Developmental Brain Research, 58 (1991) 59-65 59 Elsevier

BRESD 51202

Macaque anteroventral cochlear nucleus" developmental anatomy

Dwight Sutton 1, Octavia Y. Hathaway 1, Thomas Seib I and Francis A. Spelman 2

1Virginia Mason Research Center, Seattle, WA 98101 (U.S.A.) and 2Regional Primate Research Center, University of Washington, Seattle, WA 98195 (U.S.A.)

(Accepted 25 September 1990)

Key words: Cochlear nucleus; Macaca nemestrina; Auditory system; Development; Brainstem development

The development of the anteroventral cochlear nucleus (AVCN) in fetal and infant monkeys (Macaca nemestrina) was analyzed for gross morphologic changes together with growth-related modifications in constituent cell size and cell distribution. Rapid and extensive prenatal volumetric changes were followed by slow and limited postnatal volumetric changes. The time course of packing density and cell size changes paralleled the volumetric changes. At each age the packing density along the rostrocaudal axis of the AVCN was constant except in the youngest specimens (mid- to late-fetal), where local variations occurred. Similarly, the size of AVCN cells along the rostrocaudal axis remained approximately constant at any given age. In comparison with the human and mouse, the macaque exhibits relatively less pronounced postnatal change in overall volume and cellular growth features.

INTRODUCTION

A number of anatomical changes characterize the brainstem auditory system in the perinatal period. Al-

though the cochlea is essentially mature at birth 6,

continuing modifications in postnatal growth of the

cochlear nucleus complex and its cells have been de- scribed for the mouse 12'23, rat 3, ferret 13, cat 1°'16,

chicken 2, and human 9. Most of the analyses have

focused upon postnatal developmental changes, among

which are progressive differentiation of clearly defined cell types, increases in overall nuclear volume, growth in

size of various cell types, growth of interconnecting fiber

pathways accompanied by modifications in dendritic

morphology, and changes in packing density. The overall geometric features of the cochlear nuclei

have been described in limited detail for the cat s and human 2~. Moore and Osen 14 sketched the geometry of

the adult human cochlear nuclei but provided no infor- mation regarding developmental changes. Konigsmark and Murphy 9 found that the total number of neurons in the neonatal human VCN was equal to that of the adult.

In this context, they pointed out that the AVCN

continued a steady volumetric expansion from the neo- natal stage onward through the 4th decade of life. Cell

size and packing density were not targets of study. A few growth characteristics of auditory brainstem

have been studied in rat and mouse. Coleman, Blatchley and Williams 3 reported approximately linear growth of

the rat ventral cochlear nucleus for a prolonged period.

The volume increased more than 3-fold between 10 and 70 days of age, an interval extending beyond onset of

sexual maturity in this species.

Cells in the mouse auditory brainstem structures are

formed approximately midway in the gestational period 12, but these have not been analyzed in terms of

their subsequent growth characteristics. Larsen l° re-

ported that cat AVCN cell area and volume doubles from birth to 12 weeks of age, the point at which mature adult

values occur. Concurrently, the cell packing density reduces by approximately 50% during this time.

Strain variations dictate in part the timing of matura- tional processes. Webster 22 noted that the cell count and

volume of ventral cochlear nuclei in CBA/J mice in-

creases in the postnatal period up to the age of 90 days, but Mlonyeni 12 recorded a maximum VCN cell census in

the immediate postnatal interval, with subsequent dec- rement to a stable mature level. Willott et al. 23 have

reported that the AVCN of C57 mice is developmentally mature at a considerably earlier age than in CBA/J animals. With respect to this latter strain, Webster 22 also

reported that cell size increases more than four-fold and cell packing density diminishes by approximately 66% as the animal matures.

Limited information is available regarding the cochlear nucleus development of non-human primates. Moskowitz is measured cell packing density in the squirrel

monkey, although his data yield no details regarding

Correspondence: D. Sutton, Virginia Mason Research Center, 1(100 Seneca Str., Seattle, WA 98101, U.S.A.

0165-3806/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)

60

ma tu ra t i ona i changes . O n the basis of small samples ,

H e i m a n - P a t t e r s o n and S t rominge r 7 r e p o r t e d A V C N cell

size i nc remen t s of 3 0 - 2 0 0 % dur ing neona ta l to adult

d e v e l o p m e n t in macaques . Ne i t he r the overa l l g rowth

pa t te rns nor detai ls of ce l lu lar d e v e l o p m e n t in the

m a c a q u e have been fully examined .

The p re sen t s tudy repor t s d e v e l o p m e n t a l character is -

tics o f the an t e roven t r a l coch lea r nucleus in M a c a c a

nemes t r ina .

MATERIALS AND METHODS

Eight M. nernestrina (ages ranging from 90 days gestational age to 3 years post-partum) were used. The fetal and early post-natal specimens were obtained as ancillary material from a study using timed-pregnancy animals to assess visual development. Body weights and sex information were not availabe. All of the cases were presumed normal with respect to auditory development, although hearing was assessed in only one animal (age 13 months). Only one-half the brainstem was available for study in two instances. As a result, 14 AVCNs were included in the study. Not all were subject to each step in the analysis.

The tissues were embedded in celloidin, stained with Cresyl violet and serially sectioned at 30 /~m in transverse orientation. For volumetric measures, the AVCN in each section was projected at 47 x magnification and outlined on tracing paper, commencing with the most rostral section that displayed AVCN cells. Fidueials placed in the tissue blocks helped maintain the relative position of consecutive sections. The serial tracings were then transferred to a digitizing tablet interfaced to a microcomputer. The AVCN outlines from all sections provided the data for a program that generated a 3-dimensional representation of the AVCN. Because the sections were of uniform, known thickness, this program also yielded volume values for individual sections and for the overall AVCN. Related programs generated cell cross-sectional areas together with mean and variability data.

The absolute posterior boundaries of the AVCN as defined by the separation between AVCN/PVCN and AVCN/DCN were difficult to establish, particularly in the fetal specimens. Criteria relying upon different cell types or distinct changes in the predominant cell type as defining the absolute posterior limits of AVCN were inapplicable in the youngest specimens because the cells were poorly differen- tiated at this stage. Consequently, we selected a landmark (rostral tip of PVCN) that was clearly identifiable in the transverse sections at all ages. This point lies inferior and caudal to the main body of the AVCN, and is clearly separated from the AVCN by the cochlear nerve root, a structural arrangement that has been characterized in M. mulatta 15, Saimiri sciureus 2° and human 7. The posterior limit for reconstruction of the AVCN was defined as the section in which the rostral tip of the PVCN was first encountered. This method eliminated uncertainty in specifying a 'standardized' caudal limit of the AVCN, but certainly excluded a limited amount of caudal AVCN tissue (estimated as 15-20%).

We estimated AVCN cell size, number, and packing density on the basis of data from 5 equally spaced sections from each case. These were selected at the following antero-posterior points: 17%, 34%, 50%, 67%, 84%. The AVCN in each of these sections was systematically scanned under oil immersion (1000x). All neuronal cells were enumerated without regard to type. (There is poor differentiation of cell types in young fetal animals (F90, FlI3), making a general analysis of type-across-age virtually impossible.) The outline of each cell that displayed a nucleolus was traced on a digitizing pad that was viewed through a camera lucida. Software routines computed the individual area, average cross-sectional area and standard deviation, and tallied the total number of cells measured.

No correction for tissue shrinkage was imposed on the measures of cochlear nucleus or cell areas obtained by the above methods.

RESULTS

V o l u m e

R e c o n s t r u c t i o n of the A V C N f rom serial t ransverse

sect ions y ie lded a f l a t t ened , rough ly conical conf igura t ion

(Fig. 1). T h e f l a t t ened aspect fo l lowed a long a dorso-

caudal , ven t ro l a t e r a l axis that was s u p e r i m p o s e d on the

genera l ly conical s t ruc ture (par t icu lar ly in the caudal

reg ion) , and was m o r e dist inct in the m a t u r e stage. In the

oldest case the ou t l ine of the caudal A V C N f o r m e d a

crescent shape (Fig. 1C). T h e f l a t t ened cone d isplayed

tors ion (i.e. slight ro ta t ion) a round the A V C N rostro-

caudal axis. T h a t is, the m a j o r axis of each succeed ing

el l ipt ical sec t ion was p rogress ive ly ro t a t ed with respect to

a do r soven t r a l r e f e r ence line. T h e m a g n i t u d e and direc-

t ion o f tors ion was u n r e l a t e d to the age o f the animals ,

varying a m o n g the d i f fe ren t spec imens by as much as 20 °

t h roughou t the length of the A V C N .

The A V C N exh ib i t ed a f o r e s h o r t e n e d or ' s tubby '

conical conf igura t ion at 90 days ges ta t iona l age. The

o lder case p re sen t ed a m o r e e l o n g a t e d and gradual ly

t ape r ed prof i le ( c o m p a r e Fig. 1A and B). The genera l

c o n f o r m a t i o n seen ear ly in the pos tna ta l pe r iod closely

r e s e m b l e d the s t ruc ture at 3 years , a l though the re was

slight addi t iona l ros t rocauda l e longa t ion in successively

o lder cases.

B

300 ~m

0 t'l' Illll Fig. 1. Schematic reconstruction of a fetal M. nemestrina AVCN (gestational age: 90 days; A, C) and a juvenile M. nemestrina (age: 3 years; B, D) showing the geometric change occurring over the maturational period covered in the study. Seen in lateral rotation, there is a distinct shift from a foreshortened to a more elongated configuration. The reconstructions are based on transverse brain- stem serial sections (30/~m). The views represent the left AVCN seen from a directly rostral perspective along a parasagittal axis (A, B), and rotated laterally 90 ° (C, D).

TABLE I

Anteroventral cochlear nucleus." developmental measures M. neme- strina

A VC N Cell packing Cell size Total number volume density average o f cells* * ( x O. 1 mm ~) (per O. 0001 area # (pm 2) (estimated)

mm ~) (S. E. M. )

F90 0.71 12.2 (1.10)* 88 (0.43) 9308 F113 1.58 7.33 (0.49) 121 (0.62) 8097 F165 3.03* 5.77 (0.49)* 180 (0.82) 16460 3D 4.12 3.83 (0.29) 167 (0.72) 15720 24D 3.92 3.72 (0.50) 197 (0.94) 14006 98D 4.52 4.10 (0.35)* 213 (1.05) 15290 13M 5.03 2.76 (0.07) 205 (1.53) 11762 3Y 7.26* 2.83 (0.06)* 200(0.85) 20631

* Left side only * 5 slides combined for each animal.

** Sum of cells in 5 slides x total slides/5.

Table I summarizes the average AVCN volume at each

age. The volume grew approximately 8-fold over the

period represented by the cases studied (gestational age

90 days to postnatal age 3 years). The volume of the

nucleus approximately quadrupled from gestational age

90 days to the neonatal stage (normal gestation period:

170 days). From the neonatal stage onward there was

cont inued growth such that the oldest animal had a

volumetric measure approximately 50% larger than the

newborn. The individual AVCN measures are plotted in

Fig. 2. Displaying the AVCN volumes along a linear

E 4 0 0 10 2 0 3 0 4 0

iii!i~

Oh E ~D m ~1 CO r,h b_ L L Od Oh

A g e

Pig. 2. AVCN volume growth from gestational age 90 days to juvenile age of 3 years. Each animal is identified by a code number indicating age of fetal specimen or postnatal age in days or months (or years, in the case of the juvenile monkey). Comparison of left and right AVCNs show small, inconstant differences (two cases yielded tissue from one side only). The marked rate at which antenatal volume increased was not sustained in the postnatal period. The inset shows measures based on a linear time scale in months and emphasizes the deceleration in growth rate immediately postnatally. Left AVCN: narrow hatch. Right AVCN: wide hatch.

61

1.0C 7, 100'-~ i - - I

Z

0.50 0.75

o 0 . 0 0 ~ L '- o.5c Z ~ 4o o 1~o 20 so 4o

s :,"

ooc ~ _ ~ 8 Oh ~ q9 ~ ',~ (13 m LL L ~_ oa Oh

A g e

Fig. 3. Length/volume ratios for the AVCNs of developing mon- keys. All ratios were made with reference to the right AVCN of a fetal specimen aged 90 days (F90) assumed as unity. The relation- ship between length and volume stabilized shortly after birth (note the constant low ratio from 3 days of age onward). The inset emphasizes the abrupt termination of differential changes in dimensions postnatally (linear time base in months). Left AVCN: narrow hatch. Right AVCN: wide hatch.

longitudinal time axis emphasizes the changing pattern of

growth during development (Fig. 2: inset). There are two

distinct arms of the curve characterizing the differential

pre- and postnatal growth rates. Although the left and

right sides had slightly different volumes, the tissues

displayed no systematically lateralized differences. The

left/right ratios of AVCN volumes ranged from 1.28 to

0.85.

The length and volume increments in the developing

AVCN were not in constant proportion. The distance

from the most rostral limit of the AVCN to the caudal

reference point (i.e. tip of PVCN) ranged from 0.36 mm

at 90 days gestational age to 1.2 mm at 3 years of age.

Although the medio-laterai and dorso-ventral dimensions

also increased, their increments were relatively less, as

indicated by a progressive decrease in length-to-volume

ratio. Thus, a nearly 4-fold length increment over the

course of development was associated with only a 10-fold

volume increase. Fig. 3 shows age-related decrements in

the length/volume ratio. These were very precipitous

prior to the neonatal stage (3 days postpartum). The plot

dissociates into two components reflecting a sharply

declining prenatal change and a very limited postnatal

decline. Each of the animals displayed bilaterally similar

patterns of AVCN growth. The left and right side AVCN

length/volume ratios of individual animals were closely

matched.

Cel l p a c k i n g d e n s i t y

We obtained complete counts of cells in the 5 equally

spaced sections that were analyzed, and from these

62

i i : l

i + / + 1 2 -

8 j l - 0 o 2~.

x

I o _ ' . 'S +F - %~'---~ -+'--

t

17 5 0 8*4

--+-- F S O

- - t + - - F N3

--o-- F 1 G b

.... 4- .... 3D --*-- 2 4 D --e-- 9 8 D

- - v - - 1 3 M

- - o - - 3 ~

Rostro-caudal s i t e ( ° 1 o )

Fig. 4. Cell packing density of AVCN at 8 different ages from mid-fetal to juvenile. Measures are displayed in relation to 5 rostro-caudai sites of the AVCN. Progressive decrements in packing density occurred as age increased. Slightly higher packing density was evident rostrally among most cases at various stages of development.

3oo[

I ~ +41 . . . . x' l i-~ +" "--- , . . . . I L - - - +

o---_.~.-+.~" . . . . . .=-+-- T-:+ ,4- . . . . . . . . . "4" . . . . . . . .

L_ ~ 1 0 0 ~ - / ' ~ . . . . a . . . . + - ~ - ~,u

<~ I / +

l 0 17 50 84

R o s t r o - c a u d a l s i t e ( ° / o

Fig. 5, Cross-sectional area of AVCN cells displayed in relation to rostro-caudal site and age. No consistent trend associating cell sizes with tile various points in the AVCN is found, although generalized increases throughout the entire structure were clearly evident at various stages of development up to 24 days of age. Beyond this age, there was little further change.

- - ~ .. . . i i ?

- - o - - ~- i 6 !

' + ' ~',C

- - a - - 2 " l L

- - e - - 9 8 D

--7--- ~ i F ,

numbers made estimates of the total number of cells in the AVCN (Table I). The cell packing density in each of these sections was also obtained and plotted separately.

The total number of cells in the two youngest fetal cases was found to be somewhat less than in the more mature animals. There were occasional instances of AVCN cell division in these fetal specimens, but none was seen in the perinatal and older cases. No further increments in cell numbers were found beyond the

neonatal stage. The packing density of AVCN cells diminished as the

animals matured (Fig. 4). The changes in packing density that were manifest in the prenatal period continued well into the postnatal period. The cell packing density at 90 days gestational age (approximately 12 cells per 100,000 tim a) decreased by half at the neonatal stage. This further diminished in the postnatal period, again by more than half to achieve an asymptotic value of approximately 3 cells per 100,000 #m 3 at some point between 3 months and 13 months of age.

The cell packing density at various points within the AVCN of individual animals were relatively constant, with the exception of marked local variability at 90 days gestational age. In this specimen the rostral AVCN exhibited relatively higher packing density, where there was also evidence of enhanced cell division. Generally, the rostral AVCN was characterized by slightly greater packing density in comparison to the most caudal zone.

Cell size

The average cell size increased with increasing age, and the underlying distribution broadened. The shape of the distributions yielded no subpeaks suggesting separate subpopulations separable according to size. Table I

summarizes the average cross-sectional area of cells measured in each case studied. The cells at gestational age 90 days were approximately half the size of those of the oldest case. Early in the neonatal period (day 24) the average cell size roughly equalled the size obtained for the 3-year-old animal.

Age-related growth of cells followed a similar course throughout the five AVCN areas that were examined. Fig. 5 shows the average size of cells in each o f the 5 sections from all specimens. There was n o evidence to indicate that cells in specific segments of the AVCN underwent different rates of growth during maturation. Further, we found no consistent asymmetry in the size of cells when comparing left and right AVCNs.

DISCUSSION

The overall geometry of the AVCN of the monkey cannot be directly compared with that of other species, such as human 14 or rat a, inasmuch as the reconstruction procedure used in the present work has not been applied to those other species. In the monkey, the roughly conical configuration of AVCN becomes increasingly accentuated during the maturational period, The result in the relatively mature monkey (3 years old) is a compact 'horn' or aggregation of cells comprising the rostral third of the AVCN, which continues to enlarge progressively in its caudal region. It appears that the adult human AVCN forms a blunter, more diffuse geometry TM.

The last half of the gestation period witnesses a large (approximately 6-fold) increase in AVCN volume, with further increments continuing postnatally. AVCN vol- ume growth is markedly greater than overall volume of the medulla, which approximately doubles in this

period 4. Postnatally, the volume of the macaque AVCN may increase 50-75% in reaching the advanced juvenile stage (3 years). Our single case at this age presented a larger volume than other, younger animals. This suggests that peripheral processes of the cells continue to grow, thereby forcing expansion of the boundaries of the nucleus. At 13 months of age the AVCN volume reaches a value which is about 80% of the 3-year (juvenile) monkey. The data do not speak to the question whether additional growth occurs beyond the juvenile stage.

Reports based on both the mouse and the human indicate that they undergo a relatively prolonged volu- metric development of the AVCN. Webster 22 reported

relatively slow growth of the mouse VCN during the immediate postnatal period, followed by a period of more rapid growth, in turn succeeded by slow, sustained expansion of volume. This slow growth persisted until the mice were terminated at 90 days of age (well beyond the age of sexual maturity). Measures of the absolute volume of the VCN increased almost 5-fold during this time. Coleman et al. 3 noted a 4-fold increase in volume of the mouse cochlear nucleus between postnatal age 10 days and the adult stage. The growth rate of VCN was approximately constant over this period.

The volume of the human AVCN undergoes an approximately 5-fold increase during postnatal matura- tion, reaching its maximum at middle age 9. At approx-

imately 1.5 years of age, the volume of ventral cochlear nucleus is slightly more than half the adult volume. Although we do not have full maturational data from monkeys, the comparative postnatal course of volumetric growth suggests that, in macaques, a far greater propor- tion of growth occurs prior to the juvenile stage.

Larsen m reported that the kitten AVCN volume stabilizes by age 12 weeks. The relatively early stabili- zation of this growth marker in cats resembles the pattern in monkeys, but both the cat and monkey exhibit cochlear nucleus growth characteristics that differ from the more prolonged growth found in human and mouse. The effect may represent species differences, or it may reflect differences in the techniques whereby growth changes have been measured.

Konigsmark and Murphy 9 showed that the variability in volume between left and right human AVCN is about 10%, with no clear evidence of consistently lateralized bias in size. Similarly, the monkey presents no strong indication of wide bilateral variation. If there is gross structural asymmetry associated with auditory lateraliza- tion in man or monkey, this is not expressed as a volume disparity at the level of the AVCN. Furthermore, left-right comparisons of the macaque tissues present no indication of systematic asymmetrical development with respect to cell packing density and cell size.

63

Our measures of the volume of the macaque AVCN ignored the caudal-most region (estimated at 15-20%) where AVCN, PVCN and DCN are juxtaposed. Unless there are differential age-dependent changes within the posterior AVCN, the estimates of macaque AVCN volume are assumed to be approximately 80-85% of the true value for all ages (unadjusted for shrinkage).

Volumetric changes in the monkey AVCN are prob- ably not due to extensive postnatal proliferation of nerve cells. Although the total number of AVCN cells at 90 days gestational age is approximately half the number seen in the juvenile monkey, the neonate displays about 75% of the maximum complement of cells. The similarity in total cell counts in the two animals that were studied at approximately full-term (F165, 3D), together with evidence of modest postnatal increments in cell numbers, reinforces the concept that the cell population evolves relatively early in the maturational period. This obser- vation agrees with evidence from the human, indicating that the infant has a full complement of AVCN cells 9.

The time course of AVCN cell development in the monkey does not fully parallel observations from the mouse (in which various studies present contradictory outcomes). Martin and Rickets ~1 demonstrated that mouse cochlear nucleus cells become differentiated in utero, the process occurring prior to the 15th gestational day. Indeed, all categories except small and granule cells can be identified prior to gestation day 13. Only glial cells emerged postnatally. However, Webster =, noted that cell differentiation in the mouse continues beyond the perinatal period. Webster 22 also observed that the num- ber of VCN neurons in the adult mouse approximately doubles between birth and maturity, but Mionyeni ~2 reported that the maximum population of cochlear nucleus cells occurs at the perinatal stage, with a significant decrease thereafter. Further information is required to resolve the conflicting evidence in the mouse, and to clarify the underlying differences with primates.

The defining features of different categories of cells are not as well delineated at the juvenile stage in the monkey as they are in other mammals 1 , and the cell types are virtually indistinguishable in animals at approxi- mately the mid-fetal stage of development. Thus the present study has not attempted to measure the sizes of different cell types.

The mature size of cells is apparently reached in the immediate postnatal stage in the macaque, whereas packing density and volume may increase over a some- what more prolonged postnatal period. The 3-year old macaque of the present study had an average cell size (all categories lumped together) of 200 ~m 2. This was virtually the same size as in the 24-day age animal. The early maturation in size of monkey AVCN cells agrees

64

with the evidence regarding the cat w, which achieves full

adult cell size in the young juvenile (i.e. within 7-10

weeks) but is dissimilar to the deve lopment sequence in

the mouse. Abso lu te cell size within the mouse AVCN is

r epor ted to increase over a pro longed per iod extending

well into adult life 22.

The juvenile M. nemestrina AVCN cell size is rela-

tively small in compar ison to the human (200/~m 2 vs 320

/~m e (Bacsik and Strominger l ) ) . We rarely found cells

with areas exceeding 300 /.tm 2. Our observat ions also

differ from another repor t on the macaque 7 (320 /~m 2

(ovoid cells), 383 ~m 2 (globular cells) and 112 ~m 2 (small

cells)). Differential staining techniques and criteria for

defining cytoplasmic boundar ies may account for the

dispari t ies observed.

Homogene i ty with respect to cell size throughout

various AVCN regions suggests that there are few, if any,

r emarkab le gradients in the young macaque, al though it

is our impression from fragmentary observat ions that

o lder macaques present some degree of segregation by

cell type (ovoid being somewhat more prevalent than

globular cells in rostral regions).

The cell packing density of A V C N varies across species

as well as relat ing directly to level of maturat ion. The cell

packing densi ty in the macaques of this study ranged

from approximate ly 12 cells per 100,000 ~m 3 in the

youngest specimen to 2 cells per 100,000/.tm 3 in the most

mature individual. Other species reveal 3- to 4-fold

decrements in cell packing density during the postnatal

matura t ion process. Konigsmark and Murphy 9 found

densities of 2.4 cells per 100,000 ~m 3 in the human

neonate , decreasing to approximate ly 0.7 cells per

100,000/~m 3 in the adult. Webster az and Willot t et al. 23

noted that the neonatal mouse exhibits approximate ly 18

cells per 100,000/2m 3, decreasing to about 6 cells per

100,000 ~m 3 at age 90 days.

The cell packing density in the cat AVCN was

examined by Larsen w, whose approach focused on

individual cell types. Larsen ' s observat ions in the kitten

indicated 0.005-0.015 cells of a given type per 100,000

t im 3, decreasing to approximate ly 0.004-0,008 cells per

100,000/~m 3 in the mature cat. Even presuming additive

values for each of 8 different cell types, the project ion of

total cell packing density ranges from 0.75 to 0.4 cells per

100,000 ~tm 3. Such values are sharply lower than mea-

sures obta ined from human, monkey , and mouse. Fur-

ther, Larsen repor ted only slight matura t ional changes in

AVCN cell packing density of the cat. In this feature the

cat appears to stand apar t from other species.

In summary, the overall geomet ry of the AVCN in the

developing macaque has a characterist ic, vaguely conical,

morphology. The AVCN exhibits substantial prenata l

volumetr ic changes, which are largely complete within a

few months postnatal ly, but may continue over a pro-

longed period. This per iod may extend for perhaps as

much as 3 years, al though we have only one case

represent ing the 'ma tu re ' stage. The size changes of

AVCN cells occur mainly prenata l ly , with relat ively little

addi t ional growth in the postnata l period. The packing

density follows a similar pat tern. In comparison to the

human, the growth-re la ted changes in the macaque

A V C N apparent ly occur during a relat ively a t tenuated

postnatal deve lopmenta l period. These views are offered

cautiously, given the l imited number of specimens avail-

able for the study.

Acknowledgements. This work was supported by NIH Grants NS 23930, NS 21440, RR 05588, RR 00166 and by the William G. Reed Fund.

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