Adult-lesioned Cats Research Articles

Cerebral metabolism following neonatal or adult hemineodecortication in cats: effect on oxidative capacity using cytochrome oxidase histochemistry

In order to determine the degree and extent of changes in cerebral oxidative capacity following cerebral hemineodecortication, adult cats which had undergone surgery early postnatally (mean age: 11.4 days) or during adulthood were studied using cytochrome oxidase histochemistry. A total of 18 animals were employed and 50 brain regions were quantified bilaterally using optical densitometry. Although many subcortical regions exhibiting extensive degenerative features revealed lower levels of cytochrome oxidase (C.O.) activity, this reduction was relatively unremarkable compared to intact controls. Nevertheless, it was interesting that this decrease (down to 66–89%) of normal was more pronounced in neonatal-lesioned cats, reaching significance in a number of ipsilateral thalamic nuclei, compared to adult-lesioned animals (91–100% of normal), suggesting a contribution of glial cells to the density of C.O. staining in the latter cats. Regions of the brain spared from degeneration exhibited a bilateral increase in C.O. activity which may reflect the demands for energy to support the anatomical reorganization which is prevalent in these animals. Surprisingly, such increases were more robust within spared regions of the adult-lesioned brain, reaching significance in four ipsilateral and nine contralateral areas with the density of the reaction attaining levels over 125% of control. This may indicate different demands for oxidative metabolism in the adult-lesioned cats. These results enhance our understanding of the mechanism(s) underlying the greater extent of functional sparing or recovery in cats sustaining injury to the cerebral cortex early vs. late in life. In addition, the findings complement our previous companion report on glucose metabolism supporting the concept of energy compartmentalization, which reflects the dynamic interaction between anatomical and functional changes in this age-at-lesion model of recovery.

Differences in D 2 dopamine receptor binding in the neostriatum between cats hemidecorticated neonatally or in adulthood

In order to study differences in response to neocortical injury sustained at different ages at the neurotransmitter level, we examined the density in D 2 dopamine receptors in the neostriatum of cats hemidecorticated neonatally ( N=4) or in adulthood ( N=4), as well as in intact brains ( N=6). Receptor densities were measured using quantitative autoradiography and [ 3H]-spiperone binding in 12 regions of the neostriatum and nucleus accumbens septi. We found that the anterior lateral caudate nucleus on both sides of the brain contained a higher D 2 receptor density in neonatal-lesioned as compared to adult-lesioned brains. Ipsilateral to the lesion, the increase was 101% ( P<0.05) and contralaterally it amounted to 77% ( P<0.05). Moreover, this region of the ipsilateral caudate nucleus of neonatal-lesioned cats tended to be more densely labeled than that of intact brain by 58% ( P<0.1). D 2 receptor densities in adult-lesioned cats did not differ from that of intact controls. Comparison of these data with those of a former morphological study using the same animals suggested that this bilateral elevation of D 2 receptor density in neonatally lesioned brains represents a higher mean density of binding sites per neuron. The elevation in the neonatal-lesioned cats might be a response of the striatum to neuroplastic changes in the striatal neuropil, including the corticostriatal afferents, since such changes are different in neonatal- as compared to adult-lesioned cats.

A critical period for reduced brain vulnerability to developmental injury: II. Volumetric study of the neocortex and thalamus in cats

Groups of young adult cats with a left hemineodecortication at postnatal (P) ages (in days) 5–15 (P10), 30 (P30), 60 (P60), 90 (P90), 120 (P120) and in adulthood, were used to measure the volume of the thalamus, bilaterally, and of the remaining neocortex (right hemisphere). The same subjects were employed for the behavioral studies reported in the preceding paper. There was a bilateral, age-dependent, thalamic volume decrease. Ipsilateral to the resection, the thalamic shrinkage was the largest for the adult-lesioned cats (by 56.7%) and it was the smallest for the P30 group (43.3%), with a tendency towards a greater atrophy as the age at lesion increased. A similar pattern of atrophy was seen for the contralateral thalamus but the volume reduction was much less pronounced such that it was significant only for the four older age-at-lesion groups (ranging from 18.2% to 11.2% for the P120 and P90 groups respectively). Once again, the shrinkage was the smallest for the P30 group (5.3%). The remaining neocortex also shrunk in these animals, but the volume decrease was significant only for the adult-lesioned (17.8%) and the P120 group (15.4%), while the P30 group had practically no shrinkage (2.4%). The frontal cortex had no atrophy or it was minimal but the shrinkage gradually increased caudally such that all lesioned groups had some size reduction of the occipital cortex. The present results, together with the main conclusion of the preceding paper, indicate that there is a critical maturation period (CMP) of reduced forebrain vulnerability to neocortical injury which, in cats, tends to end between 30 to 60 days postnatally. The implications for developmental brain damage in other higher mammal species as well as the possible morphological ontogenetical underpinnings of this period are discussed.

Quantitative cytoarchitectural analysis of cellular degeneration in the dorsal lateral geniculate nuclei of cats and kittens with cerebral hemispherectomy

Quantitative morphometry was used to study the effects of maturationally dependent responses to brain trauma on the cytologic organization of the dorsal lateral geniculate nucleus (LGd). The left hemitelencephalon was removed in adult cats and in neonatal kittens and resultant changes in cell size and density were compared between these groups and with intact controls. Morphological changes were found bilaterally in all lesioned cats. Ipsilaterally, geniculate volume was reduced by 23% in kitten-lesioned cats and by 33% in adult-lesioned cats. The geniculate of both lesion groups contained fewer neurons in all laminae than did the nucleus of intact cats, but only the adult-lesioned cats showed a substantial increase in glial cell counts. Contralaterally, there was a tendency for a lower neuronal density in both lesion groups, but this was significant only for the A-laminae of adult-lesioned cats. Therefore, neonatal lesions spared more neurons bilaterally and produced minimal ipsilateral gliosis compared to the adult ablation. Results are discussed within the context of the “Gudden effect” which asserts that there is more retrograde degeneration in neonatal versus adult brain-lesioned animals.

Sparing of visual field perception in neonatal but not adult cerebral hemispherectomized cats. Relationship with oxidative metabolism of the superior colliculus

Following cerebral hemispherectomy and using a lick-suppression test, adult-lesioned cats showed a complete contralateral hemianopsia, while neonatal-lesioned animals reliably responded to stimuli presented out to 45° in the visual field contralateral to the lesion. In adult-lesioned cats oxidative metabolism of the superior colliculus ipsilateral to the hemispherectomy was markedly depressed as compared to the contralateral colliculus. In contrast, in the neonatal-lesioned cats this metabolic imbalance was mild. We propose that this ipsilateral depression of oxidative metabolism reflects the loss of excitatory corticotectal input which has been postulated as being partly responsible for the hemianopsia following a unilateral visual cortex ablation. Here we demonstrate, in addition, that this phenomenon is affected by developmental factors and suggest that differential age-at-lesion anatomical effects may also be involved.

Bilateral pericruciate cortical innervation of the red nucleus in cats with adult or neonatal cerebral hemispherectomy

We studied remodeling of the remaining corticorubral projections in adult cats sustaining a left cerebral hemispherectomy in adulthood or neonatally using cortical injections of [ 3H]leucine-proline. Injection sites and terminal fields were reconstructed from autoradiography-processed tissue. In all cats, the label filled similar extents of areas 4γ and 3a of the right frontal cortex. We used sections at 8 coronal planes throughout the red nucleus (RN) for computer-assisted analysis of visually estimated density and topography of distribution of terminal label, and for calculation of RN cross-sectional area. Additionally, at 3 coronal planes we further quantified terminal label using computerized procedures (number of particles for surface area). In all lesioned cats we found terminal label in the RN contralateral to the injection site with a topographic distribution similar to that of the RN ipsilateral to the injection in normal or lesioned cats and in absence of any significant shrinkage of the nucleus. The difference between the 2 age-at-lesion groups was that in the cats with neonatal ablation the density of contralateral terminal label was about double that seen in adult-lesioned subjects. However, the amount of contralateral labeling in adult-lesioned cats was substantial and represented a significant increase over the minimal labeling seen in normal cats. There were no differences between groups in labeling or size of the RN ipsilateral to the injection site. For reasons discussed, we interpret the label on the side of the hemispherectomy as representative of reinnervation of the cortically deafferented RN by crossing collaterals of fibers arising in the remaining motor cortex and not as lesion-sustained persistent prenatal connections.

Novel crossed corticothalamic projections after neonatal cerebral hemispherectomy. A quantitative autoradiography study in cats

This is a quantitative study of remodeling of the corticothalamic projections in cats with a left cerebral hemispherectomy performed neonatally or in adulthood. Kittens were lesioned at a mean postnatal age of 10 days and compared, as adults, to adult-lesioned cats of prolonged survival time. All cats received injections of [ 3H]leucine-proline in the right pericruciate cortex and were sacrificed 5 days later. Injection site and terminal field areas were reconstructed from autoradiography-processed tissue. For the 3 animal groups the label filled a similar extent of cortical areas 4γ and 3a. Computerized procedures were used to count labeled particles from multiple bilateral sites of ventral thalamic nuclei (VTN), intralaminar nuclei and midline/paramedial regions at 2 thalamic coronal planes. In control cats the only labeling in the hemithalamus contralateral to the injection was in the intralaminar nuclei and medial-most region of VTN but the counts were low. In contrast, the contralateral hemithalamus of neonatal-lesioned cats showed: (a) a significant increase in terminal field density relative to control cats throughout the VTN, at both coronal planes, and with a distribution of labeling different to the intact side (suggesting heterotypic growth); (b) an increase in counts of labeled particles in intralaminar nuclei which was significant for one sampling site; and (c) an increase in counts for midline/paramedial regions which was significant for all sites at the caudal plane. Adult hemispherectomized cats were similar to intacts except for a tendency to increased VTN counts. These novel terminals were interpreted as collateral sprouting of corticofugal fibers from the intact motor cortex which crossed the midline to reinnervate the decorticate hemithalamus. Findings are discussed in the context of our reported behavioral and anatomical results.

Reorganization of Pericruciate cortical projections to the spinal cord and dorsal column nuclei after neonatal or adult cerebral hemispherectomy in cats

This is a quantitative study of changes in distribution and density of terminals of the corticospinal tract in the cervical spinal cord and dorsal column nuclei (DCN) in cats with left cerebral hemispherectomy performed neonatally or in adulthood. Kittens received hemispherectomy at a mean of 12.1 postnatal days and were compared, as adults, to adult-lesioned cats of similar survival time. All animals, including controls, received injections of [ 3H]leucine-proline and were sacrificed 5 days later. Injection sites and terminal fields were reconstructed from autoradiography-processed tissue. The label filled comparable extents of areas 4γ and 3a of the right cerebral cortex. Coronal sections from upper and lower cervical cord levels, and from the brainstem (cuneate and gracile nuclei) were studied. Computer-image processing procedures were used to count labeled particles from multiple sites of the dorsal horn and DCN, bilaterally. In the spinal cord of intact and adult-hemispherectomized cats, most terminals were found in lamina VI, and adjacent laminae V and VII contralateral to the injection side. The major finding was that neonatal-lesioned cats showed a significant increase in axon terminals in areas ipsilateral to the injection. The topography of distribution of the novel terminals was similar to that in the contralateral side and the originating fibers appeared to have crossed the midline from that side. A similar reorganization occurred in the gracile nucleus where, in intact and adult-lesioned cats, the cortical terminals also predominated in the side contralateral to the injection. In contrast, neonatal-lesioned animals showed a significant increase in terminal density ipsilateral to the cortical injection. These findings are discussed as an alternative mechanism for postlesion remodeling of the corticospinal tract in animals with the pyramidal crossing completed at the time of birth.

Recovery of functions after neonatal or adult hemispherectomy in cats. III. Complex functions: Open field exploration, social interactions, maze and holeboard performances

Complex behavioral patterns were studied in cats with removal of the entire left cerebral hemisphere either as neonates ( n = 10) or adults ( n = 11), and in intact control cats ( n = 24). Adult-lesioned cats showed decreased open field activity in locomotion, rearing and sniffing. Lesioned kittens showed similar deficits at 100 days of age, but by 150 days of age they resembled normal littermates in all 3 measures. In the presence of another cat, adult-hemispherectomized cats violated species-typical body-buffer space, approaching and attacking other cats. By comparison, normal cats never attacked and seldom approached in the open field. Neonatal-lesioned adults showed only occasional approach and a tendency to sit or stiff-walk in the presence of other cats; attacks were rare. Adult-lesioned cats responded poorly to reversal training for preferred arm of a T-maze, whereas neonatal-lesioned adults were significantly more trainable. Similarly, adult-lesioned cats exhibited a search deficit in a baited holeboard, while neonatal-lesioned adults searched normally. Overall, these results demonstrate that in this animal model, enhanced recovery following early vs adult lesions can also be found in relatively complex, spontaneous behavioral responses not previously studied in this regard.

Recovery of function after neonatal or adult hemispherectomy in cats. II. Limb bias and development, paw usage, locomotion and rehabilitative effects of exercise.

To investigate the relationship of age-related processes in the recovery of complex motor functions of the limbs, a variety of neurobehavioral assessments were applied to cats with either neonatal (n = 9) or adult (n = 11) removal of the entire left hemitelencephalon (hemispherectomy). Neonatal-lesioned kittens showed no paw preference in reaching for a manipulandum between 5 and 8 weeks of age; thereafter they developed a preference (5.6%) for the unimpaired left limb which persisted throughout adulthood. Adult-lesioned cats showed a significantly greater left bias (13.9%) than neonatal-lesioned cats and they exhibited more abnormal movements and postures when reaching with the impaired limb. Exercising the impaired limb, was effective in reversing the paw preference bias in all lesioned cats. To master a food retrieval task with the impaired limb, adult-lesioned cats required more trials than the neonatal-lesioned group, extensive food deprivation and at least 1 month of postsurgical recovery. However, after mastering this task all cats could continue to perform it indefinitely in their home cages. In a paw print analysis of locomotion, only adult-lesioned cats showed abnormalities including splayed paws, decreased stride length, and adduction of the right hind limb. The results support the 'Kennard Principle' of enhanced recovery following neonatal vs late brain lesions for the present complex motor patterns and are interpreted in the context of neural plasticity and anatomical reorganization during development.

There is less thalamic degeneration in neonatal-lesioned than in adult-lesioned cats after cerebral hemispherectomy

In order to study age-related processes of degeneration and recovery, the left hemitelencephalon was surgically removed in 5 adult cats and 5 neonatal kittens which were compared to 5 intact controls. After long survival, brains were sectioned in the coronal plane and thionine-stained. Drawings of gross and microscopic thalamic structures were made at 4 planes and computer-digitized to provide 7 measures: total thalamic area at planes A 7.5 and A 8.5; counts of neuroglia, small neurons (31-100 microns2) and large neurons (101-1000 microns2); area of neuroglia, small neurons and large neurons. All cellular measurements were in the ventrobasal complex at planes A 8.0 and A 10.0. Morphological changes were found bilaterally in all lesioned cats. Ipsilateral to the ablation in adult-lesioned cats, thalamic area, large neuron count and glia cells size were markedly and significantly decreased (P less than 0.01), while in neonatal-lesioned cats these changes were present but significantly reduced in magnitude compared to adult-lesioned animals. In addition, adult-lesioned cats showed a marked increase in glial cell numbers (P less than 0.01) and a decrease in small neuron size (P less than 0.01), while kitten-lesioned animals did not show changes in these measures. In the intact side of the brain, the thalamus of adult-lesioned cats was decreased in size (P less than 0.01), and glial cells were decreased in number and size (P less than 0.05), while in kitten-lesioned brains there were few changes. In both lesioned groups large neurons showed a significant increase in size (P less than 0.01). We conclude that neonatal hemispherectomy results in markedly less thalamic atrophy, retrograde neuronal degeneration and gliosis than the equivalent lesion in adults. The changes are discussed in the context of the increased neuroanatomical reorganization and functional recovery which were reported in neonatal- vs adult-lesioned animals.

Recovery of function after neonatal or adult hemispherectomy in cats: I. Time course, movement, posture and sensorimotor tests

Cats with removal of the left hemitelencephalon (hemispherectomy) as neonates (n = 12) or in adulthood (n = 14), were compared using a battery of 16 neurological and behavioral tests given when they were young adults (kittens) or at least 5 months after the lesion (adults). The neonatal-lesioned subjects grew normally and performed markedly and significantly better than adult-lesioned cats in 13 tests covering the wide range of movement, posture and sensory functions which were assessed. None of the animals recovered tactile placing of the right forelimb or a normal vision in the right visual field. However, the overall recovery was outstanding for all cats such that the neonatal-lesioned were hard to differentiate from intact controls in their spontaneous, daily activities. Because the lesions were similar in the two age-at-lesion groups, and since numerous functions were followed for prolonged, comparable postlesion time, we conclude that, after hemispherectomy in the cat, there definitely is greater functional recovery if the lesion is sustained early in life. We propose that the enhanced recovery of function in neonatal-lesioned cats is largely due to the extensive anatomical reorganization which we have demonstrated in ongoing studies, and which contrasts with a lesser remodeling in adult-lesioned cats.