Postnatal Neural Ontogeny: Environment-Dependent and/or Environment-Expectant?

MARC BEKOFF MICHAEL W. FOX

Department of Psychology Washington University St. Louis, Missouri
Recent advances in the study of postnatal neural development, an adaptive process dependent on an intimate interplay of both genetic and environmental factors, are reviewed in mouse, rat, cat, and man. Since developmental neuroanatomical studies provide a useful and relevant way of approaching the much belabored and controversial nature-nurture issue, behaviorally oriented workers should be made aware of the heuristic value of the field as both an impetus and a guide for future research, and as a means for providing explanations for observations unexplainable at the ethological or behavioral descriptive level. The conclusion reached in this review is that postnatal neural ontogeny is both environment-dependent and environment-expectant. To divide the process into mutually exclusive halves is indefensible.

Introduction
That the nervous system is capable of undergoing morphological, physiological, and biochemical changes postnatally is a well established fact. Postnatal modification of the central nervous system may be viewed as an adaptive process. At birth, the quality and modalities of afferent stimuli impinging upon the organism are radically altered to which the nervous system must adapt by appropriate postnatal modification, as has been suggested by some workers. Arbib and Kahn (1969) viewed the brain as a computer that develops to survive in an environment, and conceptualize this developmental process in a neurocybernetic framework. Anokhin (1964) postulated that postnatal plasticity should be viewed as an adaptive process, that development follows a path which allows maximum adaptation for the survival of the neonate. This is Received for publication 12 April 197 1 Developmental Psychobiology, 5(4), 323-341 (1972) 0 1972 by John Wiley & Sons, Inc.

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similar to Carmichaels law of anticipatory morphological maturation (Carmichael, 1970) in which is implied an intimate structure-function relationship or, as emphasized by Gottlieb (1 970), a structure-fiinction-structure relationship. The pertinent questions that have been given great consideration are: (1) are the developmental changes seen after birth genetically determined, delayed maturational growth processes? (2) Are these postnatal changes influenced by the patterns of interaction between the developing organism and its environment? The first question involves consideration of the environmental-expectant model and the second, consideration of the environmental-dependent model. [See Hebb (1953); Lehrman (1953, 1970); and Lorenz (1965) for in depth discussions of this controversial developmental issue]. The question that should be considered, however, is: How are maturational processes influenced by interaction with the environment? Schneirla (1966) stated that the developmental contribution of maturation and experience must be viewed as fused at all stages of ontogenesis of any organism. Krushinskii (1962) and Chance and Jolly (1970) add further support to the view that the determinants of behavior of all kinds always involve the interaction between hereditary disposition and experience. Nevertheless, the postnatal changes may not be the opportunity for plasticity for externally conditioned and input-contingent reorganization of the neonates wiring system (Altman, 1967) since the precise contribution of the experiential history of the neonate to postnatal plasticity has not been established, and the genetic contribution likewise remains unknown. Moreover, the plasticity phenomenon may be an innate or genetic endowment with clear species-phylogenetic differences. [Note Masons (1968) notion of neoteny in primates capacity for structuro-functional change as a consequence of experience.] The major part of this review concerns itself with presentation of the evidence thus far elucidated for postnatal modification in structure and function in both the cerebral cortex and the cerebellum.

Postnatal Changes in the Nervous System

Before discussing the evidence for postnatal neural modification, we must consider the neural and behavioral criteria that are used as indices of the maturational status of the developing central nervous system. They are as follows: (1) total number of neurons in a particular area (Eayrs & Goodhead, 1959; Rabinowicz, 1967); (2) patterns of connectivity of the neuronal processes (Conel, 1941); (3) size of the perikaryon (Noback & Purpura, 1961; Purpura, Schofer, Housepian, & Noback, 1964); (4) number of dendrites and branches; size, caliber, and length of the perikaryal processes; presence of dendritic: spines (pedunculated bulbs, thorns, or gemmules); number and length of axon collateral branches (Conel, 1941; Noback & Purpura, 1961; Purpura et al., 1964);

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(5) increased thickness of the cortex; increased brain weight (Conel, 1941; Noback & Purpura, 1961; Purpura et al., 1964); (6) cellular proliferation, migration, and biochemical differentiation (Altman, 1967, 1969, 1970; Altman & Das, 1964; Angevine, 1965; Haas, Weiner, & Fliedner, 1970; Uzman, 1960). (7) packing density (Haddara, 1956; Eayrs & Goodhead, 1959); (8) degree of myelination (Langworthy, 1933; Conel, 1941; Jacobson, 1963; Yakovlev & Lecours, 1967; OBrien, 1970). (9) appearance of certain enzyme systems (Himwich, 1962; Himwich & Dravid, 1967; Richter, 1967; Altman & Das, 1970); (1 0) electrophysiological parameters of the developing brain (Purpura, Schofer & Scarff, 1967; Myslivecek, 1970; Rose & Ellingson, 1970); (1 1) electrolytic patterns (Swaiman, 1970); (12) reflex patterns (Fox, 1970; Humphrey, 1970); (13) perceptual and motor development (Cratty, 1970). Although the greatest part of maturation of most mammalian nervous systems occurs prior to parturition, ongoing changes are evident in the neonate (as listed above) and, in certain parts of the central nervous system, even late in adult life. Exceptions include marsupials in which the greatest part of maturation occurs after parturition. The latter are born in a condition which can be considered only that of a relatively mature fetus (Langworthy, 1928; Carmichael, 1970).

Cerebral Cortex: Neuronal Development

Nissl (1898) observed that cells are more closely packed in the cortex of species lower on the phylogenetic tree than those species occupying higher branches, that is, that are more evolutionarily advanced. Phylogenetically, the high gray/cell coefficient (volume of Griseum/volume of nerve cells contained in it) which expresses the packing density of the neurons-first used by von Economo (Haug, 1956)-is the result of an elaborate development of the dendritic processes of neurons, permitting a higher degree of functional association among the neurons, and possibly contributing to mans intellectual capacity. Computation of the gray/cell coefficient clarifies the relations between the volumes of the nerve cells and the volumes of other griseal structures comprising glia cells, blood vessels, nerve fibers, and intercellular substance proper (Haug, 1956). In addition to his previously mentioned observation, Nissl suggested that the development of the intercellular gray could be used as an index of phylogenetic evolution. Haug has pointed out that the volume of cortex increases during phylogeny to a greater extent than the number of nerve cells, hence a high coefficient in higher animals. Developmental studies support the idea that the growth of the neuropil is an important aspect of the evolution and morphogenetic development of neural capacity in animals, including man (Altman, 1967). Postnatal neural development and its modification has been studied extensively in

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the rat. At birth, the rat superficial cortex is largely made up of undifferentiated cells, tightly packed in vertical columns. During the first 2 weeks, these cells differentiate into either neuroblasts or neurons or into spongioblasts and neuroglia. The rough endoplasmic reticulum swells during the transition into neurons during the second week, and the number of ribosomes increases (Caley & Maxwell, 1968). Cellular organelles increase in both number and intensity. Eayrs and Goodhead (1959) studied the growth and ramification of cell processes in rat sensori-motor cortex using the Golgi-Cox staining method. For quantitative evaluation they used the graytcell coefficient, since formation of the neuropil and corresponding reduction of cell density is an important parameter of brain maturation. They found that the greatest reduction in cell density occurs in the first 6 days postnatally, in spite of the fact that the cell number increases. The period of most rapid increase in the density of axons is 6-18 days and of dendrites, 18-24 days. The few axons at birth have a predominantly tangential course; radially oriented axons (presumably specific thalamic afferents) appear at 12-18 days. The mean number of dendrites arising from the perikaryon reaches the adult level as early as the 12th day of life. Subsequent development of the dendritic field is marked by peripheral extension of the dendrites and an increase in branching. By the 3rd week of life, Nissl-stained sections of the cerebral cortex resemble the adult brain, but impregnated sections show a continuing growth of neuronal processes and, in addition, a further reduction in the packing density of the neurons (Altman, 1967). The rat is an altricial animal with a gestation period of only 21 days, and undergoes a good deal of postnatal neural development and modification. Altman and Das (1964), using tritiated thymidine (3HT) autoradiography, found the proportion of labelled cells in the granular cortex of the rat at 30 days of age to be 45%, confirming the extensive duplication of cells subsequent to birth and the injection of the DNA precursor. In contrast, Dobbing and Sands (1970) state that the timing of events in the central nervous system development of the guinea pig, a precocial animal, is in accordance with the precocity of central nervous system development in h s species. The guinea pig, with greater neurological endowment at birth, undergoes less rapid postnatal neural changes than the rat. The major site of cell proliferation in the rat neonate is in the subependymal layer of the brain ventricles. Cell proliferation is very low in the caudal neuraxis (spinal cord, fourth ventricle, and aqueduct) and very rapid around the third ventricle and lateral ventricles in the olfactory lobes (Altman, 1970). This fact has recently been confirmed by Haas, e t al. (1970). They injected 3HT into rats intra-peritoneally, during the course of pregnancy and studied the development of the brain in the neonatal period by observing the diminuition of the labelling index and labelling intensity of various cell types. They demonstrated that in the subependymal layer of the lateral ventricle, cellular proliferation includes various medullary layers and fiber tracts such as the fimbria of Ihe hippocampus, meduallary layer of the cerebellum, gray matter in the hippocampal region, and various layers of the cerebral cortex. The subependymal layer of the lateral ventricles in the anterior forebrain retains its high

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proliferation even in the adult stages (Altman, 1962). [Postnatal cell proliferation in the cat (Altman, 1967; Smith, 1969) and in the guinea pig (Altman & Das, 1964) has also been reported.] The cell migration in rats surviving for 1-20 days after injection is from the subependymal layer of the lateral ventricles to the hippocampal dentate gyrus, where the ordering is chronological according to time of arrival: the first cells reaching the hippocampal dentate gyrus go to the superficial layer. Postnatal neurogenesis tends to be restricted to microneurons (Altman, 1967, 1970). These are the small nerve cells with very short axons, or possibly no axons at all, as in the amacrine cells of the retina or the short axoned cells which terminate within the structure in which their cell bodies are located, as in granule cells of the hippocampus or cerebellar cortex. Exceptions seem to be large neurons which are formed after birth in the caudate nucleus, the putamen, and the accumbens septal nucleus in the rat (Altman, 1970; Das & Altman, 1970). The postnatally formed neurons in the caudate and putamen originate from the lateral wall of the lateral ventricles whereas those in the accumbens septal nucleus arise from the ventral aspects of the lateral ventricles. As mentioned above, undifferentiated cells are formed in the subependymal layer of the internal wall of the lateral ventricles and migrate to the granular layer of the hippocampus. The first step in differentiation, the establishment of synaptic contact and the induction of axon formation, begins only after the undifferentiated cells have reached the dendritic fields of the pyramidal cells of Ammons horn (Altman, 1970). There they form synaptic contacts with the dendrites of the pyramidal cells. The cells then continue to the basal zone of the granular layer where the second step in the differentiation takes place: the outgrowth of its dendrites into the molecular layer and the establishment of dendritic synapses. Altman suggested that the cell bodies of the precursor cells of the microneurons must move past the dendritic field to macroneurons with which they have synaptic contact when matured, and that some influence emanates from the dendritic plexuses of existing macroneurons. What is responsible for this macroneuronal induction of maturation is not yet known. Noback and Purpura (1961) and Purpura et al. (1964) have recently completed detailed studies of postnatal ontogenesis of neurons in the cat neocortex. They used the Golgi-Cox staining technique along with the following indices of maturational state: (1) number of dendrites and their branches; (2) size, caliber, and length of these processes; (3) presence of dendritic spines (pedunculated bulbs, thorns, or gemmules); and (4) number and length of axon collateral branches. They classified cortical neurons into 3 basic cell types: pyramidal cells, stellate cells, and horizontal cells of Retzius-Cajal. Their results are as follows. The cortex increases in thickness from .8 to 1.5 mm during the first 3 postnatal weeks. The pyramidal neurons, from the time of their initial development until their morphological maturation during the first postnatal month, maintain their radial orientation with axons directed into the white matter and apical dendrites extending distally toward the molecular layer (layer I of the cortex). Since differentiation of the collateral branches of axons and of apical dendrites and basilar dendrites to produce

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tangential or lateral extensions is essentially a postnatal event in the cat, the changing pyramidal neurons constitute the major postnatal maturational event in the development of the cerebral cortex. During the perinatal period (birth to 3 days), short unbranched basilar dendrites and unbranched apical dendritic collateral branches are present. At 8 days of age, basilar and apical dendrites are branched; a few have dendritic spines. Between 8- 14 days, the basilar dendrites show further branching, collateral branches of apical dendrites divide, and dendritic spines are abundant and prominent. By 21 days of age pyramidal cells are almost completely differentiated morphologically. The number of basilar dendrites and apical dendritic collateral branches are essentially the same as seen in the mature cats cortex. Spines are numerous and indistinguishable in overt characteristics from those observed in the adult animal (Noback & Purpura, 1961). The terminal branches of apical dendrites of pyramidal cells in superficial layers of the cortex are more numerous and have a wider lateral spread in the molecular layer I than the terminal branches of apical dendrites of pyramidal cells in deeper layers. In addition, pyramidal neurons of superficial layers develop more rapidly than do those of the deeper layers. Pyramidal neuron axons undergo relatively delayed growth and myelination with respect to differentiation of dendrites (Purpura et al., 1964) in accord with a three-phase partially overlapping sequence: (1) development of apical dendrites; (2) cell body and basilar cell body development in which apical dendritic growth continues to completion; and (3) axon growth and myelination. After the first month, the major neocortical maturational event is related to an increase in conduction velocity of pyramidal neuron axons. The processes of growth and myelination which underlie changes in the physiological properties of pyramidal neuron axom proceed slowly to completion during the fourth to fifth postnatal month (Purpura et al., 1964). Thus in the cat, in addition to postnatal neurogenesis, extensive modification also occurs in neural architecture and neural physiology. Conel (1941) studied the development of the human cerebral cortex during the first month of life. Although the cortex vanes considerably in shape and linear measurements are of little significance with respect to increase in size, Conel was able to report that on the average, at the end of 1 month of life, the brain is 1 cm higher and 1 cm longer than that of the newborn. Conel followed the growth changes and made these age comparisons: (1) More consistent and noticeable maturation occurs in layer V (internal pyramidal layer) than in any other layer. The greatest gain in layer V is in the region of the trunk, shoulder, and arm in the anterior central gyrus; no gain is seen in layer V in the region of representation of the lower extremities. (2) The nerve cells generally decrease in number and increase in size although the pyramidal cells in layer V show the greatest increase. (3) The dendrites and axons increase in size during the first month. The processes of the giant pyramidal cells in layer V (anterior central gyrus) are largest and longest and those in the region of the hand show the greatest development. Cells in layer I1 (internal granular layer) and I11 (external pyramidal layer) show the least increase. (4) The number of spines (pedunculated bulbs) increases particularly on apical dendrites of layer V. (5) Axons of Golgi I1 cells form a mesh of

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fine fibers in all layers throughout the cortex. The mesh is densest in the receptive areas with the somesthetic area showing the greatest gain. (6) The size and number of exogenous fibers increase during the first month. (Exogenous fibers are fibers which invade any area of the cortex from more or less distant centers.) The greatest increase is in the giant pyramidal cells in the anterior central gyrus.

Cerebral Cortex: Myelination

Jacobson (1963) studied the sequence of myelination in the cerebral cortex of the laboratory rat. He found that the cerebral cortex myelinates successively with the projection fibers myelinating before association fibers: the sensory radiations myelinate first; the cortico-fugal radiations next; and finally, the callosal projection fibers. Myelination of the medulla, pons, and midbrain is started and completed earlier than that of the thalamus and cerebral cortex. The rat cortex myelinates in a similar manner to the cat and human cortices: the process starts in motor, somesthetic, auditory, limbic and pyriform cortex and spreads to neighboring regions; the visual sensory regions myelinate last. Myelination in the human fetus and infant has been studied by Flechsig and Kaes [cited by Altman (1970), Langworthy (1933), Conel (1941), and Yakovlev and Lecours (1967) and has been recently reviewed by OBrien (1971)]. Only a slight increase in myelination occurs during the first postnatal month (Conel, 1941). Myelination is great in the area of the trunk, shoulders, and arms in the anterior central gyrus. The greatest increase in the anterior central gyrus is in the region of the hand. Very little increase is seen in the auditory receiving area and only a slight increase in the visual receptive area. Some general features of t h ~ myelination process s in man, probably also applicable to other mammalian species, are as follows. (1) Myelination does not occur at a uniform rate, but in what seems to be pulses or waves (Fox, 1971a; Yakovlev & Lecours, 1967). Myelination, once begun in one system of fibers, often does not continue rapidly and may be surpassed by another system in which the process began much later. For example, the acoustic pathway is myelinated to the level of the inferior colliculus in the 8-month human fetus. By contrast, the optic fibers receive no myelin until the time of birth. Nevertheless, the optic projection fibers to the cortex are myelinated slightly in advance of the tracts from the cochlear nuclei (Langworthy, 1933). Although development is not uniform within the central nervous system, the fully mature organism seems to depend on developmental and functional convergence; it functions as an integrated whole, making specific adaptations to its own environment, and acquiring species-characteristic behavioral patterns. (2)In general, myelination first occurs close to the cell body and slowly proceeds to the terminal portion of the nerve (OBrien, 1970). (3)Tracts become myelinated in the order of their importance in controlling the fundamental activities of the organism (Langworthy, 1933). Myelination occurs in various tracts of the spinal cord prenatally whereas myelination of tracts in the forebrain occurs postnatally during early or late infancy. The myelination of cortical gray matter continues past

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puberty, possibly into adulthood (Yakovlev & Lecours, 1967). Flechsig (cited by Altman, 1970) postulated a considerable difference in the rate of myelination of different cortical regions. He constructed a myelogenetic map of the human cerebral cortex, claiming that sensory projection areas and the motor areas myelinate much earlier than the intercalated, phylogenetically more recent brain regions, i.e., association areas. Since myelination of axons alters conductile properties, progressive myelinatiori may reflect the recruitment of more conductile elements into the circuitry of the brain. (4) Tracts in the nervous system become myelinated at the time when they become functional. The fetus receives tactile, proprioceptive, auditory, and gustatory stimuli in utero and the tracts converying the input from these various systems are partially myelinated in the fetus at 6 months and are myelinated to the level of the thalamus at birth (Langworthy, 1933). However, myelination of the optic and olfactory tracts is delayed until birth. They become fully myelinated when light and smell become major stimuli to the body. However, function is possible without myelin; absence of myelin does not mean absence of function (Fox, 1971a). For example, simple reflexes develop in the cat prior to myelination (Windle, Fish, & ODonnell, 1934). Nevertheless, an increase in the amount of myelin is correlated with an increase in functional capacity (Fox, 1971a). Huttenlocher (1970) suggests that increases in myelination of the central nervous system (CNS) may increase the ability of central axons to fire repetitively. Langworthy (1933) felt that initiation of activity in a group of neurons stimulated the laying down of myelin. Myelination can be diminished by preventing the conduction of impulses in a nerve or the opening of an eyelid (Gyllenstein, Malmfors, & Norrlin-Grettve, 1967; OBrien, 1970). However, although an impulse is an important stimulus to myelination in a nerve, it is not known how the nerve impulse conduction stimulates myelin formation at the cellular and molecular levels. In summary, the rate of development is not uniform throughout the cerebrum. The development and complication of the structure and function of the cortex correspond to the perfection in the forms of behavior and to complication, or increasing complexity, of the neural systems concerned with analysis and synthesis of stimuli reaching the body (Sarsinov, 1964).

Cerebellum
The cerebellum effects smootlxng error correcting, feedback regulation of postural adjustments, locomotion, and performance of skilled acts (Altman, 1969). By following the development of these suggested functions, we recognize in the cerebellum a good system in which to correlate developmental changes in anatomy with both environmental feedback and the behavior of the neonate. In the rat, the area of the cerebellum increases 20-fold over the first 21 days of life. This is primarily due to growth of the cerebellar cortex (Altman, 1969). Del Cerro and Snider (1 968) conducted electron microscopic studies on the developing cerebellum, studying particularly the growth of axons and dendrites between the 1st and 45th

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postnatal day. The growth process starts under the cell membrane as a local accumulation of vesicles without any visible contents. This is followed by an outward bulging of the membrane which then becomes filled with vesicles and is known as the primary growth cone, described as early as 1890 by Cajal (Del Cerro & Snider, 1968). In axons, the synaptic and growth cone vesciles cc-exist until the third week or longer. In dendrites, secondary growth cones exist at the tip of the branching dendrites and spines. Variations in the shape of the growth cone vesicles are related to the age of the animal. Growth cones change in appearance as other structures evolve. The biological significance of growth cones is still unknown, nor is it known how they disappear with maturation. There are 3 periods of accelerated maturation: at 1-3, 9-12, and 16-19 days of age, which appear as waves of cell migration and mitotic activity separated by intervals of less intensive activity. The period from 9-12 days is further characterized by a tremendous burst of protein synthesis (Del Cerro & Snider, 1968). Altman (1966, 1969, 1970) and co-workers (Altman & Das, 1970) have studied cell proliferation, migration, and differentiation in the cerebellum of the rat, and have concluded that cellular proliferation takes place in the germinal layer of the cerebellar cortex, that is, the external granular layer. The migration of precursor cells lasts for about 3 weeks. The differentiating cells move laterally over the dendritic field of the maturing Purkinje cells. As the cell moves horizontally, the lateral arms of the parallel fiber axons are formed. The cell body then dips down and, moving through the molecular layer and past the bodies of the Purkinje cells, forms the vertical branch of the parallel fiber axon. With the arrival of the granule cell in the internal granule layer, the formation of the axon is completed. The formation of the short dendrites and synaptic contact with mossy fibers subsequently takes place. As cells migrate from the external granular layer into the molecular and internal granular layers, the external granular layer becomes depleted of cells. Basket cells in the lower half of the molecular layer are formed before stellate cells in the upper half. Most of the granule cells are formed during the 2nd and 3rd week of life. Purkinje cells have not been labelled with 3HT: apparently, the short-axoned, small neurons (microneurons) of the cerebellar cortex are of postnatal origin (microneurons), whereas the Purkinje cells (macroneurons), large with long axons, are formed prenatally. Altman and Das (1970) have also confirmed the chronology of the maturation in the cerebellum by studying the concentration and distribution of cholinesterase in the rat. The duration of cerebellar neurogenesis is judged by the time of dissolution of the external granular layer (Altman & Das, 1967). In the rat, the cerebellar external granular layer disappears at the end of the 3rd week, in the cat at the end of the 2nd month, and in man between the 12th and 20th month of life (Altman, 1970). The duration seems to be correlated with the period necessary for the maturation of the animals locomotor and related skills and also with the species differences in complexity of these skills. The most recent and intensive studies on postnatal cerebellar development in the cat has been conducted by Purpura et al. (1964). They studied postnatal ontogenesis

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of Purkinje cells at different time periods. By the first week, the Purkinje cells have a well developed main stem with a small, highly branched axon distributing collaterals in relation to adjacent Purkinje cells and other neurons. The main dendritic trunk is not very prominent. The tips of the dendrites terminate at the lower border of the external granular layer, which is about 10-12 layers thick in the immediate neonatal period. Granule cells are more superficially located: Furkinje cell dendrites expand greatly during the 2nd week (8-12 days). The external granular layer is less densely packed and about 8-12 layers ~ c k Between 3-6 weeks Purkinje cell dendrites elaborate . further with elongation of the main stem dendritic trunks. The external granular layer progressively attenuates by inward migration of cells leading to increased cellularity of the molecular layer. At the end of 6 weeks, the external granular layer is about 1-2 layers thick. The dissolution of the germinal layer therefore takes about twice as long in the cat as in the rat. At the end of 2 months, the external granular layer has virtually disappeared and the Furkinje cells are fully elaborated. In man, development of the cerebellum continues beyond the first year (Altman, 1970). In the kitten (birth to 8 weeks postnatal), Smith (1969) observed postnatal development in Clarkes column (the area in the spinal cord from which the posterior spinocerebellar tract arises) in the L2-3 segments. At birth there is a lack of stainable synapses, with great changes by 3 weeks when there are 2 types of synaptic endings. There is centripetal orientation of the dendritic tree in relation to the center of Clarkes column. Altman (1967) and Dobbing, Hopewell, Lynch, and Sands (1970) demonstrated the high susceptibility of the developing rat cerebellum (in contrast to other brain regions) to X-irradiation leading to eventual impairment in motor tasks. Recently, Altman, Anderson, and Strop (1971) have shown that focal X-irradiation during infancy can lead to a decrease in the mature weight of the rats cerebellum due to interference with acquisition of microneurons. Further, animals given numerous exposures persisted longer in displaying infantile motor patterns. Tasks in which locomotor and manipulatory appendages of the body are used for complex motor performances require central nervous mechanisms in which the connections among the neural elernents are not determined totally by morphogenetic mechanisms but are influenced environmentally (Altman, 1966). The postnatal genesis and maturation of the modulatory components of the cerebellar cortex can be related to the circumstance that the connections established by these elements are conditioned by environmental feedbacks or by input-contingencies which connotes a comparator or matching mechanism. (See, for example, Altman, 1967, and Sokolov, 1960). Held and Bossom (1961) demonstrated that self-produced movements, (sensory feedback) are necessary for adult humans to adapt to re-arrangement of their environment and that passive motion is not sufficient. They questioned whether development and compensation reflect the same process. If these processes do, then the need for self-produced movement and contingent reafferent stimulation in compensationenvironmental feedback-are equally applicable to development. Held and Hein (1963) demonstrated that self-produced movement with concurrent visual feedback is neces-

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sary for the development of visually guided behavior in the cat. (See, also, Held, 1968). Hein, Held, and Gower (1970) have very recently demonstrated that if one eye is covered during self-produced movement then the visually guided behavior acquired by the open eye is not transferred to the unused eye, even with the corpus callosum and other commissures intact. They demonstrate that environmental feedback is important in the development of a behavioral repetoire although the relative contributions of the built-in factors and of the environmental feedback system remain difficult to assess.

Environmental Influences on the Developing and Mature Nervous Systems

In a series of studies, Hubel and Wiesel investigated both the effect of visual deprivation on the development of the striate cortex in kittens and recovery from the deprivation over a period of time. They made recordings at 3 months from the visual cortex of kittens raised from birth with one eye sutured closed and showed that few cells could be driven from the deprived eye (Wiesel & Hubel, 1963). By producing artificial squints in kittens, Hubel and Wiesel (1965) demonstrated that binocular interaction in the developing striate cortex is important. They severed the right medial rectus muscle at about the time of normal eye opening and produced thereby a divergent squint. The animals were then raised for periods of 3 months to 1 year in a normal environment. When the 2 eyes were tested, no behavioral visual deficits were evident. Electrophysiological recordings from the striate cortex were normal; however, the proportion of binocularly driven cells was markedly decreased from about 80% to 20%. The cortex appeared microscopically normal. The investigators concluded that a shift in ocular dominance had occurred due to the squint, with a cell coming to favor more and more the eye that dominated it at birth and ultimately losing all connection with the nondominant eye. The lack of synergy in the input from the 2 eyes was sufficient to cause a profound disruption in the connections that subserve binocular interaction (Hubel & Wiesel, 1965). Furthermore, recovery from the effects of early monocular or binocular visual deprivation, whether measured behaviorally, morphologically, or in terms of single-cell cortical activity, was severely limited even for recovery periods of a year or more (Wiesel & Hubel, 1965). That the fine structure of the nervous system can be altered by changes in the environment has been demonstrated by a number of workers. Holloway (1966) presents evidence that supports the suggestion that dendritic branching is increased in the visual cortex of animals raised in a complex, enriched environment. Cragg (1969), studying rod-bipolar junctions in the rabbit, demonstrated microscopic (electron) changes within the first few minutes of exposure to daylight in dark-raised animals. Schapiro and Vukovich (1970), studying the rat cortical pyramidal cell, showed that early stimulation (handling, stroking, shaking, placing in hot and cold water) leads to an increase in the number of dendritic spines and the number of neurons staining at

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8-16 days of life. They postulated that the neurons stained are those that are functionally involved at the time of staining. These authors concluded that the effect of afferent input on development of the dendritic spine may represent the neuroanatomical basis for the influence of early experience on subsequent behavior. Hirsch and Spinelli (1970) raised cats from birth with one eye viewing horizontal lines, and the other eye viewing vertical lines. They found that units in the visual cortex with horizontal fields were activated only by the eye exposed to horizontal lines, and units with vertical fields were activated only by the eye exposed to vertical lines. Unit recordings yielded no oblique visual fields. The investigators concluded that functional neural connections can be selectively and predictably modified by environmental stimulation. Fifkova (1970a, b, c) has recently demonstrated anatomical changes in the visual cortex of rats unilaterally deprived of visual stimulation. Changes were detectable 1 0 days after lid suture; the changes were independent of previous visual experience (Fifkova, 1970a). In rats monocularly deprived at 14 days of age, the mean density of synapses in pre-visual cortex supplied by the deprived eye was 20% less than the controls (Fifkova, 1970b), and the size of axo-somatic synaptic contacts were smaller throughout all the layers studied (Fifkova, 1 9 7 0 ~ ) . Sugita (191 8) experimentally starved young rats, by separation from the nursing mother for a stated period each day, by entrusting one mother with an excessive number of young (greater than 17) and thereby reducing the milk for each youngster, and by starving the nursing mother producing a decrease in milk secreted. He found that myelination was somewhat retarded in the underfed rats and that, although cell division was normal, the underfed rats were smaller and weighed less. He reported n o decrease in cell number, but rather decreases in the growth or development of the constitutent neurons. However, Dobbing, Hopewell and Lynch (197 1) have recently demonstrated that moderate undernutrition during the first 21 days of life produces a deficit of neurons in the rat cerebral cortex and a reduction of weight and cell number in the cerebellum (granular layer). Gyllenstein e t al. (1967), workmg with rats, compared the effect of bilateral removal of both eyes at birth with that of rearing animals in complete darkness. They studied the developing visual cortex, lateral geniculate nucleus, and superior colliculus and noted that the effect of bilateral enucleation was greater than dark-rearing on the developing visual system. They concluded that impulses along the optic nerve, originating from the retinae of the dark-reared animals, were important in the developmental process. Motor neurons in the developing spinal cord are greatly influenced by the developing limb, as revealed in experiments consisting of grafting of additional limbs or of amputating a limb at different developmental stages. Hamburger (1934) found that removal of the wing bud of the chick embryo at 255-3 days of incubation resulted in a reduction of the number of motor neurons in the ventrolateral column of the spinal cord. Within 3 days after removal of the hindlimb bud in the chick embryo, approximately 20,000 motor neurons died in the lumbosacral region of the spinal cord (Hamburger, 1958). (See Hughes [1968, Chapter 31 and Jacobson [1970, pp. 2402463 for reviews of t h s literature).

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Altman and Das (1967); Altman, Wallace, Anderson, and Das (1968); Diamond, Krech, and Rosenzweig (1964); and Diamond, Law, Rhodes, Linder, Rosenzweig, Krech, and Bennett (1966) studied the effects of enriched versus impoverished environments on the structure and function of the rat cortex. The brains of animals exposed to enriched environments were found to have the following characteristics in comparison with the brains of the animals exposed t o impoverished conditions: increased weight of the cerebral cortex, increased total activity of acetylcholinesterase throughout the brain, increased cortical depth, some indications of increased vascularity in the cortex (Bennett, Diamond, Krech, & Rosenzweig, 1964; Diamond et al., 1964; Rosenzweig, Krech, Bennett, & Diamond, 1968), and an increased number of newly formed glia cells (Diamond et al., 1966; Altman & Das, 1967). Some of these induced cerebral changes may regress after animals are removed from the enriched conditions (Zolman & Morimoto, 1962; Valverde, 1971) but how these changes in brain structure affect the organism is not yet understood.

Comment
Future research in the study of postnatal neural ontogeny should concern itself with investigating the interplay of genic-environment influences on the developing nervous system. Efforts must be made to correlate behavioral and anatomical findings. At the molecular level, the conditions necessary for the initiation of the myelination process should be investigated and the relationship between stimulation (i.e., function) and myelination should be more carefully defined. Better definition and control of stimulus conditions must be undertaken (Fox, 1971b). Enriched and deprived are relative terms and have different meanings in different laboratories. In themselves, they do not reveal very much about the true laboratory environment. Control of temperature, visual, auditory, tactile, and olfactory cues is mandatory as is precise control of handling of the animals. [See Morton (1968) for a review of the effects of handling in laboratory animals.] Cage size (Bell, Miller & Ordy, 1971), litter size (LaBarba & White, 1971; Poole, 1966), time of weaning, and the existence of possible endogenous rhythms must also be controlled for. Little is gained by knowing the genetic strain of the animal under study if the experiential life-history is only partially accounted for (see Denenberg, 1969). Brain (1971) suggested that critical periods may be the source of nongenetic variation sometimes encountered in pure strains of rats and mice; Henderson (1968, 1970) has demonstrated that laboratory rearing and treatment effects in early experience can obscure genetic influences on behavior. Furthermore, Henderson (1970) concluded that investigators must be aware of the possibilities that early environmental interactions with genotype may limit the validity of their findings to their own laboratory situations. Genetic and environmental (experiential) control must complement one another in order to produce meaningful and valid results. Further understanding of the premature and of the birth process might also shed light on CNS development. Changes in stimulus parameters between late fetal and

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early neonatal life should be considered as might the effects of various modes of birth (cesarean vs. vaginal parturition) (Meier, 1964; Meier & Garcia-Rodriguez, 1966; Grota, Dennenberg, & Zarrow, 1966). Careful control of the prentatal environment may be as important in some species as is control of the postnatal environment. It should be stressed that the developmental method provides a key to understanding the workmgs of the mature, integrated nervous system. The study of individual components during their maturation must lead to further consideration of how these parts fit together to form a whole, a whole that is far greater than the sum of its parts. A gestalt of CNS interaction is the end-product of the developmental method. Just as the nature-nurture issue is no longer separable into mutually exclusive halves, neither is the nervous system divisible into isolated discrete parts.

Conclusion
Postnatal neurogenesis and/or neuronal plasticity has been repeatedly confirmed in mouse, rat, cat, and man. It takes place at different rates in different parts of the brain, the heterochronicity of which may have adaptive value for the neonate (Anokhin, 1964). This level of neurogenesis appears to be restricted to microneurons which modulate interaction among macroneurons. The microneurons function to channel neural information and to increase the number of synaptic connections, and therefore the presumed computing power and storage capacity of the brain. The increase in the neuropil is greatest in the higher species and reflects the importance of growing connectivity. Microneurons situated near the juncture of the first- and second-order afferents are found to be recipients of centrifugal efferents descending from the higher levels of the nervous system, such as centrifugal efferents of the olivo-cochlear bundle that terminate on granule cells (microneurons) in the ventral cochlear nucleus and centrifugal efferents of the optic tract that terminate on amacrine cells in the retina. Neuroanatomical, chemical, and physiological studies suggest that environmental stimulation may be necessary for normal postnatal growth but the unique contributions of environmental influences on postnatal neurogenesis are difficult to assess. To view the nature-nurture in an either/or, mutually exclusive framework is unreal. Normal development most certainly requires both the proper genetic endowment of the developing structure and the proper environmental stimulation for development after birth. Postnatal development relies solely neither on the evolutionarily built-in directive forces (environmental expectancy model) nor on the immediate postnatal environment (environmental dependency model) but rather on the intimate interplay of the two.

Notes
Marc Bekoff was supported by a pre-doctoral fellowship under PHS Grant GM-1900, from the National Institutes of Health.

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Many thanks to Alice Bronsdon for her patience and careful typing of the manuscript. Send reprint request to: Marc Bekoff; Department of Psychology, Washington University, St. Louis, Missouri 63 130 U.S.A.

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