelimbs.


Fig. 55. Photoicrograph of the dorsal funiculus (zt).j.) f the spinal cord of: a 13 mm. cat embryo showing the Erst collateral branches (col.) of primary aikerent neuronsz these serve to complete the first spinal reflex arcs. Pyridine-silver stain x 510.


Fig. 56. Camera lucida tracings ok the dorsal roots (d.s·.) and dorsal kuniculus (d.f.) ok sheep embryos M) Do mai» (B) 23 kam» and (c) 24 nun. long. The developrnent ok collaterals (col.) ok the dorsal kuniculus which curve rnedially around the gelatinous substance (gel.) ok the gras matter is correlated with the appearance ok the tirst korelitnb retiexes. Pyridine-silver stainz X 72.


Fig. 57. Diagrammatic cross Section through the embryonic spinal cord just before (lekt side) and just after (right side) the completion ok reilex arcs malte the earliest retiexes e1icitable. The earliest connections ok aiketent neurons (·a) appear at the lateral end ok the dorsal kuniculus and complete unisegtnental reklex arm. some ok these involve an interneuron but others (c) make direct connections with the pritnary motor neurons kor the limb rnuscles. Only later do the dorsal kuniculus übers krom lower segtnents ok the spinal cord connect with the Commissural interneurons by means ok collaterals O) and thus etkect contralateral trunk movements.



The correlation between completion of anatomical reflex arcs in the spinal cords of cat embryos and the manifestation of forelimb reiiex function has been confirmed in the chiclc, rat and sheep. The stage of development reached in the spinal cord of these four species at the time reiiexes appear varies to some extent, but the responses occur in all at the time reflex arcs are ready irrespective of other structural variations.


such evidence as has been disclosed by the correlated histologic and physiologic experiments reviewed here briefly leads to the conclusion that the early foreIimb movements are local, uni— segmentah homolateral two- and three—neuron reflexes. Mammalian behavior has its genesis, not in a mass reaction or total pattern like that of lower vertebrates, but in these relatively Simple reilexes which are at first entirely nonintegrated.

Other Simple Reflexes and Their Integration

During the course of development of cat embryos, many re— flexes malte their appearance. Just as the first responses at the shoulder can be elicited before the limbs move spontaneously and before they move with the neclc and trank, local reilexes appear at the elbow and wrist joints as separate entities before the distal portions of the« limbs become integrated with other parts of the body. Local flexion at the elbows occurs at about the 16—mm. steige. It is often followed by other more distant movements, such as bending at the shoulder or extension of the head and flexion of the trunk. However, these more proximal and cephalic movements are not followed by rnovement at the elbow at this time. similarly, local wrist movements seen in embryos about 17 mm. long, are at first unrelated to other movements.


Local movements at the proximal hind-leg joint, unintegrated with trunlc responses, are encountered in specimens between 15 and 16 mm. long. Those at the lcnee appear at 17.5 mm. The earliest independent motility of the tail is found at the same stage.


Although the first head reilexes can be elicited by stimulating only a small area near the tip of the snout in embryos 13—14 mm. long, it is but a short time later that they occur in response to stimulation of most of the facial area. In specimens 15—16 mm. long, contralateral head flexion is obtainable from all parts of the face except that supplied by the ophthalmic division of the trigeminal nerve. From the ophthalrnic region, extension with flexion to the same side occurs. With further developmenh stimulation of more and more Portions of the face leads to the homolateral response until, at about the 20 mm. stage, only the ear gives a contralateral head flexion.


These and other interesting reflex sactivities have been observed in embryos. All possess an element of individuality at first, but ultimately most of the local responses are brought together into more generalized movements. This comes about by integration within the frameworlc of a growing central nervous mechanism. Longitudinal tracts of nerve ftbers develop within the spinal cord, and as they make connections with afkerent and efkerent neurons they begin to exert an integrating function over the local, isolated reactions.


The earliest secondary pathway in the spinal cord is a ventral longitudinal bundle, primarily an ascending tract formed by the axons of commissural neurons. Impulses carried by it apparently are able to discharge motor neurons supplying trunk and neck musc1es at more rostral 1evels. Cel1 bodies of the commissural neurons, lying near the medial border of the dorsal funiculus, receive impulses from primary afferent neurons which have been coursing rostrally for some distance in the dorsal funiculus. Consequently the local homo1ateral forelimb reflex is sometimes followed, at the 15 to 1 6 mm. stage, by a contraction of neclc muscles similarly at a later period, hind-limb reflexes are followed progressively by responses of the forelimbs and the neck. A progressive discharge of neurons from caudal to rostral regions of the spinal cord is broughtlabout through integration of ascending neurons of the primary afferent dorsal funiculus with the commissural secondary tract.


Nerve fibers grow caudally into the spinal cord from centers in the medulla oblongata and midbrain. Many of these occupy positions in the ventral funiculus but they do n’ot reach any given point in the spinal cord until after ascending Ebers from a lower spinal segment have reached the medulla oblongata. consequently stimulation of structures near the caudal end of an embryo of about 18 mm. (Fig. 58) can result sequentially in (a) local reflexes, (b) reflexes of more rostral parts, (c) head movements and then (d) the trunk activities which are integrated with the head and which always fall just short of the most recently acquired local responses. The descending integrating tracts of nerve ftbers are so placed in the ventral portion of the spinal cord that when activated they can more eifectively bring about discharge of motor cells which supp1y the trunk muscles than neurons for the limb muscles. As a result of such an arrangement the limhs seem not to be completely integrated with the trunk during the early embryonic period. Later the association becomes more intimate. On the other hand, the trunlc movements become integrated with those of the neclc almost as soon as they begin to appear at the 15 mm. stage. With growth in size of the individual, more and more muscles of the back are added to the trunk activities in a caudal1y expanding Progression.


Fig. 58. Cat embryo 18.5 mm. C. R. 1ength, from which local reHexes as well as early integrated movements could be elicited. Magniiication is the same as that in Figs. 44 and 47.



Some recent experiments involving the production of states of anoxemiaU have added important information to our conception of the relation of simple reHexes to the more massive integrated activities of cat embryos. When decerebrate cats were allowed to breathe atmospheres low in oxygen before the uterus was opened it was found that local reflexes became depressetd and the integrated head and trunk movements were exaggerated and more sustained or tonic than normally. Irritability of the embryos wss diminished during anoxemia. Extended use ok the gas mixture brought about more complete anoxemia and all responses ceased. spontaneous movements and responses to stimulation ok embryos studied under conditions ok partial anoxemia resemble mass reactions and might easily lead one to the conclusion that behavior develops in mammalss in a manner very similar to that in the Salamander. Only when such conditions are avoided can the various simple reflexes be observed as separate elements.

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