Sexually dimorphic responses to neonatal basal forebrain lesions in mice: I. Behavior and neurochemistry

The nucleus basalis magnocellularis (nBM) provides the primary source of cholinergic input to the cortex. Neonatal lesions of the nBM produce transient reductions in cholinergic markers, persistent abnormalities in cortical morphology, and spatial navigation impairments in adult mice. The present study examined sex differences in the effects of an electrolytic nBM lesion on postnatal day 1 (PND 1) in mice on behavior and neurochemistry in adulthood. Mice were lesioned on PND 1 and tested at 8 weeks of age on a battery of behavioral tests including passive avoidance, cued and spatial tasks in the Morris water maze, simple and delayed nonmatch to sample versions of an odor discrimination task, and locomotor activity measurements. Following behavioral testing, mice were sacrificed for either morphological assessment or neurochemical analysis of a cholinergic marker or catecholamines. There were no lesion or sex differences in acquisition or retention of passive avoidance, performance of the odor discrimination tasks, or activity levels. Control mice showed a robust sex difference in performance of the spatial water maze task. The lesion produced a slight cued but more dramatic spatial navigation deficit in the water maze which affected only the male mice. Neurochemical analyses revealed no lesion-induced changes in either choline acetyltransferase activity or levels of norepinephrine or serotonin at the time of testing. The subsequent report shows a sex difference in lesion-induced changes in cortical morphology which suggests that sexually dimorphic cholinergic influences on cortical development are responsible for the behavioral deficits seen in this study.     

Retrograde degeneration of thalamic neurons in the mediodorsal nucleus after neonatal and adult aspiration lesions of the medial prefrontal cortex in the rat. Implications for mechanisms of functional recovery

The behavioural consequences of neonatal lesions of the frontal cortex are limited as compared with similar lesions performed in adulthood. The present study has investigated, using unbiased quantitative methods with randomized systematic sampling, the total neuronal cell numbers in the mediodorsal nucleus of the thalamus after aspiration lesions of the medial prefrontal cortex performed in neonatal and in adult rats. It was found that the reduction in total cell numbers after neonatal prefrontal cortex lesions was similar to that found after adult cortex lesions. In neonatally lesioned animals the neuronal cell density was significantly increased by 13%, whereas in adult lesioned animals it was unchanged. On the other hand, the volume of the mediodorsal nucleus was reduced by 27% in neonatally, and 20% in adult lesioned animals. Total neuronal cell number of the mediodorsal nucleus was significantly decreased in neonatally as well as in adult lesioned rats, by 14% and 21%, respectively. These findings are discussed in the light of the previously proposed role of the thalamus as a neural substrate of functional sparing after neonatal cortical lesions.     

Effects of neonatal mediodorsal thalamic lesions on structure and function of the rat prefrontal cortex

The morphological and behavioral effects of neonatal electrothermal lesions of the mediodorsal thalamus on the development of the prefrontal cortex were studied. Lesions of the mediodorsal nucleus (MDT), inflicted on the day of birth, caused no significant changes in prefrontal architecture on day 35. On the other hand, a significant decrease in cortical width (4.7-7.7%) was observed at some places within the lateral and supragenual parts of the prefrontal cortex. However, these local decreases in cortical width were not reflected by a significant decrease of the total volume of the particular prefrontal subareas. In adulthood, rats with neonatal MDT lesions were exposed to an operant delayed alternation task, which is known to depend upon the integrity of the prefrontal cortex, in order to investigate the behavioral consequences of the lesions for prefrontal functioning. The lesions did not impair the rats abilities to learn the spatial delayed alternation task. Neonatally lesioned and control rats scored equally. Given the relatively mild effects of MDT lesioning, thalamic fibers do not seem to play a crucial role, at least not during the postnatal period of prefrontal cortical development. It is discussed whether or not this is a specific characteristic of agranular association cortex, in which the termination of thalamic and cortical afferents overlap in layer III.     

CHRONOMERGE: an application for the merging and display of multiple time-stamped data streams

Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.     

Neonatal motor cortex lesions in the rat: Absence of sparing of motor behaviors and impaired spatial learning concurrent with abnormal cerebral morphogenesis.

Eight rats with removal of the motor cortex in adulthood were compared behaviorally and neuroanatomically with 10 rats with similar removals at 4 days of age. Results suggest that neonatal ablation of the motor cortex of rats is more debilitating behaviorally than similar injury in adulthood and produces abnormal morphogenesis of the posterior neocortex. Neonatal lesions of the motor cortex produced more chronic abnormalities in movements of the distal effectors that accompany adult lesions (tongue, snout, and digit use) and, in addition, produced abnormalities in limb placement on a narrow beam and a significant impairment in spatial learning, neither of which is associated with adult lesions. When the brains of neonatally operated Ss were compared with those of 10 controls or 5 Ss operated on in adulthood, there were striking differences. Although the area of cavity appeared smaller in the neonatal operates, their brains weighed less, the neocortex was thinner, and the cross-sectional area of the remaining cortex was reduced, when compared with those of the adult-operated group. It is suggested that studies of the acquisition of various neuropsychological learning tasks may have greatly overestimated the degree of sparing following anterior neocortical lesions in rats. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Extracellular matrices expression in invasion area of adenoid cystic carcinoma of salivary glands

Transient Cajal-Retzius (CR) cells in layer I of the mammalian cerebral cortex are the first postmitotic neurons and they are believed to play a role in neuronal migration and lamination during cortical development. Freezing insults to the cortex of newborn mice produce cortical malformations similar to those observed in human brain disorders. Here we have used calretinin immunostaining to investigate the response of CR cells to freezing lesions of the cortical surface. Shortly after injury, CR cells disappeared from the lesioned zone. Moreover, CR cells located near the lesioned area adopted extremely fusiform shapes. At later postnatal stages (P12), CR cells were still abundant in layer I of the lesioned zone, in contrast to their almost complete loss in control animals. These results show that CR cells survive for longer developmental periods following cortical injury. Furthermore, the initial loss and later re-appearance of CR cells suggest that these neurons might migrate tangentially from the cortical areas surrounding the lesioned zone. These findings imply a role for CR cells in brain repair after cortical injury during development.     

Dissociation of attention in learning and action: Effects of lesions of the amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex.

Many associative learning theories assert that the predictive accuracy of events affects the allocation of attention to them. More reliable predictors of future events are usually more likely to control action based on past learning, but less reliable predictors are often more likely to capture attention when new information is acquired. Previous studies showed that a circuit including the amygdala central nucleus (CEA) and the cholinergic substantia innominata/nucleus basalis magnocellularis (SI/nBM) is important for both sustained attention guiding action in a five-choice serial reaction time (5CSRT) task and for enhanced new learning about less predictive cues in a serial conditioning task. In this study, the authors found that lesions of the cholinergic afferents of the medial prefrontal cortex interfered with 5CSRT performance but not with surprise-induced enhancement of learning, whereas lesions of cholinergic afferents of posterior parietal cortex impaired the latter effects but did not affect 5CSRT performance. CEA lesions impaired performance in both tasks. These results are consistent with the view that CEA affects these distinct aspects of attention by influencing the activity of separate, specialized cortical regions via modulation of SI/nBM. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The laminar organization of the afferent connections of the cortical column in field 17 in the cat

The laminar structure of the cortical column connections in area 17 of the cat was studied using the microiontophoretic injection of the horseradish peroxidase. Following the enzyme injection in one column at different depths below the cortical surface the identification of morphological types of labelled neurons and the estimation of their localization were performed. When enzyme has been delivered in the whole depth of the column pyramidal neurons labelled were found in upper (I/III) and lower (V/VI) layers (ratio II;I). When the depth of enzyme injection exceeded the cortex width the cells in layer IV were labelled as well. The ratio between the quantity of cells labelled in upper and lower layers was preserved. (II; I). After the enzyme injection in the upper part of the column labelled cells were found mainly in the upper layers. It is concluded that the neurons of the column of have extensive (up to 5 mm), predominantly horizontal afferent connections with the cells in upper and lower layers while the connections with neurons in layer IV are local and do not extend beyond 0.5 mm.     

Postnatal development of calcium-binding proteins calbindin and parvalbumin in human visual cortex

In adult primate visual cortex, the calcium-binding proteins calbindin (CB) and parvalbumin (PV) are localized in different subsets of GABAergic neurons with a characteristic laminar distribution. However, the emergence and development of CB and PV in relation to the periods of functional maturation of the human visual cortex are not known. Therefore, we examined (i) postnatal changes in the distribution of immunoreactivity (ir) for CB and PV in the visual cortex; (ii) the pattern of changes in immunoreactivity in relation to the synaptic maturation; and (iii) differences in the maturation of CB and PV immunoreactivity between areas 17 and 18. We found a consistently high expression of CB in neonatal visual cortex, particularly in layer IV and infragranular layers. However, despite an early appearance of PV, its peak in development occurred only after 2 months of age, characterized by a transient overexpression in the thalamo-recipient layer IV and a continuous inside-out maturation in supragranular layers. The neonatal pattern of high CB-ir in layers IV-VI was transformed during infancy and childhood into an adult pattern of high CB-ir in layer II, but low CB-ir in layer IV and infragranular layers. There was no difference in pattern and tempo of maturation of calcium-binding proteins between area 17 and 18, indicating simultaneous development of cortical inhibitory circuits among cytoarchitectonically and functionally distinct cortical areas. In addition, the reorganization of CB/PV expression temporally and spatially coincides with the course of cortical synaptogenesis, and delineates the major stages of maturation of the human visual cortex.     

Differential sparing of depth perception, orienting, and optokinetic nystagmus after neonatal versus adult lesions of cortical areas 17, 18, and 19 in the cat.

Performance by cats with lesions of the visual cortex made in infancy or adulthood was examined on tasks of visually guided behavior that do not require specific training. Cats with lesions confined to areas 17, 18, and 19 made during the 1st postnatal week showed more sparing of function on a visual cliff, at orienting to targets suddenly appearing in the visual field, and at optokinetic nystagmus than did cats with equivalent damage incurred as adults. Cats with lesions that included areas 17, 18, 19 and most of the contiguous visual areas were severely impaired at all tasks whether the lesions were incurred neonatally or in adulthood. These findings suggest that sparing of vision after neonatal lesions of cortical areas 17, 18, and 19 is not confined to pattern learning tasks and that remaining lateral cortical visual areas are importantly involved in such sparing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disconnection of the amygdala central nucleus and substantia innominata/nucleus basalis disrupts increments in conditioned stimulus processing in rats.

Rats with a neurotoxic lesion of the amygdala central nucleus (CN) in one hemisphere and a 192 immunoglobulin G (192IgG)-saporin lesion of cholinergic neurons in the contralateral substantia innominata/nucleus basalis (SI/nBM) failed to show the enhanced attentional processing of a conditioned stimulus (CS) observed in sham-operated rats when that CS's predictive value was altered. Performance of these asymmetrically lesioned rats was poorer than that of rats with a unilateral lesion of either structure or with a symmetrical lesion of both structures in the same hemisphere. These results implicate connections between the CN and SI/nBM in the incremental attentional processing of CSs, extending previous research that has shown similar effects of bilateral lesions of either the CN or the SI/nBM. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neonatal hemidecortication or frontal cortex ablation produces similar behavioral sparing but opposite effects on morphogenesis of remaining cortex.

Made behavioral comparisons between Long-Evans rats with complete removal of the neocortex of one hemisphere (hemidecorticate) or of the cortex anterior to bregma in both hemispheres (frontal cortex) in adulthood and rats with similar removals at 7 days of age. Neonatal ablation of the frontal cortex produced partial sparing of performance on the Morris water task and reduced the thickness of the remaining neocortex. Neonatal hemidecortication produced similar sparing of function on the water task but increased the thickness of the contralateral neocortex. Results are consistent with hemispherectomy studies done with children and imply that behavioral sparing following neonatal cortical lesions is independent of the gross morphogenesis of the remaining neocortex. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visual discrimination by cats given lesions of visual cortex in one or two stages in infancy or in one stage in adulthood.

Sparing of visual function was studied in cats with bilateral cortical damage to Areas 17 and 18 and most of Area 19. Cats with lesions made in 2 stages, on Postnatal (P) Days 3 and 6, in 1 stage on P6, or in 1 stage in adulthood were compared with sham-operated controls on 10 visual discrimination tasks. On some tasks, both groups of cats that underwent surgery as infants showed considerable sparing of function compared with cats that had surgery as adults; the latter group showed a marked impairment. However, on several of the discriminations, 2-stage lesions permitted almost total sparing of pattern vision, whereas 1-stage lesions made neonatally were almost as debilitating as those incurred in adulthood. The findings suggest that differential behavioral consequences can follow physiological or anatomical changes, or both, that occur within a 4-day neonatal interoperative period. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The impact of muscular dystrophy on limb bone growth and scaling in mice

Muscular loading affects bone growth and the factors determining size and shape. However, it is not known what epigenetic impact muscular dystrophy (dystrophia muscularis) has on limb bone growth or ontogenetic scaling. To assess the effects of two types of muscular dystrophy (genotypes dy/dy and dy2J/dy2J) on limb bone growth, we measured lengths and widths of the right humerus, femur and tibia, and lengths of the ulna and radius from dorsal/ventral radiographs of mice taken over a period of 270 days. Radiographs were taken approximately 3 times a week, and the sampling frequency was gradually reduced to once a month. We plotted measurements from each individual against time and fit a Gompertz equation to the growth of each bone. Parameters of the equation were compared using ANOVA across genotypes and between sexes. Slopes of length versus width were calculated for the limb bones of each individual using linear regression. Slope differences among genotypes and between sexes were tested using ANOVA. Control and dy2J values were significantly longer than those of dy mice in all bones, but there was considerable variation across genotypes for the various width measurements. Sexual dimorphism was found in several measurements, where males were always larger than females. There were few significant differences in limb scaling (lengths vs. widths) among genotypes and almost no scaling differences between sexes despite the size differences. Differences among widths suggest that muscular dystrophy affects different parts of limb bones in different ways. This may be the effect of the type and number of muscular attachments, as well as the usage of the limb. The sexually dimorphic measurements suggest that there are size differences in the skeleton between sexes, regardless of the genotype. Our ontogenetic allometry results indicate that size is affected by the muscular dystrophic condition and by sexual dimorphism, while shape remains largely unchanged.     

Localization of the m2 muscarinic acetylcholine receptor protein and mRNA in cortical neurons of the normal and cholinergically deafferented rhesus monkey

The m2 muscarinic acetylcholine receptor in the cerebral cortex has traditionally been thought of as an autoreceptor located on cholinergic fibers that originate from neurons in the nucleus basalis of Meynert. We now provide evidence for widespread localization of the m2 receptor in noncholinergic neurons and fibers of the cerebral cortex. The cellular and subcellular distribution of the m2 receptor protein and mRNA were examined in normal monkeys and in monkeys in which the cortical cholinergic afferents were selectively lesioned by injection of the specific immunotoxin, anti-p75NTR-saporin into the nucleus basalis. Both in normal and immunolesioned monkeys, the m2 mRNA and protein were localized in pyramidal and nonpyramidal neurons. In pyramidal neurons, membrane-associated receptor immunoreactivity was found exclusively in dendritic spines receiving asymmetric synapses, indicating that the m2 receptor may modulate excitatory neurotransmission at these sites. In nonpyramidal neurons, the m2 immunoreactivity was present along the cytoplasmic surface of membranes in cell bodies, dendrites and axons. Both in pyramidal and nonpyramidal neurons of normal and lesioned monkeys, the m2 receptor was located peri- and extra-synaptically, suggesting that it may be contacted by acetylcholine via volume transmission. The localization of the m2 receptor in cortical neurons and the sparing of m2 immunoreactivity in lesioned monkeys indicates that the m2 receptor is synthesized largely within the cortex and/or is localized to noncholinergic terminals of either intrinsic or extrinsic origin. These findings open the possibility that the loss of the m2 receptor in Alzheimer's disease may in part be due to degenerative changes in m2 positive neurons of the cortex rather than entirely due to the loss of autoreceptors.     

Behavioral effects of spinal cord transection in the developing rat

Albino rats, 0, 9, 12, 15, 18, 21 or greater than 90 days of age, were given a mid-thoracic spinal cord transection. Evaluation of responses of the hindlimbs to a variety of behavioral tasks was begun on the day of surgery and at intervals throughout the postoperative survival period (up to 300 days). Two investigators, independently and without knowledge of the animals' ages or survival times, rated the response data. Histological study showed all transections to be complete. Large differences in behavior are observed when animals trasected at the neonatal stage (0-4 days of age) are compared with animals transected at the weanling stage (21-26 days of age)37. Results of the present investigation indicate a critical period near 15 days of age; animals lesioned prior to this age (0, 9, 12 days of age) show response development and recovery similar to the neonatally lesioned animal, whereas those animals lesioned at a later age (18, 21, greater than 90 days of age) show little recovery and are behaviorally similar to the weanling transected animal. In animals lesioned prior to the fifteenth postnatal day, postural responses appear depressed for a brief period but recover rapidly while most responses of animals in the older groups are depressed for longer periods and never attain the degree of recovery characteristic of the neonatally transected animal. Finally, like the neonatally transected animal, rats lesioned on the ninth and twelfth postnatal day develop certain responses at appropriate times relative to normal response development. If, however, these responses are mature and supraspinal control is present at the time of lesioning, they appear to be permanently depressed and fail to recover.     

The effect of neocortical lesions on the number of cells in neonatal or adult feline caudate nucleus: comparison to fetal lesions

After a unilateral resection of the frontal cortex in fetal cats the volume of the caudate nucleus increases while the packing density of neuronal and glial cells does not change. In the present report we address the questions of whether a similar lesion sustained neonatally or a more extensive neodecortication sustained neonatally or in adulthood may have the same unusual effect. Stereological methods were used to determine bilaterally the volume of the caudate nucleus as well as to estimate the total number and packing density of neurons and glial cells in the caudate nucleus ipsilateral to the lesion. Comparisons between each of three experimental groups and intact animals were made at a time when all animals were young adults. In cats with a unilateral frontal cortical lesion performed between postnatal days 8 and 14, none of the measured parameters changed significantly compared to intact controls. In cats with removal of the entire left neocortex in adulthood, the ipsilateral caudate nucleus volume decreased by 18.1% and by 21.5% relative to intact and to neonatal hemidecorticated cats respectively (P < 0.05), with no change in the contralateral caudate. In the ipsilateral caudate the total number of neurons decreased by 21.8% (P < 0.05) compared to controls while the number of glial cells did not change significantly. In the same caudate the packing density of neurons did not change significantly (except for a 17.1% decrease, P < 0.05, relative to frontal-lesioned cats) while that of glial cells increased by 19.9% and by 24.7% compared to intact and neonatal neodecorticated cats respectively (P < 0.05). In adult cats in which a similar hemineodecortication was performed between postnatal days 8 and 13, the only significant changes were a 25.8% (P < 0.05) and a 30.6% (P < 0.05) decrease in neuron packing density compared to intact and frontal-lesioned cats, respectively. In summary, a restricted unilateral neocortical resection in neonatal cats did not induce any morphological changes in the caudate nucleus that we could detect with the methods employed. In contrast, an extensive neodecortication sustained in adulthood produced ipsilateral caudate shrinkage with substantial neuron loss and increase in packing density of glial cells, while a similar lesion but sustained neonatally only altered substantially the packing density of glial cells (decreased). Therefore, we concluded that (i) the caudate nucleus hypertrophy which we reported after a unilateral discrete cortical removal during the prenatal period is a unique phenomenon which is peculiar to the cat brain during the last third of gestation; (ii) the caudate nucleus changes seen in the cats with hemineodecortication in adulthood are degenerative in nature and closely resemble those which we reported for other subcortical nuclei following a similar lesion; and (iii) the animals with neonatal hemidecortication are relatively spared from these degenerative effects. Overall, these results indicate that, as for other structures, the morphological changes of the caudate nucleus following neocortical damage depend on the maturational state of the brain at the time of the injury and on the size of the lesion, and support the notion that the consequences of cerebral cortex lesions upon subcortical brain nuclei are of a different nature when sustained in prenatal as compared to postnatal cats.     

Neonatal monoaminergic depletion in mice (Mus musculus) improves performance of a novel odor discrimination task

This experiment examined behavior and neurochemistry in adult mice (Mus musculus) after neonatal depletion of monoaminergic fibers projecting to the neocortex and hippocampus. Lesions were made on Postnatal Day 1; mice developed to adulthood and were assessed on simple odor discrimination (SOD) and odor delayed nonmatch-to-sample (DNMS) tasks, passive avoidance (PA), and locomotor activity. On SOD, lesioned mice performed faster than controls but with similar accuracy. On the DNMS task, the lesioned mice performed faster and more accurately than controls. On PA, the lesioned mice exhibited a retention deficit relative to controls. Locomotor activity was similar in the 2 groups. Postmortem analyses revealed that the lesions reduced significantly norepinephrine and serotonin levels in both the neocortex and hippocampus. The data suggest that cortically projecting monoaminergic fibers play an important role in normal cognitive development.     

Innervation of VIP-immunoreactive neurons by the ventroposteromedial thalamic nucleus in the barrel cortex of the rat

We investigated the synaptic terminals of fibers originating in the ventroposteromedial thalamic nucleus (VPM) and projecting to the main input layers (IV/III) of the rat posteromedial barrel subfield. It was our aim to determine whether or not the subpopulation of vasoactive intestinal polypeptide (VIP)-immunoreactive neurons in these layers are directly innervated by the sensory thalamus. Anterograde tracing with Phaseolus vulgaris leucoagglutinin (PHA-L) and immunohistochemistry for VIP were combined for correlated light and electron microscopic examination. Columns of cortical tissue were well defined by barrel-like patches of PHA-L-labeled fibers and boutons in layers IV and III. Within these columns VIP-immunoreactive perikarya were located mainly in supragranular layers. Marked perikarya were also seen in infragranular layers, but their immunoreactivity was often weaker. Granular layer IV, which is the main terminal field for thalamic fibers, contained fewer VIP neurons than supragranular layers. In the light microscope, however, PHA-L-labeled fibers appeared to contact the somata or proximal dendrites of 60-86% of the layer IV VIP neurons . By contrast, only 18-35% of the VIP neurons in the supragranular layers, which receive a moderately dense projection from the VPM, appeared to be contacted. PHA-L-labeled boutons were seen close to 13-25% of infragranular VIP-positive cells. Electron microscopy showed that thalamic fibers formed at most four asymmetric synapses on a single layer IV, VIP-positive neuron. Although the proportion of VIP-positive neurons with labeled synapses was lower in supragranular layers, most of them shared multiple asymmetric synapses with labeled thalamic fibers. Up to six labeled synapses were seen on individual VIP neurons in layer III. We conclude that subpopulations of VIP-immunoreactive neurons, located in layers IV, III, and II are directly innervated by the VPM. These neurons may be involved in the initial stages of cortical processing of sensory information from the large, mystacial vibrissae. Since VIP is known to be colocalized with the inhibitory transmitter GABA, it is likely that VIP neurons participate in the shaping of the receptive fields in the barrel cortex.