abnormalities in cortical and subcortical morphology after neonatal neocortical lesions in rats

EXPERIMENTAL NEIJROUXY 79,223-244 (1983)

Abnormalities in Cortical and Subcortical Morphology after Neonatal Neocortical Lesions in Rats

BRYAN KOLB, ROBERT J. SUTHERLA~, AND IAN Q. WHISHAW

Department of Psychology, The University of Lethbridge, Lethbridge, Alberta TlK 3M4, Canada

Received June 4, 1982; revision received August 12, I982

The brain weight, cortical thickness, cross-sectional areas of subcortical structures, and various retrograde changes were compared in rats with neonatal or adult ablation of all or part of the neocortex. Neonatal lesions produced a widespread reduction in brain size accompanied by a variety of major structural changes including modification of the thickness of the residual cortex, necrosis and calcification of subcortical structures, and gross distortion of the structure of the hippocampus. The modification of the cortical thickness, but not the other changes, depended on the site and extent of cortical removal: neonatal frontal cortex ablation reduced the thickness of the remaining neocortex, neonatal posterior cortex ablation had no significant effect upon the thickness of the remaining neocortex, and neonatal hemidecortication increased the thickness of the remaining neocortex.

INTRODUCTION

Within the last decade our knowledge of the posttraumatic effects of brain injury has undergone a remarkable transition. Until about 1970 it was generally assumed that degeneration was the primary, and perhaps even the only, consequence of brain injury. Although sprouting of new axons after dorsal root transection was reported in the 1950s (23), regenerative posttraumatic changes within the brain were not reported until the 1970s (7, 24, 26, 32). It has now become clear that brain injury results in a variety of regenerative as well as degenerative changes. In addition, there is evidence that the embryo, infant, and adult respond very differently to injuries (7).

The possibility of differential anatomic effects of brain trauma at different ages is especially important because it may form a basis for the differing behavioral effects of lesions incurred at different ages, particularly if the locus of brain injury is in the neocortex (6). To date, however, most sys-

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0014-4886/83/010223-22$03.00/O Copyright 0 1983 by Academic Ress, Inc. All rights of reproduction in any form resewed

224 KOLB, SUTHERLAND, AND WHISHAW

tematic studies of these posttraumatic changes have concentrated upon the effects of subcortical lesions, although Hicks and D’Amato’s elegant studies of the effects of neocortical trauma both pre- and postnatally are an important exception (6-8). In the course of studying the recovery of function which follows removal of various neocortical regions of rats at different ages, various anatomic abnormalities were observed to follow cortical excisions at different ages (5, 14, 17, 18, 25, 37, 39). For example, neonatal removal of the frontal cortex allowed sparing of certain behavioral functions, even though the brains of these neonatal rats at maturity revealed a significantly thinner posterior neocortex, and the overall brain weight was reduced by about 15% relative to that of rats receiving analogous lesions in adulthood (18). We describe here in more detail the anatomic changes that we noted previously en passant in rats that had received bilateral or unilateral removal of all or part of the neocortex at different ages. We measured cortical thickness and brain weight, and examined the shape and structure of subcortical structures such as the thalamus and hippocampus.

METHODS

Subjects. The observations were made on 241 rats, derived from the Long-Evans strain, divided into 12 groups, 6 of which were operated upon as adults (120 days of age) and 6 of which were operated upon as neonates (2 to 6 days of age). Table 1 summarizes the gender, lesion location, and number of rats per group.

The frontal lesions included the entire frontal neocortex bilaterally anterior to bregma and the posterior lesions included the entire neocortex posterior to bregma. All neocortex was removed in the decorticate groups. The removals in the unilateral groups were similar in extent to the bilateral removals except that only one hemisphere was damaged. Half of the unilateral operations were carried out on the left hemisphere and half on the right hemisphere.

Surgical Procedure. The adult animals were anesthetized with sodium pentobarbital(50 mg/kg for male, 40 mg/kg for female rats). The frontal or posterior neocortex was exposed by removing the skull with rongeurs from bregma anterior to the frontal bone suture, and lateral to the rhinal fissure or posterior to bregma. Care was taken to leave intact the dorsal sagittal venous sinus and the anterior cerebral artery. After retraction of the dura the exposed neocortex was aspirated. Total decortication was achieved by removing both the frontal and posterior cortex. After establishing hemostasis the scalp wound was closed with wound clips. The operated controls were anesthetized, the scalp incised, and sutured with wound clips.

CORTICAL MORPHOGENESIS AFTER NEONATAL INJURY 225

The neonates were anesthetized by cooling them in a Thermatron cooling chamber until their rectal body temperatures were in the range of 18 to 20°C. (See Kolb and Whishaw (17) for details of this procedure.) The ap propriate skull bones were removed with iris scissors and ablation was achieved as in the adult rats. The incisions were sutured with silk thread as soon as the cortical removal was accomplished. The operated neonatal controls were anesthetized in the same manner, and the skin was incised and sutured.

Anatomical Procedure. At the conclusion of the experiments all rats were deeply anesthetized and intracardially perfused with 0.9% NaCl followed by 10% Formalin. The brains were removed, weighed, photographed, embedded in celloidin, and cut into 26-pm sections, which were mounted on glass slides and stained with cresyl violet. To ensure that the postoperative morphologic changes had stabilized in both the adult and neonatal operated groups we waited until 12 to 14 months postoperative to kill the rats.

Before weighing, the brains were all trimmed as follows: the spinal cord was cut off even with the caudal edge of the cerebellum, the cerebellar parallocculi were removed, the optic nerves were severed 1 to 2 mm anterior to the chiasm, the pineal gland was removed, and all remaining dura was stripped off.

Several measurements of both cortical and subcortical structures were made from projections of the processed tissue. (i) The thickness of the remaining neocortex was measured by projecting the NM-stained sections on a Zeiss DL 2 POL petrographic projector set at a magnification of 13X. Following the procedure of Diamond et al. (4), measurements were taken using a plastic millimeter rule at planes corresponding to the levels illustrated in Fig. lA, D, and F. The most anterior measurement was the only one that could be made in the posterior lesion rats, whereas the central and posterior measurements were the only ones that could be made in the frontal lesion rats. Three measurements were made at each plane in each hemisphere [see Fig. 3 in (18)] and the mean of these three measurements was taken as the neocortical thickness at that plane. (ii) The cross-sectional area of the remaining neocortex was measured by projecting the Nissl-stained sections from a Bausch & Lomb projector on an Apple II plus graphics tablet. The area function on the graphics tablet was selected and the perim- eter of the neocortex and cingulate cortex was traced at planes corresponding to K&rig and Klippel’s (20) A 4 110, A 3290, A 2580, and A 16 10. Similarly, the area of the thalamus and brain stem was measured at planes corresponding to K&rig and Klippel’s A 4110 and A 3290 for the thalamus and A 1610 for the brain stem. (iii) The length of the pyramidal and granule cell layers in the hippocampus were measured by selecting the distance


A __._.. .-I- I..,. _.-.. ___

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,’ I ’ \. ,- r\

.

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FIG. 1. Serial sections illustrating the plane of measurement of cortical thickness as well as computerized measurement of the cross-sectional areas of the neocortex, hippocampus, thalamus, and brain stem. A-H-see text.

function on the graphics tablet and then tracing the appropriate cell layers at planes corresponding to Kiinig and Klippel’s A 4110, A 3290, A 2580, and A 16 10. Because slight differences in the plane of sectioning can produce


rather large differences in the length of the pyramidal and granule cell layers it was frequently necessary to perform the hippocampal measurements on the let? and right hemispheres of individual brains on different sections in order to ensure consistency in locus measured.

RESULTS

The main finding was that although the adult and neonatal lesions involved comparable neocortical regions, the neonatally damaged brains showed dramatic cortical and subcortical changes distal to the lesion sites. These changes were different from the changes observed in the adult groups and dependent on the site of the neonatal lesion. The following sections summarize the changes that could be observed under light microscopy.

Gross Inspection. The cortical removals in analogous adult and neonatal groups appeared to be comparable upon gross inspection of both the brains and the photographs of the brains. The frontal cortex lesions removed all neocortex anterior to bregma including the prefrontal cortex of Leonard (21), the frontal polar cortex, and the anterior region of the motor cortex [Fig. 2; also see Figs. 1 and 2 in ( 18)]. The posterior cortex lesions removed all neocortex and cingulate cortex posterior to bregma including the au- ditory, visual, and parietal cortex in addition to occasional small amounts of the entorhinal cortex (see Fig. 2). The decortications removed all neocortex and most of the cingulate cortex as well as occasional small amounts of pyriform and entorhinal cortex. The restricted cortical excisions seldom involved direct damage to subcortical structures such as the caudate-putamen or thalamus but there was frequently superlicial damage to the hippocampus in the decorticate and posterior lesion rats [see Figs. 1 and 2 in Kolb and Whishaw ( 18)].

Bruin Weight. Table 1 summarizes the brain weights for the various groups. Owing to the gender difference in brain weight, we separated the male and female brains. Rats with neonatal frontal, posterior, or hemi- cortical lesions had significantly smaller brains than rats with similar excisions in adulthood. Neonatal decortication did not result in smaller brains, however, than occurred after adult decortication.

Neocorticul Thickness. Table 2 summa&es the measures of neocortical thickness. The main findings were: (i) the remaining posterior cortex of the rats with neonatal frontal removals was abnormally thin, (ii) the remaining anterior cortex of the rats with neonatal posterior removals was of normal thickness, and (iii) the undamaged hemisphere of the neonatal hemidecorticate rats was abnormally thick (Fig. 3).

Statistical analyses were made on the adult and neonatal control groups versus each set of analogous adult and neonatal lesion groups. Although we


nci. 2. Reconstructions of serial sections through an adult frontal cortex lesion rat (left) and an adult posterior cortex lesion rat (right). Black regions indicate areas of calcification and necrosis, light stippling indicates regions of gliosis, and diagonal lines indicate regions of cavity or ventricle.

reported elsewhere significant left/right differences in cortical thickness ( 15) we combined the data for the two hemispheres for the current analyses because we have found equivalent effects of neonatal lesions in the two hemispheres (16, 18). The analyses of variance and follow-up tests (alI are

CORTICAL MORPHOGENESIS AFIER NEONATAL INJURY

FIGURE 2 (Continued)

Tukey’s tests) are summarized in Table 2. Neonatal frontal lesions significantly reduced cortical thickness to 80 to 85% of control values ipsilateral to the lesion, but, if the contralateral side was undamaged, its cortical thickness was normal. In contrast, neonatal hemidecortication produces an in- creaSe of 10 to 15% in the unoperated neocortex, although this increase is significant only at the anterior and central planes of measurement.

Neocorticul Cross-sectional Area. The cross-sectional area of the left, undamaged, hemisphere in the neonatal hemidecorticate group was measured in five male rats and compared with the right and left hemispheres of five male control rats. The total cross-sectional area, calculated from the eight planes of the section illustrated in Fig. 1, was significantly greater (by 15%) in the hemidecorticate than control groups (two-tailed t = 3.06, df 13, P < 0.01).

Subcortical Measurements. The cross-sectional area of the thalamus and brain stem were measured at planes corresponding to Fig. lD, F, and H. The deco&ate and hemidecorticate groups were analyzed separately from the frontal and posterior cortex groups (see Tables 3 and 4). The overall finding was that neonatal neocortical lesions resulted in significantly smaller thalami than analogous adult lesions but there was no reduction in brain stem size after the early lesions. In addition, decortication at 2 days of age produced a smaller thalamus than decortication at 6 days of age. Neonatal


TABLE 1

Summary of Distribution to Groups and Mean Brain Weights in Each Group

Group

Adult Neonate t test

n weight (g) n weight (9) t P

Male rats Control Bilateral frontal Bilateral posterior Bilateral decorticate Unilateral frontal Unilateral decorticate N

Female rats Control Bilateral frontal Bilateral posterior Bilateral decorticate Unilateral frontal Unilateral decorticate N

10 8 5

20 17 20 80

5 8 7 0 0 0

20

2.257 1.966 1.933 1.424 2.175 1.755

2.052 1.729 1.842 -

10 8 7

15 12 10 62

10 13 6

15 19 16 79

2.174 0.6 NS

I .678 4.4 <O.Ol 1.768 3.2 co.01 1.484 1.1 NS 1.849 8.9 <o.o 1 1.671 4.2 co.01

2.066 1.636 1.623 1.424 1.598 1.607

0.2 2.4 2.7 -

NS

to.05 x0.01

-

frontal cortex lesions produced a smaller thalamic size than neonatal posterior cortex lesions, even though the latter lesions were much larger.

Simple analyses of variance comparing the decorticate and hemidecorticate groups to the control group showed significant main effects at both thalamic levels (F = 28.99, P < 0.001; F = 19.02, P < O.OOl), but not in the brain stem (F = 2.11, P < 0.09). A second analysis of variance was performed upon the brain stem measurement by collapsing across the experimental groups and comparing this group with the control group. This analysis revealed a significant main effect (F = 5.12, P < 0.03) that was presumably obscured by the relative insensitivity of Scheffe’s F to small differences in analyses with large numbers of similar groups. Tukey’s follow- up tests were carried out for all analyses and are summarized in Table 3.

Although there was no difference in the brain weights of the 2-day- and 6-day-old deco&ate rats, it was evident from inspection of the thalamus that there was a difference in the thalamic measurements. So, for this analysis the two neonatal decorticate groups were separated. The data showed that decortication at 2 days of age was associated with the development of a thalamus that was approximately 65 to 70% smaller than the thalamus of rats decorticated at 6 days of age. There was no difference in the size of the brain stem in the two groups (see Table 3).


TABLE 2

Summary of Neocortical Thickness Measurements0

@ouP n Adult Neonate F

Anterior measurement Control I 1.57 1.58 NS Biiteral posterior 7 1.62 1.62 1.9 NS Unilateral deco&ate 7 1.53 1.72 11.0, P < 0.01

Central measurement Control 7 1.37 1.38 NS Bilateral frontal 7 1.39 1.10 15.0, P < 0.01 Unilateral frontal

ipsi. 7 1.37 1.08 11.7, P < 0.01 contr. 7 1.43 1.38 0.7, NS

Unilateral deco&ate 7 1.36 1.51 7.0, P < 0.01

Posterior measurement Control 7 1.10 1.13 NS Bilateral frontal I 1.15 0.96 10.0, P < 0.01 Unilateral frontal

ipsi. 7 1.15 0.89 9.3, P < 0.01 contr. 7 1.13 1.12 0.6, NS

Unilateral decorticate 7 1.08 1.18 2.4, NS

’ Numbers indicate one-thirteenth of the value measured in centimeters on a Zeiss DL 2 POL petrographic projector set at a magnification of 13X. Values were obtained by taking the mean of the average left plus right measurements at each plane.

Analysis of variance of the measurements from the frontal and posterior groups showed a significant main effect at both the anterior and posterior thalamic levels as well as at the brain stem plane (F = 15.34, P < 0.001; F = 19.20, P c 0.001; F = 5.20, P < O.OOS), respectively. Follow-up tests (Tukey’s) are summarized in Table 4. The results showed that neonatal frontal lesions were associated with thalami that were much smaller than those observed to follow analogous adult frontal lesions. In particular, unlike adult frontal lesions, neonatal frontal lesions resulted in a 30% reduction in the area of the posterior thalamus, even though the nuclei at this level should not have been directly affected by the anterior cortical damage and did not show any obvious retrograde changes (see below).

Retrograde Changes. There were extensive retrograde changes in portions of the thalami of all operated rats. In the adult neonatal frontal groups, there was gliosis and cell loss in the dorsal medial nucleus (medial and lateral zones), the medial anterior and ventral anterior nuclei, and through- out the anterior and medial portions of the ventral nuclei (see Fig. 2). In


FIG. 3. Photomicrographs illustrating cortical thickness of a neonatal frontal (top), control (middle), and neonatal hemidecorticate (bottom) rat. The left photograph illustrates the cortical thickness on the dorsal lateral surface and the right photograph illustrates the cortical thickness on the ventral lateral surface, with the rhinal fissure shown at the far right, in the same section as the left-hand photographs.

addition to the gliosis and neuronal loss in the neonatal frontal group, several thalamic structures appeared markedly shrunken, especially the ventral nuclei. Although the particular nuclei were not individually measured, indirect confirmation of decreased size came from our measurements of cross-sectional area in the thalamus (see above).

In the adult and neonatal posterior groups, there was gliosis and extensive cell loss in the anterior dorsal and ventral nuclei, the lateral nucleus, and the lateral and medial geniculate nuclei (see Fig. 2). The degeneration was

CORTICAL MORPHOGENESIS AFl-ER NEONATAL INJURY 233

TABLE 3

Summary of Brain Stem and Thalamic Croswectional Areas in Decorticate and Hemidecorticate Groups’

Group n Anterior Posterior Brainstem

Control 7 loob loob 1W Adult decor&ate 5 50 59 84 6-Day decorkate 5 49 68 82 2-Day de4mticate 9 32b 48’ 89 Adult hemidecorticate 5 73c 75d 81 6-Day hemidecorticate 5 60 68 86

a Numbers are percentages of control value. b Differs from all other groups (P -c 0.01). ’ Differs from all other groups (P < 0.05). d Differs from adult decor&ate group (P -z 0.05).

more severe in the neonatal groups, for the lateral and dorsal lateral geniculate nuclei were virtually absent as only a thin layer of glial cells remained. The optic tract was still large, however, and there appeared to be an un- usually large projection to the optic tectum and pretectum, similar to that reported by Cunningham et al. (3).

The adult deco&ate and hemidecorticate groups exhibited a pattern of retrograde degeneration similar to a combination of the anterior and posterior removals, except that the ventral nuclei, especially the lateral zones, were more severely degenerated, possibly because neither the frontal nor posterior lesions completely removed the primary somatosensory cortex, whereas the decortications did. The neonatal deco&ate groups had a di& ferent pattern of degeneration from the adult group. Removal of all neocortex at 2 or 6 days of age produced substantial cell loss in the thalamus, but relatively little gliosis (see Fig. 4). Indeed, the absence of gliosis made it very difficult to identify the various nuclei. Only the medial nuclei ap peared relatively normal in shape and location. Although both the 2- and 6day operates showed this pattern of retrograde change, the effect was more pronounced in the younger operates. The older animals appeared to have more glial cells and the nuclei were easier to identify. In addition to cell loss and gliosis, there was a deposition of darkly stained material in the basal ganglia and thalamus of many of the operated animals (see Fig. 5). Some similar deposits have been reported (2, 17, 18, 22, 37, 39). In an earlier study (39) we used a stain specific for calcium (alazarin red) and found the tissue to be darkly stained. Pretreating the tissue with ethylene-


TABLE 4

Summary of Brain Stem and Thalamic Cross-sectional Areas in Frontal and Posterior Cortex Groups”

Thalamus

Group n Anterior Posterior Brain stem

Control Adult frontal Neonatal frontal Adult posterior Neonatal posterior

I 100 100 100 7 92’ 98 103 6 61b 70’ 91d 6 79d 80d 94d 7 81d 67’ 92d

n Numbers are percentage of control value. b Differs from all other groups (P < 0.01). ‘Differs from control group (P < 0.05 or netter). d Differs from control and adult frontal group (P < 0.05 or better). ’ Differs from control and adult operate groups (P < 0.0 1).

diaminetetracetic acid, which chelates free calcium, prevented this staining, thus implying the darkly stained tissue to be calcified.

Systematic Inspection of the Tissue. Table 5 summarizes the frequency of occurrence of this calcification in different structures. It was present in the caudate nucleus after cortical lesions in adulthood but very rarely followed neonatal surgery. It was present in the globus pallidus after adult decortication but never after posterior ablations. It was commonly observed in the ventral thalamus after adult or neonatal frontal cortex lesions and in the lateral nucleus, lateral geniculate nucleus, and anterior ventral nucleus after adult posterior lesions. It occurred in all these regions after decortication in adulthood or at 7 days of age. It is likely that the calcification formed in regions of necrotic cell bodies or axons as it appeared consistently in different regions in the frontal and posterior lesion animals (see Fig. 2). For example, after frontal lesions it was common in the globus pallidus and motor thalamus, whereas after posterior lesions, it was present in the dorsal caudate and posterior thalamus. The relative extent of this kind of degeneration could not be related to lesion size, however, particularly in the neonatal groups.

Hippocampal Abnormalities. Perhaps the most striking abnormality in the brains of the neonatal posterior and neonatal decorticate animals was in the hippocampus (see Fig. 6). Both Ammon’s horn and the dentate gyrus developed peculiar gyri and deformations that were clearest in the dorsal hippocampus. To determine if the hippocampus was smaller in the operated animals, the cross-sectional area of the hippocampus of eight control and

CORTICAL MORPHOGENESIS AFl-ER NEONATAL INJURY 235

four 2day neonatal deco&ate animals was measured using the graphics tablet of an Apple II plus computer, at planes corresponding to Fig. lE-H. In addition, the length of the dentate granule cell layer and the pyramidal cell layer was estimated at the same planes using the graphics tablet. The results showed that the cross-sectional areas and cell layer lengths were nearly identical in the two groups (two-tailed t tests, P’s > 0.20). Thus, it appears that although there are gross distortions in the hippocampus, its size is not significantly altered.

DISCUSSION

Our comparison of the effects of neonatal and adult ablation of all, or part, of the frontal and posterior cortex of rats revealed that the age at surgery was importantly related to changes in the structure of the remaining brain. Neonatal lesions produced a widespread reduction in brain size accompanied by a variety of major structural changes including modification of the thickness of the residual cortex, necrosis and calcification of subcortical structures, and gross distortion of the structure of the hippocampus. Some of these changes have been reported elsewhere to follow neonatal neocortical lesions in cats (10) and rabbits (29). The results of studies on rats, cats, and rabbits are thus in general agreement that, from a morphological point of view, early brain damage must be considered to produce more anomalies than later brain damage.

The general reduction in brain size after subtotal removal of the neocortex in infancy indicates that the effects of early brain damage are more diffuse than after comparable damage in adults. Subtotal lesions of both the frontal and posterior neocortex in infancy reduced wet brain weight and thalamic size, and neonatal frontal lesions reduced the thickness of the residual neocortex. (It is interesting to note however, that total decortication in infancy did not produce a smaller brain than comparable lesions in adulthood.) Like the previous studies of cats (10) and rabbits (29), we found gross distortions in the structure of the hippocampus of early operates but, unlike the earlier studies, we found no evidence that the hippocampus was smaller after neonatal lesions.

In contrast to the consistent reduction in brain size that follows subtotal neocortical lesions in infancy, the remaining neocortex could be either decreased, increased, or unchanged in thickness depending on the placement of the neonatal excision. Removal of the frontal cortex resulted in a posterior neocortex that was 20% thinner than in the control or adult-operated brains or, in the case of unilateral frontal lesions in infancy, than the neocortex in the intact hemisphere. In contrast, removal of all cortex of one hemisphere resulted in an increase of 15% in the thickness of the intact hemi-


FIG. 6. A collage of photomicrographs illustrating hippocampal distortion in neonatally decorticated brains. The photomicrographs on the facing page show paired sections from each of four animals. The photographs below are higher magnifications of sections from two animals shown on the left. Note the relatively normal appearance of the pyramidal and dentate cell layers, despite the overall distortion of the hippocampus.


FIGURE 6 (Continued)

sphere. Removal of the posterior neocortex did not significantly alter the thickness of the anterior cortex.

In view of the variable nature of the effects of neonatal lesions on the thickness of the neocortex, a simple explanation in terms of blood supply or nutrition can hardly account for the data. Perhaps the changes in cortical thickness could result from alterations in catecholamine or other transmitter concentrations. Because more is known about noradrenaline at present, discussion about its possible involvement will serve as an example. Norad- renergic projections to the neocortex pass through the entire medial and dorsolateral surface of the frontal cortex (27, 28, 31) en route to innervate the entire neocortex. Because it has been suggested that noradrenaline is necessary for neocortical plasticity ( 11, 12), it seems likely that interruption of noradrenergic input to the residual cortex could affect development. In particular, removal of the frontal neocortex would be expected to reduce the noradrenergic projections to the posterior cortex, whereas removal of


TABLE 5

Summary of Frequency of Calcification in Basal Ganglia and Thalamus

n Caudate-Putamen Globus pallidus Thalamus

Control 10 0 1 0 Adult frontal 12 8 3 4 Neonatal frontal 7 0 0 7 Adult posterior 6 4 0 6 Neonatal posterior 8 0 0 1 Adult decorticate 9 7 8 9 7-Day decorticate 9 2 4 9 2-Day decorticate 10 0 0 4

the posterior neocortex would have little or no effect on the noradrenergic projections to the frontal cortex. Indeed, we found (34, 35) that neonatal frontal cortex lesions reduced noradrenaline in the posterior cortex by approximately 60%. We have no data on noradrenaline concentrations after neonatal posterior cortex lesions, however.

If a decrease in noradrenaline input to the posterior cortex results in a decrease in the thickness of this cortex, then it is plausible to propose that an increase in noradrenergic projections to the contralateral hemisphere after neonatal hemispherectomy could increase cortical thickness. This does not occur, however, as it has been shown (36) that neonatal hemispherectomy resulted in a chronic increase in brain stem but not neocortical noradrenaline. Perhaps the increased cortical thickness after neonatal hemidecortication, rather than neonatal hemispherectomy, is associated with increased noradrenaline in the contralateml cortex, but at present it appears that the increased cortical thickness is more likely to result from some other factors such as an increase in cortical efferent fibers to ipsilateral and contralateral structures (7).

Finally, are the chronic changes in the brain observed alter neonatal subtotal cortical lesions related to behavior? Lesions of the frontal cortex of rats in infancy are associated with substantial sparing of function on a variety of behavioral tests [e.g., (13, 14, 16, 18, 30, 34, 391, and hemidecortication is associated with sparing of function on certain cognitive (16) and motor (7) tests. There are few studies of rats with neonatal posterior lesions as large as those in our study but there is little evidence for sparing of visual functions in rats with similar lesions (1). Neonatal decortication is not associated with any sparing of function (17). The fact that sparing of function occurs in the presence of smaller brains and independent of the thickness of the residual cortex suggests that behavioral sparing may occur

CORTICAL MORPHCKIENESIS AFTER NEONATAL INJURY 243

in spite of, rather than because of, the changes in the brain. This view is consistent with the increasing skepticism regarding the extent of behavioral sparing that follows brain injury in infancy (9, 10, 19, 32, 33), and the necessity for careful and thorough behavioral observation (19,38).

REFERENCES

1. BLAND, B. H., AND R. M. COOPER. 1970. Experience and vision of the posterior neo deco&ate rat. Physiol. Behav. 5: 21 l-214.

2. BRAUN, J. J. 1975. Neocortex and feeding behavior in the rat. J. Comp. Physiol. Psychol. 89: 507-522.

3. CUNNINGHAM, T. J., C. HUDDELSTON, AND M. MURRAY. 1979. Modification of neuron numbers in the visual system of the rat. J. Comp. Neural. 184: 423-434.

4. DIAMOND, M. C., R. E. JOHNSON, AND C. A. INGHAM. 1975. Morphological changes in the young, adult and aging rat cerebral cortex, hippocampus, and diencephalon. Behav. Biol. 14: 163-174.

5. GOLDMAN, P. S. 1976. Maturation of the mammalian nervous system and the ontogeny of behavior. Adv. Study Behav. 2 l-90.

6. HICKS, S. P., AND C. J. D’AMATO. 1970. Motor sensory and visual behavioral alter hemispherectomy in newborn and mature rats. Exp. Neurol. 29: 416-438.

7. HICKS, S. P., AND C. J. D’AMATO. 1975. Functional adaptation after brain injury and malformation in early life in rats. Pages 27-47 in N. E. ELLIS, Ed., Aberrant Development in Infancy. Wiley, London.

8. HICKS, S. P., AND C. J. D’AMATO. 1980. Development of the motor system: hopping rats produced by prenatal irradiation. Exp. Neural. 70: 24-39.

9. k%4ACSGN, R. L. 1975. The myth of recovery From early brain damage. Pages l-25 in N. E. ELLIS, Ed., Aberrant Development in Infancy. Wiley, London.

10. ISAACSON, R. L., A. J. NONNEMAN, AND L. W. SCHMALTZ. 1968. Behavioral and anatomical sequelae of damage to the infant limbic system. Pages l-2 1 in R. L. ISAACSON, Ed., The Neuropsychology of Development. Wiley, New York.

11. KASAMATSU, T., AND J. D. PETrIGREW. 1976. Depletion of brain catecholamines: failure of ocular dominance shift after monocular occlusion in kittens. Science 194: 206-209.

12. KASAMATSU, T., J. D. PETTIGREW, AND M. ARY. 198 1. Cortical recovery from effects of monocular deprivation: acceleration with norepinephrine and suppression with 6-hydroxydopamine. J. Neurophysiol. 45: 254-266.

13. KOLB, B., AND A. J. NONNEMAN. 1976. Functional development of the prefrontal cortex in rats continues into adolescence. Science 193: 335-336.

14. KOLB, B., AND A. J. NONNEMAN. 1978. Sparing of function in rats with early prefrontal cortex lesions. Brain Res. 151: 135-148.

15. KOLB, B., R. J. SUTHERLAND, A. J. NONNEMAN, AND I. Q. WHISHAW. 1983. Asymmetry in the cerebral hemispheres of the rat, mouse, rabbit and cat: the right hemisphere is larger. Exp. Neural. 78: 348-359.

16. KOLB, B., R. J. SUTHERLAND, AND I. Q. WHISHAW. 1983. Neonatal hemidecortication or frontal cortex ablation produce similar behavioral sparing but opposite effects upon morphogenesis of remaining cortex. Behav. Neurosci., in press.

17. KOLB, B., AND I. Q. WHISHAW. 1981. Decortication of rats in infancy or adulthood produced comparable functional losses on learned and species-typical behaviors. J. Comp. Physiol. Psycho/. 95: 468-483.

18. KOLB, B., AND I. Q. WHISHAW. 198 1. Neonatal frontal lesions in the rat: sparing of learned


but not species-typical behavior in the presence of reduced brain weight and cortical thickness. J. Comp. Physiol. PsychoI. 95: 863-879.

19. KOLB, B., AND I. Q. WHISHAW. 1982. Principles and problems in cross-species generaliza- tions. In T. E. ROBINSON, Ed., Behavioral Contributions to Brain Research. Oxford Univ. Press, New York, in press.

20. KOENIG, J. F. R., AND R. A. KLIPPEL. 1963. The Rat Brain. Williams&Wilkins, Baltimore. 21. LEONARD, C. M. 1969. The prefrontal cortex of the rat: I. Cortical projections of the

mediodorsal nucleus. II. Efferent connections. Brain Rex 12: 321-343. 22. LEVINE, S. 1960. Anoxic-ischemic encephalopathy in rats. Am. J. Pathol. 36: l-17. 23. LIU, C. M., AND W. W. CHAMBERS. 1958. Intraspinal sprouting of dorsal root axons.

Arch. Neurol. Psychiatr. 79: 46-61. 24. LUND, R. D., AND J. S. LUND. 1973. Reorganization of the retinotectal pathway in rats

after neonatal retinal lesions. Exp. Neurol. 40: 377-390.

25. LYNCH, G., B. STANHELD, AND C. W. COTMAN. 1973. Developmental differences in post- lesion axonal growth in the hippocampus. Brain Res. 59: 155-168.

26. MOORE, R. Y., A. BJORKLUND, AND U. STENEVI. 197 1. Plastic changes in the adrenergic innervation of the rat septal area in response to denervation. Brain Res. 33: 13-35.

27. MORRISON, J. H., M. E. MOLLIVER, AND R. GRZANNA. 1979. Noradrenergic innervation of cerebral cortex: widespread effects of local cortical lesions. Science 205: 3 13-3 16.

28. MORRISON, J. H., M. E. MOLLIVER, R. GRZANNA, AND J. T. COYLE. 1981. The intracortical trajectory of the coeruleo-cortical projection in the rat: a tangentially or- ganized cortical afferent. Neuroscience 6: 139- 158.

29. NONNEMAN, A. J., 1970. AnatomicalandBehavioral Consequences ofEarly Brain Damage

in the Rabbit. Unpublished doctoral dissertation, University of Florida, Gainesville. 30. NONNEMAN, A. J., AND J. V. CORWIN. 1981. Differential effects of prefrontal cortex

ablation in neonatal, juvenile, and young adult rats. J Comp. Physiol. Psychol. 95: 588- 602.

31. SCHLUMPF, M., W. J. SHOEMAKER, AND F. E. BLOOM. 1980. Innervation of embryonic rat cerebral cortex by catecholamine-containing fibers. J. Comp. Neurol. 192: 36 l-376.

32. SCHNEIDER, G. 1973. Early lesions of the superior colliculus: factors affecting the formation of abnormal retinal projections. Brain, Behav. Evol. 8: 73-109.

33. ST. JAMES-ROBERTS, I. 198 1. A reinterpretation of hemispherectomy data without functional plasticity of the brain. Brain Lang. 13: 3 l-53.

34. SUTHERLAND, R. J., B. KOLB, J. B. BECKER, AND I. Q. WHISHAW. 198 1. Neonatal 6- hydroxydopamine administration eliminates sparing of function after neonatal frontal cortex damage. Sot. Neurosci. Abstr. 7: 41.

35. SUTHERLAND, R. J., B. KOLB, J. B. BECKER, AND I. Q. WHISHAW. 1982. Cortical noradrenaline depletion eliminates sparing of spatial learning after neonatal frontal cortex damage in the rat. Neurosci. Lett. 31: 27 l-276.

36. TOYAMA, M., AND M. STAKE. 1981. Increased concentration and accelerated synapto- somal uptake of noradrenaline in the central nervous tissues of neonatally hemispher- ectomized adult rats. Brain Res. 208: 447-450.

37. WHISHAW, I. Q., AND B. KOLB. 1983. Can male decorticate rats copulate? J. Comp.

Physiol. Psychol., in press. 38. WHISHAW, I. Q., B. KOLB, AND R. J. SUTHERLAND. 1982. The analysis of behavior in the

laboratory rat. In T. E. ROBINSON, Ed., Behavioral Contributions to Brain Research. Oxford University Press, New York, in press.

39. WHISHAW, I. Q., T. SCHALLERT, AND B. KOLB. 198 1. An analysis of feeding and sensori- motor abilities of rats alter decortication. J. Comp. Physiol. Psychol. 95: 85-103.

abnormalities in cortical and subcortical morphology after neonatal neocortical lesions in rats

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