Dendritic Growth Cones Research Articles

Dendritic growth cone and filopodia formation as a mechanism of spinal cord regeration

Following hemisection of the rat spinal cord at the T1–T2 vertebral interface, dendritic sprouting was observed on neurons in the motoneuron pool at 45 days postoperative. The sprouting resulted in increased numbers of dendritic terminals, dendritic growth cones, and dendritic filopodial growth. The morphologic characteristics of the dendritic sprouts are similar to neurons in developing as well as in mature animals, and are correlated with synaptic renewal during spinal cord regeneration.

Neuronal maturation and synaptogenesis in the rat ventrobasal complex: Alignment with developmental changes in rate and severity of axon reaction

AbstractDevelopmental alterations in the rate and severity of axon reaction are thought to be influenced by the level of neuronal maturation and synaptogenesis. As an initial step in more carefully examining this issue, two concurrent series of studies were performed using the ventrobasal complex as a model.Sprague‐Dawley albino rats, ranging in age from neonate through 60 days postnatal (dpn) were subjected to unilateral aspiration lesions encompassing somato‐sensory cortex. Two to four animals were sacrificed at various postoperative periods of from one through 40 days. The reactive ventrobasal (VB) complex was qualitatively and quantitatively analysed employing electron microscopy and the Cajal‐DeCastro reduced silver technique or a hematoxylin‐eosin‐Orange‐G method for light microscopic study. Neuronal degenerative changes are prominent within 48 hours following ablation of neonate through 9 dpn animals. These alterations include a loss of cytoplasmic basophilia together with vacuolization, and rapid disappearance of the cell. Swelling and vacuolization of axons and dendrites is seen throughout the zone of degeneration accompanied by the rapid accumulation of numerous reactive non‐neuronal elements, some of which resemble those mesodermal elements designated as “M” cells. Following equivalent lesions of animals 12 through 60 dpn, neurons within the VB undergo degenerative changes which are qualitatively similar to those seen in younger animals but require between 6 and 20 days postoperative to appear. While most such cells will disappear the degenerative process is temporally extended by as much as one order of magnitude.The normal ventrobasal complex was examined in 7,12,15,20, and 60 dpn rats. Golgi‐Cox impregnations of thalamic neurons reveal such cells at 7 dpn to be characterized by short, stubby, irregular dendrites with distinct growth cones and filopodia, whereas by 12 dpn Golgi analysis demonstrates prominent morphological changes indicative of considerable progress in thalamic neuronal differentiation including dendritic elongation with secondary and tertiary branching, and the appearance of spinous protrusions. The use of the Rasmussen stain for synapses, as well as electron microscopy, shows distinctive trends of synaptogenesis typified by a paucity of synaptic complexes but large numbers of dendritic and axonal growth cones at 7 dpn. However, by 12 dpn a 3‐fold increase in the number of synapses has taken place together with an enhanced morphological complexity and variety of individual synaptic profiles, some of which are known to represent lemniscal input. Further prominent increases in synaptic population density are observed at 15dpn but the rate of synaptogenesis appears to become attenuated after this period. Finally, patterns of distribution of perikaryal RNA become altered from a predominance of polyribosomes at 7 dpn to characteristic multilamellate aggregations of granular endoplasmic reticulum initially observed at 12 dpn. With subsequent neuronal enlargement this component proportionally increases in amount but is qualitatively unchanged with respect to morphological arrangement. The close temporal correlation between the specific developmental events documented in this study and the postnatal age during which VB neurons become less susceptible to injury suggests that important changes in maturation of intrinsic neuronal metabolism involving rates of RNA and protein synthesis may be, in part, initiated and regulated by extrinsic factors related to the establishment of pre‐synaptic input upon VB neurons. A number of putative molecular substrates for these influences are discussed.

Cellular morphology in the visual layer of the developing rat superior colliculus

Golgi studies were undertaken in the superficial (visual) superior colliculus of 53 rat pups (106 colliculi) from birth to 31 days postnatal. Golgi-Cox techniques revealed discrete periods of development based upon changes in cell morphology. Major orientation of cells occurred between birth and 3 days postnatal. From 4 to 5 days postnatal, major cell populations could be identified, as (1) marginal cells; (2) horizontal cells; (3) piriform cells; (4) narrow-field vertical cells; (5) wide-field vertical cells; and (6) stellate cells. The period from 6 to 8 days was marked by a significant increase in dendritic growth cones, spicules, and varicosities, accompanied by some dendritic elongation and branching. From 9 to 10 days postnatal, further increases in dendritic elongation and branching occurred, with disappearance of dendritic growth cones, spicules, and varicosities. Further dendritic growth and branching was observed between 15 and 23 days. The period between 23 and 31 days was characterized by the appearance of spiny types of all cell populations. Correlations between these periods of cellular differentiation and stages of synaptogensis are discussed.

Histochemical evidence of altered development of cholinergic fibers in the rat dentate gyrus following lesions. II. Effects of partial entorhinal and simultaneous multiple lesions.

It has been concluded previously that the septohippocampal fibers which project to the rat dentate gyrus extend or branch in the denervated area of the molecular layer following a complete ipsilateral entorhinal lesion. The septohippocampal fibers thus appear to replace some of the perforant fibers which degenerate as a result of the lesion. The reactive fibers eventually become localized to a much smaller and more superficial area after lesions of immature rats than after lesions made in adulthood. To determine whether this difference in the response results from a selective reaction to loss of the lateral perforant path in the immature rat, various portions of the entorhinal cortex were removed at the age of 11 days, and the cholinergic septohippocampal fibers were visualized by acetylcholinesterase histochemistry. An alternative possibility, that the difference between immature and adult rats is attributable to an interaction with other reactive afferents, was tested by removing other sources of input (the contralateral entorhinal cortex, contralateral hippocampal formation or both) along with the ipsilateral entorhinal cortex at the age of 11 days and then demonstrating the septohippocampal fibers histochemically. Lesions of the lateral part of the ipsilateral entorhinal cortex (source of the lateral perforant path) at 11 days of age evoked a septohippocampal reaction along the outer edge of the molecular layer, where the lateral perforant path fibers normally terminate. This result matched that produced by a complete entorhinal lesion. Lesions of the medial entorhinal cortex evoked no obvious reaction. In contrast, the septohippocampal fibers in adult rats proliferated in the denervated area of the molecular layer after lesions of either part of the entorhinal cortex. Combining lesions of other sources of innervation to the dentate gyrus with an ipsilateral entorhinal lesion at 11 days of age did not alter the response of septohippocampal fibers, as determined histochemically. Neither did the septohippocampal fibers react to removal of commissural afferents alone. The response at any age was unaffected by prior or subsequent removal of the contralateral entorhinal cortex. These results indicate that in immature rats the septohippocampal fibers respond only to loss of the lateral perforant path, but these same fibers can later react to loss of any part of the perforant path. They are regarded as support for the hypothesis that the reactive septohippocampal fibers preferentially interact with dendritic growth cones. Our results do not support explanations based on a hypothetical attraction between septohippocampal and crossed perforant path fibers (which react in the same area) or on competition with commissural fibers (which reinnervate an adjacent area). We suggest further that proximity to the degenerating elements does not in itself determine the pattern of reinnervation after lesions of the central nervous system.

Synapse formation in the mouse olfactory bulb. II. Morphogenesis

Serial thin sections of the mouse olfactory bulb from the fourteenth day of gestation (E14) to postnatal to 44 (P44) have been examined in order to study morphogenesis of individual synaptic junctions. At the initiation of synapse formation structures are found that resemble postsynaptic densities but are facing extracellular space or unmodified processes. Transition forms between these isolated postsynaptic densities and undoubted synapses have been found. These observations as well as quantitative studies support the hypothesis that isolated postsynaptic densities can form independently and be converted to synapses when a presynaptic specialization develops opposite them. Detailed studies of olfactory axodendritic synaptogenesis throughout the entire developmental period suggests strongly that these asymmetrical synapses pass through an immature symmetrical phase: (1) symmetrical olfactory axodendritic synapses are found in significantly higher concentration on axonal and dendritic growth cones than on more common processes; (2) the number of symmetrical synapses is correlated with the rate of formation of new synapses determined previously. The time for a recognizable symmetrical synapse to be transformed into a recognizable asymmetrical one has been calculated to be 9--10 hours. A scheme of synapse formation in the CNS has been proposed in which a post-synaptic structure forms independently followed by aggregation of pre-existing presynaptic components into a presynaptic specialization. Different morphogenetic sequences of synapse formation from region to region are attributed simply to different relative rates in the development of the postsynaptic density and the presynaptic specialization.

Surface specializations of neurites in embryonic mouse spinal cord

Focal surface specializations occur upon axons, axon growth cone filopodia and, somewhat less frequently, upon dendrites as well as dendritic growth cones in embroyonic mouse spinal cord. These surface specializations are observed during the early synaptogenic period (embryonic days 12–16) when the axons of the marginal zone are forming synaptic junctions with motor neuron dendrites growing into their domain. At relatively low electron microscopic magnifications, the specializations appear as discrete patches of electron-dense material located just outside the plasma membrane. Higher resolution and an optimum section plane reveal the following ultrastructural characteristics of these specializations. There is a narrow (∼ 5 nm) less dense layer between the outer surface of the plasma membrane and the thicker (∼ 11.5–15 nm) electron-dense, distal layer of the specializations. The dense layer contains spherical profiles (∼ 10–15 nm in diameter) which have relatively clear centers and non-laminar, opaque perimeters. The surface specializations are commonly associated with an accumulation of dense, fibrillar cytoplasmic material that undercoats the cytoplasmic surface of the plasma membrane directly opposite to the external specializations. Furthermore, some of these surface specializations appear to be forming or merging with the cleft material of protosynaptic junctions and primitive puncta adhaerentia-like contacts. We have also examined the pattern of concanavalian A-peroxidase staining on the cell surfaces in embryonic spinal cord. At embryonic day 13, the earliest stage examined in the concanavalin A-peroxidase experiments, there is already an ubiquitous staining around all the cellular processes in the marginal zone as well as around the perikarya and processes of cell located in the intermediate and ventricular zones. No selective enhancement of neurite surfaces occurred which might have correlated with the surface specializations describes above. Finally, the possibility is discussed that the neurite surface specialization might play some role in intercellular recognition phenomena leading to the formation of synaptic juctions and puncta adhaerentia.

Maturation postnatale des noyaux vestibulaires chez le chat: Etude histologique par la methode de Golgi-Cox

Postnatal maturation of vestibular nuclei in the cat was studied from both the qualitative and quantitative points of view, following impregnation of the sections by the Golgi-Cox method. Three principal data arise from our results. (1) The different vestibular neurones undergo significant growth during the first two weeks of extra-uterine life: during this time, the progressive disappearance of dendritic growth cones and filopodia, an increase in area and volume of the perikarya as well as that of dendritic fields are remarkable; the smallest neurones completing their maturation before the largest. (2) Average sized neurones of the superior vestibular nucleus show a significant increase in the number of dendritic spines between birth and the age of 3 days. (3) On the 12th day, a decrease in the number of dendritic spines is noted. This decrease is accompagnied by a modification in spine density along the dendrites.

The application of network analysis to the study of branching patterns of large dendritic fields

Network analysis of dendritic fields not only defines the topology and connectivity of segments of an arborescence, but offers a means of discovering how networks grow. An important theory has recently been formulated 29 suggesting that dendritic branching patterns may be established by synaptogenic interaction of dendritic growth cones with growing axons. This thesis may be verified through network analysis since the theory predicts that growth at pendant vertices will predominate in dendritic networks, that dendritic growth will be directed into areas of maximal synaptogenic activity and that arc lengths will be inversely related, and the order of branching at vertices directly related, to the magnitude of the synaptogenic activity operating about growing dendritic terminals. The possibility of a preponderance of terminal growth may be detected by comparing the topologies in an observed dendritic network with those of a series of hypothetical growth models. This paper provides the frequency tables for models grown by monochotomous, dichotomous and trichotomous branching on random pendant vertices and random arcs for large networks in which ‘set theory’ contingencies are included. The paper also describes a method of calculating branching probabilities from the measurement of segment lengths, which is a means of testing the last mentioned prediction of the synaptogenic theory of dendritic growth. The method of network analysis is then discussed in relation to probable dendritic growth patterns, the constancy of segment lengths and the interaction of extrinsic and intrinsic factors in determining branching probabilities.

Fine structure of growth cones in medullary raphe nuclei in the postnatal cat

Morphological aspects of the dynamic processes of growth cone formation and synaptogenesis have been studied in neonatal kitten (2–17 days) medullary raphe nuclei. The formation and elaboration of dendritic growth cones and primary dendritic trunks is actively taking place on the medium size class neurons (stellates) of these nuclei. The dendritic growth cones are morphologically distinctive due to their population of large dense-core vesicles and postsynaptic position. Another growth cone morphology, interpreted as axonal, is also described. This growth cone is typically found in close association or synaptic contact with the dendritic growth cones and contains, in addition to synaptic vesicles, a dense-core vesicle population distinguishable from that of the dendritic growth cone by the presence of a variety of vesicles containing an eccentrically positioned dense particle. No evidence of axo-axonic or dendrodentritic synapses has been found. Synaptogenesis was found to be occurring on somas, dendrites and dendritic growth cones throughout the medullary raphe nuclei, though this phenomenon was more apparent in indistinctly localized subnuclear spaces termed synaptogenic zones. Within these zones large class neurons are found to have greater densities of both axodendritic and axosomatic synapses than medium and small class neurons respectively. Axodendritic synaptic densities on primary and secondary dendrites of large and medium class neurons are greater than their respective axosomatic synapse densities, which may suggest that the latter forms at a later period of development.

Fine structural relationships between neurites and radial glial processes in developing mouse spinal cord.

Neurites have been observed in various types of fine structural associations with developing radial glial processes in the lateral marginal zones of embryonic mouse spinal cords. The least complex of the neurite-glial relationships involves a simple apposition of dendrites and dendritic growth cones with radial glial processes. We interpret this relationship to mean that dendrites, growing from the somata of the lateral motor nucleus, may preferentially move along the interface between radial glial processes and the adjacent axons of the marginal zone. A somewhat more specialized neurite-glial association is the occurrence ofpuncta adhaerentia between neurites and radial glial processes. Finally, the most elaborate morphological relationship observed is that of synapse-like contacts between axons and radial glial processes. These ‘axoglial synapses’ begin to appear at E11 and E12, are most numerous in E13 and E14 spinal cords, but they can not be found after embryonic day 15. Based on these observations, we make the following speculation: the formation of synaptic junctions occurs in a hierarchy of steps with a process of trial and error primarily involved in the initial stages of synapto-genesis, while more specific requirements are involved in the later steps of synaptic differentiation. Thus, the formation of ‘axoglial synapses’ may reflect errors in development while their disappearance may result when more specific mechanisms of synaptic differentiation become operational.

A quantitative study of synapses on motor neuron dendritic growth cones in developing mouse spinal cord.

The proportion of synaptic contacts occurring on dendrites as well as on dendritic growth cones and filopodia was determined from electron micrographs of developing mouse (C57BL/6J) spinal cord. Comparable areas of the marginal zone adjacent to the lateral motor nucleus were sampled from specimens on the 13th-16th days of embryonic development (E13-E16). At the beginning of this period, synapses upon growth cones and filopodia comprise about 80% of the observed synaptic junctions, but this proportion decreases with developmental time so that in E16 specimens growth cone synapses account for slightly less than 30% of the synaptic population. Conversely, at E13, synapses upon dendrites comprise less than 20% of the total number of synapses, but increase with developmental time so that they account for about 65% of the synaptic population of E16 specimens. From these data, we suggest the following temporal sequence for the formation of synaptic junctions on motor neuron dendrites growing into the marginal zone. New synapses are initially made upon the filopodia of dendritic growth cones. A synaptically contacted filopodium expands to become a growth cone while the original growth cone begins to differentiate into a dendrite. This process is repeated as the dendrite grows farther into the marginal zone so that synapses originally made with filopodia come to be located upon dendrites. This speculation is briefly discussed in relation to the work and ideas of others concerning synaptogenesis and dendritic development.

Fine structure of dendritic and axonal growth cones in embryonic chick spinal cord.

AbstractOur preliminary electron microscopic observations of embryonic chick spinal cord indicate that the majority of synapses in the cervical cord at the fourth and sixth days of incubation are found in the marginal layer rather than the mantle layer. These findings raise two basic questions about the type of connections in the marginal zone during the first week of development: are all these early synapses axondendritic, and are synaptic junctions present on axonal and dendritic growth cones? Since criteria for distinguishing between axonal and dendritic growth cones are scarce or nonexistent, serial section electron microscopy was employed to definitively identify the two types of terminals.Two types of dendritic growth cones are present in the marginal layer during the first week of development. The first type is distinguished by a dendritic stalk which expands into a club‐shaped or bulb‐like terminal. A characteristic feature of this type of dendritic ending is the presence of numerous vesicles which vary in diameter from about 1000 Å to 2500 Å. Its cytoplasm has a floccular appearance and is frequently electron lucent. In contrast, the second type of dendritic terminal is electron dense, has a consistently homogeneous appearance, and usually lacks the large vesicles of the first type. The shape of the second type is a finger‐like process (filopodium) roughly of the same diameter as the main dendritic trunk. Evidence is presented that some dendritic growth cones observed in this study represent growing, motile processes rather than quiescent enlargements. Synapses on dendritic growth cones are quite numerous and, in addition, the first synapses on dendrites appear to form on growth cones. The hypothesis is put forward that synapses on dendritic growth cones. The hypothesis is put forward that synapses on dendritic growth cones are incorporated onto the dendritic trunk as the terminal continues to grow.Axonal growth cones may be distinguished from dendritic growth cones on the basis of their overall morphology and their cytoplasmic components. An axonal growth cone is, in general, a larger and more irregular structure than the dendritic terminal. This irregularity is due to the large number of processes radiating away from the terminal enlargement or varicosity. While dendritic terminals almost always have finger‐like projections, processes of axonal growth cones are more often sheet‐like extensions of cytoplasm (folipodia). Another important difference between axonal and dendritic growth cones is that ribosomes in axonal varicosities are infrequently encountered and rarely aggregated into polysomes as in dendritic terminals. Axonal growth cones are occasionally observed to be presynaptic to a dendrite during the first week of development.

An ultrastructural study of the inner core of the Pacinian corpuscle.

Pacinian corpuscles from the hindfeet and mesentery of cats have been examined by light and electron microscopy. The study focuses on the inner core region which houses the single, non-myelinated terminal of the afferent axon. This region of the axon possesses specialized axon processes which enormously increase the surface area of the axolemma. The axon processes are long, branched, filiform structures, containing exclusively ~6 nm microfilaments, and are reminiscent of filopodia on the tips of growth cones of axons and dendrites. These axon processes emanate from the two poles of the elliptical terminal axon, from several sites in the transitional zone, and from the entire surface of the ultraterminal axon, the bulbous, branched, distal extremity of the nerve fibre. Each branch of an axon process articulates with an inner core cell hemilamella except at the distal end of the ultraterminal where axon processes may also approximate the inner edge of the outer core. The base of each axon process contains an elaborate array of organelles including clear and dense-core vesicles of synaptic vesicle size, all enmeshed in ~6 nm microfilaments. The structure and location of the axon processes appear to be eminently suitable for detecting pressure transients transmitted through the outer core of the corpuscle. It is suggested that the mechano-electrical transduction system has, as its morphological substrate, multiple units, each formed by a branched axon process and its specialized basal region. The existence of sympathetic axon terminals abutting the central axon is disputed but the presence of unusual, dense-centred and elongated vesicles within cellular profiles close to the axon is confirmed.

Synaptic junction development in the spinal cord of an amphibian embryo: an electron microscope study.

An electron microscopical study has been made of the cervical spinal cord of Xenopus laevis embryos, from the time that the neural tube closes until the larvae were hatched and could swim. Sections of the whole cord were searched for intercellular junctions during this period. Two nonsynaptic types were found, the first were widely distributed puncta adherentia, the second were rare and similar to “gap” junctions. Membrane specializations with synaptic vesicles were first found when the neural folds had fused; “membrane-vesicle clusters” which looked like the presynaptic half of a synaptic junction were present, together with synaptic junctions lacking any postsynaptic membrane thickening or cytoplasm density. About four hours later, mature synaptic junctions with full thickening of the postsynaptic membrane, dense cytoplasm and striated or dense material in the synaptic cleft were present. Presynaptic mitochondria, dense-cored and flattened vesicles, fibre to fibre and fibre to cell body synapses were present from the first, as were synapses onto very fine dendrites which might be filopodia from dendritic growth cones. Synaptogenesis may start with the accumulation of vesicles in dense cytoplasm near a thickened cell membrane; the postsynaptic element becomes associated with this “membrane-vesicle cluster” and matures by increasing cleft and cytoplasmic density, and by membrane thickening.

The outgrowth of rat cerebellum in organized culture.

The outgrowth of newborn rat cerebellum cultivated in the Maximow assembly was studied from the time of explanation until the end of the 1st week “in vitro”. Dynamic characteristics of migrating cells were investigated with time lapse microcinematography and with phase and interference contrast. Three types of cells were identified: bipolar fusiform cells, fibroblasts and macrophages. The ultrastructure of these cells as seen with scanning and transmission electron microscopes is described. Bipolar cells display the same characteristics as those of migrating granule cells “in vivo”. Differentiation of these cells towards neuronal types becomes evident at the end of the first week “in vitro”. Axonal as well as dendritic growth cones were examined, and their ultrastructural characteristics described. Attention is focussed into the abundance of smooth endoplasmic reticulum, which in supposed active growth has the form of thin cisternae, and, at rest or in retraction takes the form of large vesicles. In the latter case, filopodia disappear, and the tips of their processes acquire a bulbous shape.

Reconstruction of dendritic growth cones in neonatal mouse olfactory bulb.

An improved and simplified method of serial sectioning for electron microscopy was used to prepare material from which were reconstructed dendritic growth cones of mitral cells in neonatal mouse olfactory glomerulus. Growth cones are characterized by: (1) one or more filopodia, each approximately 0.2 μm in diameter, projecting from an expanded dendritic terminal or pre-terminal region; (2) a polygonal array of microfilaments approximately 50 A in diameter, filling the enlarged terminal and filopodia; (3) an absence of microtubules and a paucity of mitochondria; (4) a few profiles of smooth endoplasmic reticulum or vesicles; (5) occasional axodendritic synapses. These characteristics are compared with those of other growing processes in the nervous system and a consistent picture of the appearance of growing neuronal processes obtained, suitable to use as a guide in a search for additional growing processes in developing and mature brains.

Ultrastructure of growth cones in the cerebellar cortex of the neonatal rat and cat.

The ultrastructure of axonal and dendritic growth cones has been examined in the cerebellar cortex of 7 days old rats and 12 days old cats. The unique feature is a bulge of the perikaryon surface or a varicosity of the growing tip of nerve processes. These cone-like areas contain large amounts of tubular smooth surfaced endoplasmic reticulum (SR) and large vacuoles. They are further characterized by filopodia (Tennyson, 1970) with a fibrillary matrix. Early cell contacts with synaptic membrane specializations are described between filopodia of mossy fiber endings and dendritic growth cones of granular cells. Synaptic vesicles appear early in synaptogenesis. While both vesicles and SR tubules are confined to separate areas of the axonal growth cone it was found that a common affinity to the ZIO staining agent exists. In contrast, the neurofilaments and microtubular components as well as the growth cone vacuoles remain consistently ZIO negative.

The growth of dendrites in the mammalian brain.

The histological features of developing dendrites are analyzed in age-graded series of cats, rats, rabbits, and opossums with the Golgi techniques. Growth cones and filopodia are consistent features of growing dendrites in the sensory nuclei, motor cranial nerve nuclei, brain stem reticular formation, cerebellar cortex, midbrain tectum, thalamus, hypothalamus, striatum, olfactory bulb, hippocampus, pyriform lobe, and neopallium. Terminal dendritic growth cones occur at the tips of dendrites; preterminal growth buds occur on the dendritic shafts. Filopodia are conspicuous on the growth cones and buds, but they occur on the dendritic shafts, also. Terminal growth cones, preterminal growth buds, and filopodia associate with incipient dendritic branches. Growth cones and filopodia generally disappear when the neurons are completely differentiated. But some dendritic growth cones persist after the rest of the brain is mature and consequently may be involved in learning and other plastic changes in neural function. The analysis illustrates the following general trends in neural ontogeny, none of which are expressed without modifications and qualifications. The dendrites of the specific types of neurons differentiate in typically circumscribed periods, which occur in a fixed sequence. Within, a specific neuronal population there may be regional gradients in the degree of dendritic differentiation. Within the same region the dendrites of large cell bodies tend to differentiate before those of small cell, bodies. The dendrites of Golgi Type II neurons differentiate later than neurons with long axons from the same thalamic nucleus. In the afferent sensory systems the neurons nearer the peripheral receptors usually begin their differentiation before those nearer the cerebral cortex. The dendrites of phylogenetically older neuronal groups tend to differentiate earlier than those of more advanced or more highly specialized groups. The dendrites and the other post-synaptic surfaces of the neurons differentiate in conjunction with the particular afferent axonal end-branches that are destined to synapse with the dendrites. Dendritic differentiation may be instigated by the afferent axons, controlled by local physico-chemical conditions, and guided by contact with the afferent axonal end-branches.