Talk:Paper - Some factors in the development of the amphibian nervous system (1922)

Some Factors in the Development of the Amphibian Nervous System

C. JUDSON HERRICK' Anatomical Laboratory, The University of Chicago

Three factors, amongst others, may be recognized in the embr\'ologic development of the brain :

1. Very ancient pahngenetic hereditary influences, such as primitive metamerism. These doubtless originally had functional significance, but this is now largely lost and these vestigial features are in most eases masked or suppressed early in developmental hist or}'.

2. ObWously adaptive features which are firmly hereditary but of relatively recent (cenogenetic) origin, e.g., reflex patterns and their neuromotor apparatus.

3. The immediate effect of active function upon the progress of individual development — facilitation bj' use, trophic response of the tissue to excitation, direct action of physiologic gradients of excitation and conduction upon direction and rate of growth (Child, '21), the bioelectric phenomena of excitation and differentiation and their directive influence upon contiguous differentiating neuroblasts (LilUe, '19; Kappers, '17, '21; Bok, '15, '17; Ingvar, '20), hormone action, and probablj- many others. Some of these are critically discussed bj' Child ('21).

Students of the embryologj' of the brain have been inclined to stress the first of these factors, to touch lighth' upon the second, and to dismiss the third as irrelevant to their studies. Recent years, however, have seen a notable change brought about largely

' This summary has been written up in collaboration with a number of active students of amphibian development, and it seems to us that its publication at this time would serve a useful purpose in promoting more effective integration of efforts now somewhat dispersed among scattered workers bj' directing attention to certain features of these researches which look toward problems of more general significance.

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by improvement in the technical methods of experimental analysis of the problem, and the demand now is for coordinated attack upon the problems of development on all these frontiers.

To learn the role of functional adaptations of the second and third types, ob\'iously it is first necessary to determine what these adaptations are. As applied to the development of the central nervous system, this implies a more complete knowledge of the functional localization and functional interrelationships of parts than we possess at present for any animal except man — and even here our ignorance is more extensive than our knowledge. The inconceivable complexity of the human brain is a serious obstacle to such an analysis and, moreover, the mammalian nervous system does not readity submit itself to the methods of experimental embryology.

The amphibian nervous system is free from the two objections just mentioned and in addition it has the further advantage that it begins to function in response to external stimulation at a surprisingly early stage of development. Complex adaptive reflex mechanisms which in the human nervous system attain full structural maturity before they are called upon to act at all can in a series of 3'oung amphibian tadpoles be observed in function at progressively advancing stages from the simplest beginnings to ver,v complicated definitive forms, and the structures which are added from stage to stage of the increasingly complex reflex pattern can be identified and correlated with the specific parts which they have to play in the total physiologic complex.

Intensive studies of the development of Amblj'stoma, both observational and experimental, have been in process for a long time. Coghill has observed the earliest reactions of urodele larvae to external stimuli and determined the sequence of progressively more complex behavior patterns. These observations were first made on Diemyctylus ('09) and have since been extended to Amblystoma. The earhest reactions of these larvae to contacts on the head and trunk are of three types, but all immediately or within a fewhours come to a form in which for from 48 to 96 hours the head is regularly moved away from the side touched, an avoiding reaction. This 'early flexure' stage is followed successively by

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a series of stages leading up to the 'early swimming' stage. Later experiments on Amblystoma have shown that the 'eariy swimming stage' is followed by "non-responsive" stages (to tactile stimuU aroimd the mouth), and these by 'feeding' stages.

Coghill and his pupils have in progress an extensive study of the structural changes correlated with this sequence of clearly defined functional stages, some parts of which have been published ('13, '14, '16). The sequence of maturation of the elements of the neuromotor mechanism is found to present a very instructive paralleUsm with the demonstrated functional sequence and important contributions have been made to the question of the nature of the most primitive reflex mechanisms (cf. Herrick and Coghill, '151.

^lention should be made in this connection of the valuable studies made bj' Paton ('07) on various species of vertebrates which, though not parallel ^^-ith Coghill's, were similarly directed, and of the still unpubhshed work of Dr. H. C. Tracy on the toadfish, Opsanus. Both of these include the study of spontaneous movements and also reactions to external stimulation. Tracy has already carried his study of the sequence of the development of the nervous system in correlation with obserA'ed beha^-ior to an advanced position. TMule the details of the development of the reflex patterns of the toadfish are naturally verj- different from those of amphibians, yet there are some general principles of development common to the two which are very instructive, and the differences between the two species are not less so as illustrative of adaptive changes correlated with the long period during which the toadfish larva is firmly attached in a protected situation.

The present writer has attacked the problem from the opposite side and is engaged upon histological studies of the adult and late lar\-al nervous systems of Amblystoma and other urodeles, taking as the point of departure CoghiU's earlier ('02) analysis of the functional components of the peripheral nerves. The determination of the exact pathways between the peripheral endorgans and their cerebral centers has permitted an accurate mapping of the primary reflex centers of the brain — tactile, gustatory,

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visual, olfactory, etc., and the various motor nuclei. Anatomical continuity between these end-organs and their respective cerebral centers gives a true indication of the functions of the latter. This has been adequately controlled physiologically. By an application of the same principle anatomical analysis of the complex central fiber tracts which connect these prunary centers with each other and which connect them with their respective higher correlation centers yields definite information regarding the functions of the higher centers.

The ultimate court of appeal in searching for the precise localization of function in the nervous system is, of course, direct experimentation ; but there are many regions of the central nervous system which are as yet inaccessible to such experimental studies, and the anatomical methods just mentioned under proper control are here very serviceable.

The brain of adult Amblystoma is \'ery simply organized, with relatively little departure from the form of the early embryonic neural tube, except for the great flexures and the local thickenings of the wall produced by the various correlation centers to which reference has just been made. To these there is added in the f orebrain a considerable outpouching or evagination of the entire wall on each side, thus producing two hollow cerebral hemispheres whose pattern is in fundamentals similar to that of the hemispheres of the human brain (cf. Herrick, '21).

Beginning with an analysis of the primary reflex centers of the medulla oblongata and their secondary connections in Amblys'toma of mid-larval stages (Herrick, '14a), the higher connections of these secondary tracts and their relations to optic and olfactory centers have been determined. These studies are far advanced and, through the united labors of several neurohistologists, we have now a fairly complete knowledge of the functional pattern of the brains of Amblystoma and other urodeles. Among the more important contributions to this subject, mention may be made of papers by Kingsbury ('95), Herrick ('10, '14, '17, '21a), Rothig ('11, '11a, '12,), Bindewald ('14), Larsell ('20). The writer also has a considerable mass of observations as yet unpublished.

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Notwithstanding the simplicity of external form of these urodele brains, the knowledge of the functional localization derived from studies of the fiber tracts permits the assignment of tolerably precise functional meanmgs to numerous external landmarks. In short, the reflex patterns as functional entities can be correlated with a mosaic of structural pattern, part of which is external]}' evident. The neurons of the correlation centers occupy more space than do the related fiber tracts. Accordingly, the location of these centers is indicated by the sculpturing of the external and ventricular surfaces of the brain.

The details of the ventricular structure of the brain of adult Amblystoma have not j'et been published (for Necturus, see Herrick, '17), but .these have been carefully charted and their functional connections determined. It is, therefore, possible to define each ventricular eminence and external landmark in terms of functional correlations there effected and to compare these with corresponding regions of the human brain so far as the latter are represented in the Amphibia.

The morphological analysis of the amphibian forebrain published by the writer in 1910 was based largely upon adult material. How far this will stand the test of further embryological and experimental control remains to be determined. It is evident that these conclusions, in so fai* as they may prove valid, are expressions chiefly, perhaps wholly, of the second and third types of process mentioned at the beginning of this sketch. As was recognized at that time, they are not derived from primitive metamerism, the longitudinal columns of His, or other palingenetic features of that category; but rather they represent later structural modifications superposed upon those ancient patterns.

The next step is to read this mosaic pattern backward into successively younger stages of the development of the brain, identifying each region by its superficial markings or internal fibrous connections or by both of these criteria. This is readily accompUshed for each functionally defined area as far backward in the series as its functional fiber-tract connections are demonstrable.

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It is found, as the series is followed forward from younger to older stages, that the invasion of a given undifferentiated area by a definite fiber tract arising in a remote part and conducting some specific functional type of nervous impulses is accompanied b\' a pulse of local differentiation. As the various fiber tracts of the forebrain successively mature and functional connections are made with different regions, there is an immediate structural response in the form of more rapid local prohferation of neuroblasts in the areas newly invaded by the growing fibers. This results first in a thickening of the wall in the differentiating areas on the ventricular side, followed in many cases either by corresponding thickening on the lateral surface or by a local bowing out or buckling of the entire wall producing an evagination.

This locaUzed acceleration of growth can in some cases be correlated ■with a definite increment, on the side of behavior of the living tadpole, in the complexity of the reflex pattern. The pulse of local differentiation is, therefore, probably very largely of the third physiological type to which reference was made in the beginning, viz., a direct reaction of the embryonic tissue in question to excitation entering from without its own substance, or a true functional response. This excitation is not necessarily a functional response to the stimulation of an end-organ of adult type, but it may be a change in metabolic rate or bioelectric state produced locally by the ingrowth of new axons into indifferent embryonic tissue (cf. the experiments of IngA-ar, '20, and the transplantation experiments of Burr, '20).

'But it is possible to read this mosaic pattern of regions wliich in the adult are obviously functionally defined back to still younger stages in some cases, that is, these regions present recognizable morphological criteria at stages antecedent to the appearance of functional fiber-tract connections. Regions which in the adult are of high functional \-alue, in prefunctional stages may exhibit an acceleration of growth resulting in A-arious local thickenings and dilatations of the neural tube and the great flexures. This would seem to imply hereditary factors of the type characterized by Cope ('87, p. 126) as heterochronous accelerated development, to wit, the appearance of adaptive strue

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tures at a date earlier in the ontogeny than would be consonant with an exact recapitulation of the phylogeny. How far this type of differentiation is due to the actual inheritance of morphological pattern such that particular parts of the neural tube tend to unfold in a predetermined way through the action of resident forces, and how far this sequence of changes in a particular region is due to the present influence of morphogenetic factors acting upon it from its intraorganic environment, such as Child's gardients, hormones, etc., is an approachable problem.

An important first step would seem to be the defermination of the exact functional pattern which in the final stage — the adult brain — is reflected in the structural mosaic of the definitive neural tube. A second step carries this mosaic pattern back to the earlier stages of the ontogeny as far as the functional factors of the adult type can be shown to be operative, that is, to the first appearance of the several fiber-tract connections of known functional significance.

After the morphogenetic influence of these factors is determined, the residual factors must be further analyzed, and here a variety of methods are available. Some of these methods are purely observational, some are experimental.

The embryology of the Amphibia has been much studied. The only detailed account of the early development of the nervous system of Amblystoma is that of Griggs ('10), though there are several good accounts of the formation of the neural tube and the earlier phases of its differentiation of other urodeles. No description of the later stages of the brain of Amblystoma has been pubhshed.

Landacre is investigating the cranial gangUa of urodeles and has published ('21) an important paper giving the history of the neural crest. He describes extensive contributions of cells from this and other ectodermal sources to mesodermic structures (formation of mesectoderm) , and follows the history of some of these cells through to their ultimate differentiation into head cartilages. This commingling of cells of the same origin as those of the brain with the cells of entodermal mesenchyme in the formation of non-nervous organs of the head may play some role as yet

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undetermined in the equilibrated systems of growth. The relations of the definitive cranial ganglia to the neural crest and of both of these to the neural tube on one hand, and to the general ectoderm, on the other hand, have been investigated by Landacre in a number of vertebrates, and further studies of these questions and of the formation of mesectoderm in Anaphibia are in process. Cogliill has published ('16) graphic reconstructions of the functional composition of the cranial ganglia and related sensory centers of the medulla oblongata of Amblystoma in four of his functionally defined stages.

The further prosecution of these embryological studies will contribute much of value in the analysis of the morphogenetic factors operative in the development of the nervous system of Ambh'stoma. We wish to know what was the primitive segmentation of the urodele head and the fate of these segments in the later development of the nervous system, what are the sources from which the various parts of the central and peripheral nervous sj^stem have drawn their building material (these apparently differ in closely allied species); what (if anj-) are the inherited potencies of these various kinds of material; to what extent and in what ways do excitations acting directly upon them shape the course of their development; and the e\adence (if any) of the presence of inherited patterns of adaptive (cenogenetic) tj^pe in this development.

E^^dently observational methods alone are incompetent to answer all of these questions, but observation must furnish the sound basis upon which crucial experimental tests can be de^^sed. And it is indispensable that the observational studies and the experimental program be kept in the closest possible articulation. Coghill, for instance, is engaged upon a correlation of the growth rhj'thms of the central nervous system (as measured by the number and distribution of mitotic figures at successive stages of known physiological type) with those of various non-nervous organ systems. This may shed light upon the nature of the physiological equilibrium in the organism as a whole during the march of these events, and it would not be at all surprising if these observations would correlate in a fruitful way with studies on the morphogenetic influence of the ductless glands.

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Experimental investigation of the interrelationships of the endocrine organs during development has already brought to Ught some surprising facts. As illustrations of these, mention may be made of the studies upon the Ampliibian h>-pophysis of Allen ('16, '20) and P. E. Smith ('20). These exhibit the influence of an organ upon remote parts of the body through the agency of transported materials.

It has long been supposed that contiguous parts may exert a chemotactic or other influence upon the development of the nen-ous sj-stem, and the recent studies of the bioelectric phenomena of metaboUsm. and especially of excitation and conduction, to which reference has already been made, have suggested a possible mechanism for this t>-pe of reaction of the tissues. The investigation in the Amphibia of the physiological gradients to which Child has devoted so much attention has been begun by Bellamy ('19). He has studied the effects of various toxic and depressing agents upon the gradients in physiological acti^•ity along the axes of the embryo and the role of the nonnal physiological gradients as morphogenetic factors. PubUcation of further results of these experiments is promised, and it maj' confidently be expected that additional data of far-reaching importance in the analysis of the functional components in the complex historj- of the development of the nenous system ■^\"ill be brought out.

From the dawn of experimental embrj'ology until now the Amphibia have presented most favorable materials for experiments in this field. Limitations of space here forbid reference to even the most important of these investigations, but it is generally recognized that this avenue offers a ver\' direct approach to the problems centering about the relations of developmental factors intrinsic to an organ or tissue and those which are the expressions of extrinsic agents. In this countrj' Amblystoma is a more satisfactory subject for many of these Unes of inquiry than any other t}-pe. The genus is widely distributed, the eggs are easil}- collected and reared, and the lan-ae are hardy and favorable for operative work. The acti^•ities of Harrison's laboratories in recent years have given e\"idence of the pecuUar fitness of this material for many lines of embryological study.

300 C. JUDSOX HERRICK

Burr in three recent studies ('16, '16 a, '20) has opened a fruitful line of investigation by a direct frontal attack upon the question of the relation between intrinsic and extrinsic factors in the morphogenesis of the cerebral hemispheres of Ambh'stoma. By an ingeniously planned series of experiments he has shown that the hemisphere develops under the influence of excitations entering at opposite ends, from the olfactory organ and the thalamus, respective!}'. The destruction of the nasal organ in prefunctional stages results in the failure of the rostral end of the hemisphere to complete its differentiation. The effect of cutting off all nervous impulses coming into the hemisphere from the thalamus was determined by transplanting the hemisphere, before the ingrowth of such fibers, into the skin of the side of the bod}'. The olfactory placode was transplanted with the hemisphere and made connection with the brain in the normal way. The hemisphere developed to nearly normal size, but the parts normally directly connected with the diencephalon were retarded in development. No part was totally atrophied, in conformity with the well-known fact that practically all parts of this hemisphere receive fibers from the olfactory bulb, which was well developed. In one series of experiments the olfactory placode was transplanted to a superficial position so that (^presumably) it was capable, in later stages, of normal peripheral stimulation; in another series the placode was buried beneath the skin so as to preclude stimulation from the exterior. The related transplanted hemispheres developed equally in the two cases, showing that the stimulus to differentiation of the olfactory centers is pro\idedby the ingrowth of the olfactory fibers, even though these are never normally excited. It would be interesting to learn the effect of carrying the experiment further and transplanting the cerebral hemisphere alone without the olfactory placode, thus isolating it completely from any form of nervous excitations. This would show whether the primitive hemisphere \-esicle has anj' capacity whatever for intrinsic differentiation beyond the stage normally reached when nerve fibers first penetrate it from adjacent parts.

In another series of experiments it was shown that extirpation of the hemispheres in prefunctional stages is followed by very

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little regeneration in case the olfactory placode is also removed; but if the latter is left in place the hemisphere does regenerate to normal form under the influence of the ingrowing olfactory fibers.

Such experiments can be indefinitely multipUed, and it is very desirable that this should be done, and also that after such operations the lar^'ae should be reared (in so far as they are \'iable) to a sufficiently advanced stage of functional development as to permit of precise determination of the regulatorj- changes in the arrangement of the fiber tracts and correlation centers by comparison with normal larvae of corresponding ages. This can be accomphshed -n-ith considerable completeness by the use of the silver-impregnation methods of Cajal and Bielschowsky. Normal specimens of various ages up to adult are already available in the collections of Coghill, ^IcKibben, Watkins, Burr, and others, and these are now in process of intensive study.

It is no accident that these and many other energetic workers in so diverse fields have converged their acti\-ities upon the development of the .\inphibia. This material is very favorable for attack upon the most fundamental problems of growi;h and differentiation. In the cerebral hemispheres we find here the same morphological t}-pe as in mammals, but reduced to lowest terms, and the morphogenetic factors in the two cases doubtless have much in common. Studies on the early development of the himaan cerebral hemispheres made by Dr. ^Marion Hines Loeb and others in the laboratories of the University of Chicago have brought to Ught unexpected similarities with those of lower vertebrates, features which have in the past been overlooked just because the simpler paradigm was not taken into the reckoning.

The various researches to which reference has been made here and others on kindred topics which might have been mentioned have, for the most part, been independently planned and executed. They represent no formal collaboration, no elaborate machinery of organization. ^Men of diverse trainuig and aptitudes have studied problems as they were presented, and their natural interests have drawTi them together from different quarters. In the aggregate these investigations form an impressive

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exhibit of successful accomplishment and still greater promise for the future.

As for this future, the best results will probably continue to follow from the unrestrained mitiative of the individual workers. But, in \iew of the fact that this entire body of research does have so ob\-ious an application to fundamental problems, and that the concentration of so diveree inquiries upon a single species gives broader promise than could be expected from any single Une of investigation, it is probably expedient for those now working on Amblystoma to seek somewhat closer contacts with each other and more consciously so to direct their programs of research as to make the largest possible use of data supplied bj' their coworkers.

In particular, the experimental workers, who may not be in a position to carrj' to completion the verj' desirable (but very laborious) morphological studies necessary for the broadest interpretation of their results, may find it advantageous at times to seek conference on these questions. I refer especially to matters of internal structure, courses of fiber tracts, functional connections of correlation centers, etc., at definite ages, regarding which there is a large body of ascertained fact, much of which is as j-et unpubUshed.

One of the first desiderata is an authoritative record of the chief characteristics of the nervous system at successive stages of development, arranged preferably by stages, as j-et unpublished, as defined by Harrison, and these in correlation with known stages of phj^siological development — in short, a series of nonnal tables of the nervous system, based on the sequence of both structural and functional development. This enterprise it is hoped will soon be undertaken in the Yale laboratories under the direction of Doctor Burr, and wiU ser\'e as a useful norm or datum of reference for comparison with the quantitative studies of gro\\-th of mammalian tj-pes now so actively prosecuted in several American laboratories.

An account of the plastic changes in the external form should follow, 'tt'ith pictures of the stages from models. The description of these form changes is, however, largely dependent for its value

DE%'ELOPMEXT OF .VMPHIBL^X XERVOUS SYSTEM 303

upon the identification of the regions in correlation with adult structure and functional locaUzation at successive ages. The data for such a correlation are still far from complete, but are accumulating, and it is hoped that the time is not far distant when such a description can be written, with more or less of correlation of changes in external form with corresponding changes in beha^'io^ pattern and in histological differentiation internally. More detailed studies of the development of reflex patterns from early larval to adult stages are necessarj- for the consimimation of the program.

March 2, 1922

ADDENDUM

At the time when the^e proof sheets pass to the press (April 11, 1922) it can be stated that the studies referred to in the last sentence above are in process. Under a research program organized jointly by the University of Kansas and the University of Chicago, Doctor Coghill and iNIr. Watkins have this season already studied intensively the earh* development of the reflex pattern in upwards of 100 indi^^dual larvae of Amblystoma and the work is now continuing to include still other series of specimens, ^lanj' hundreds of specimens of tested phj'siological age have been fixed for future histological study.

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304 C. JUDSOX HERRICK

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1916 The same. II. The afferent system of the head of Amblj'stoma. Jour. Comp. Xeur., vol. 26, pp. 247^40.

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Kappers, C. U. Ariexs 1917 Further contributions on neurobiotaxis. IX. An attempt to compare the phenomena of neurobiotaxis with other phenomena of taxis and tropism. The dj-namic polarization of the neuron. Jour. Como. Xeur., vol. 27, pp. 261-298.

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DEVELOPMENT OF AMPHIBIAN XERVOrS SYSTEM 305

Laxdacre, F. L. 1921 The fate of the neural crest in the head of the urodeles.

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Smith, P. E. 1920 The pigmentary, growth and endocrine disturbances induced in the anuran tadpole by the early ablation of the pars buccalis of the h3rpophysis. Amer. Anat. Mem., no. 11.