Biomedical subjects

G F Sherman

Publications and source records attributed to G F Sherman.

At least 37 records · Page 2Linked to original sources

PubMed1994

A genetic analysis of neocortical ectopias in New Zealand black autoimmune mice.

Two experiments investigated the heritability of neocortical ectopias seen in 30-40% of New Zealand Black (NZB/BINJ) autoimmune mice. The first study examined the brains of mice from the NZB x SM/J recombinant inbred (RI) strains. Fifteen RI inbred strains were examined and over half had ectopias suggesting that a major gene was involved in ectopia production. A follow-up experiment comparing the incidence of ectopias among crosses between NZB and control DBA/2 strains showed that the predisposition to develop ectopias in NZB is a recessively inherited trait with incomplete penetrance.

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PubMed1993

Behavior, cortical ectopias, and autoimmunity in BXSB-Yaa and BXSB-Yaa+ mice.

The BXSB-Yaa recombinant inbred strain was created by crossing a male SB/Le with a female C57BL/6J. A Y chromosome factor derived from the SB/Le male, known as the autoimmune accelerator (Yaa), leads to an earlier onset and greater severity of autoimmune disease in males. In contrast, male BXSB mice, which lack the Yaa gene (called BXSB-Yaa+) because their Y chromosome is derived from the C57BL/6J, do not develop an autoimmune condition. To examine the influence of the Y chromosome on behavior, cortical ectopia incidence, and immune functioning, males and females of these two strains were compared. Significant strain differences (for both sexes) were found for behavioral measures including discrimination, spatial and avoidance learning, and activity. For immunological parameters, a sex difference was seen in the BXSB-Yaa (males more autoimmune), but not in the BXSB-Yaa+ strain. As expected, male BXSB-Yaas were more autoimmune than male BXSB-Yaa+s. However, there was also a strain difference for IgG in the females (BXSB-Yaa+ greater). No strain difference was found for the presence of ectopias. However, there was a sex difference across both strains, with males having a higher incidence. BXSB-Yaa and BXSB-Yaa+ mice have behavioral and immunological differences greater than would be predicted by their known genetic differences. The significant differences between the two female groups suggest that the two strains differ with respect to autosomal genes, in addition to the Y chromosome. The incidence of ectopias is independent of this genetic difference and is influenced by the subject's sex.

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PubMed1993

Neuronal subtypes and anatomic asymmetry: changes in neuronal number and cell-packing density.

The combined volume of an asymmetric cytoarchitectonic area is smaller than that of symmetric homologs. Asymmetry reflects fewer numbers of neurons in the smaller of the two sides. In this study we examined two types of neurons to check whether lateral differences in neuronal numbers affect different types of neurons comparably in the neocortex of the rat. As with overall neuronal numbers, both parvalbumin-immunoreactive (mostly long projection) neurons, and vasoactive intestinal peptide-immunoreactive interneurons increase in number in the larger of the two sides. Moreover, the concentration of parvalbumin- but not vasoactive intestinal peptide-immunoreactive neurons also increases on the larger side. Thus, there may be qualitative as well as quantitative differences in the connectivity of the larger side of an asymmetric architectonic region.

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PubMed1992

The organization of radial glial fibers in spontaneous neocortical ectopias of newborn New Zealand black mice.

Forty percent of New Zealand Black (NZB) mice, a strain that develops severe autoimmune disease, have ectopic collections of neurons in layer I of the neocortex. This strain is used as a model for similar anomalies seen in the dyslexic brain. In the present study we immunohistochemically stained radical glial fibers and their anchoring processes (which form the glial external limiting membrane) in the region of ectopias in NZB mice. The organization of glial fibers was abnormal in and around the ectopic region. Radial glial fibers underlying the ectopia were denser than in the surrounding cortex, and within the ectopia there was a disorganized matrix of glial fibers. Most glial fibers, however, did not enter the ectopia, but instead curved towards the edge of the ectopia and attached there. The glial limiting membrane was breached in the area of the ectopia, indicating that an insult to this membrane may have allowed neurons to migrate into layer I and the overlying subarachnoid space. This finding along with the results of the accompanying paper on puncture wounds of the cortex of newborn rodents supports the view that rupture of the external limiting glial membrane is responsible for the inappropriate migration of neurons into the molecular layer.

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PubMed1992

Induction of molecular layer ectopias by puncture wounds in newborn rats and mice.

Molecular layer ectopias spontaneously occur in immune-disordered mice, and the accompanying paper demonstrates that these ectopias are associated with a break in the external glial limiting membrane and with distortion of radial glial fibers at birth. It was hypothesized that injury to the developing neocortex is the main etiologic event for molecular layer ectopias. To test this hypothesis, puncture wounds were made on the surface of the cerebral cortex of newborn rats and mice. These wounds produced, in adulthood, molecular layer ectopias similar in appearance to those seen spontaneously in immune-disordered mice. Further, these ectopias show similar distortions of radial glial fibers during development, and of neurofilaments in adulthood. This work supports the notion that injury could be a factor in the production of molecular layer ectopias.

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PubMed1992

Environmental enrichment, neocortical ectopias, and behavior in the autoimmune NZB mouse.

New Zealand Black (NZB) mice have severe autoimmune disease and approximately 40% have cortical ectopias in layer I of sensorimotor cortex. Because the ectopias are similar to those found in dyslexics, NZB mice have been used as an animal model for developmental learning disorders. In addition, these mice have been used as a model of learning deficits associated with autoimmune disease. To determine whether early intervention would affect learning processes in NZB mice, they were reared after weaning in standard cages or enriched environments. They were given a battery of behavioral tests to measure learning, laterality, and activity, after which they were sacrificed and their brains examined for cortical ectopias. The tests sorted into two behavioral sets. Ectopia-associated behaviors included black-white discrimination learning and the Morris spatial maze. As a group, the mice performed well on these tasks. Ectopic mice had poorer performance than non-ectopics on these measures, and environmental enrichment countered the effects of the ectopias. Autoimmune-associated behavior involved two-way avoidance learning in a shuttlebox. Mice were uniformely poor on this task, ectopias did not affect behavior, and environmental enrichment was without benefit. Evidence from this and other studies shows that poor shuttlebox performance is related to the presence of autoimmune disease. Thus, autoimmune disease and cortical ectopias each appear to affect a separate set of behavioral processes. Environmental enrichment is most effective for behavioral impairments mediated via cortical ectopias, but is much less effective, if at all, if autoimmunity is the primary mediator of the impairments.

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PubMed1992

Behavior, ectopias and immunity in BD/DB reciprocal crosses.

In a previous study, in which fertilized DBA ova were transferred into an autoimmune female, and NZB ova were transferred into a non-autoimmune female, we found that (1) the maternal environment affected the degree of autoimmunity, (2) the incidence of cortical ectopias was not affected by the maternal environment (3) DBA and NZB females had greater paw asymmetry if reared in an autoimmune uterus, and (4) avoidance learning scores were inversely related to degree of autoimmunity. In the present experiment, reciprocal crosses of DBA and BXSB mice were studied to confirm and extend the original findings. DB mice (DBA female x BXSB male) had greater immune activity than the BD animals, had poorer avoidance learning, but were better on black-white discrimination learning and the Lashley III maze. The BD mice had greater paw asymmetry. Only one of 38 animals had a cortical ectopia. The results lead to the following conclusions: (1) there is an inverse relationship between amount of immune activity and active avoidance learning; (2) some uterine factor in autoimmune mice causes females to have greater paw asymmetry; (3) cortical ectopias are under genetic control; and (4) the lesser immune activity of the BD mice suggests that they developed a suppressor system following early exposure to autoimmunity in the uterine/maternal environment.

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PubMed1992

Lashley maze learning deficits in NZB mice.

In a prior study we found excellent Lashley III maze learning in BXSB mice and poor learning in NZB mice, despite the fact that both strains are autoimmune and develop cortical ectopias. This prompted us to examine NZB Lashley maze performance in detail, including comparisons to other strains and attempts to improve performance by giving additional trials with or without additional intramaze visual cues. In conventional Lashley testing (10 trials), RF mice (non-autoimmune and nonectopic) and BXSBs performed well in the Lashley maze. They had high learning indices and few errors. NZB mice performed poorly, with low learning indices and many errors. Even with additional trials or additional trials plus intramaze cues, NZB performance remained poor. The number of backward and forward errors stayed high; learning indices were low. Since both BXSB and NZB mice develop autoimmune disorders and cortical ectopias, it is unlikely that differential Lashley performance is the result of the presence of these phenomena. NZB mice are known to have alterations in their hippocampal morphology, and this is a possible mediator of the Lashley deficit.

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PubMed1992

Biological substrates of anatomic asymmetry.

Asymmetric cortical areas differ in volume and in the number of neurons. There are also differences between asymmetric and symmetric areas. As asymmetry increases, the total area of the region decreases, suggesting that when a brain is symmetric, it is the result of two large sides rather than two small sides. Also, these volume differences are caused by changes in the number of cells, not changes in cell-packing density. The ontogenetic basis for this difference in cell numbers likely relates to events that occur quite early in corticogenesis before final mitosis of proliferative units, but definitive proof is lacking. Finally, the pattern and degree of callosal connections differ between symmetric and asymmetric brains, with differential axonal pruning being implicated as the likely mechanism.

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PubMed1992

A behavior profile of the MRL/Mp lpr/lpr mouse and its association with hydrocephalus.

Since the NZB and BXSB autoimmune mouse strains have cortical ectopias and associated behavioral changes, mice from the MRL/l (MRL/Mp lpr/lpr) autoimmune strain were given a series of behavioral tests followed by anatomical analyses of their brains and immune assays of plasma. No cortical ectopias were found, but this strain was discovered to have a high incidence of hydrocephalus: 46% had severe dilatation of the lateral and third ventricles, 30% had moderate dilatation, and 24% had minimal or no enlargement of the ventricles (total N = 57). Those mice in the severe hydrocephalus group were poorer in a nonspatial discrimination learning task, had less paw asymmetry, and were less active in a swimming task. No association was found between degree of hydrocephalus and any immune parameter.

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PubMed1992

The development of induced cerebrocortical microgyria in the rat.

Placement of a freezing probe on the skull of neonatal rats produces four-layered microgyria, complete with a lamina dissecans and microsulcus. We studied the developmental course of this induced microgyria under light microscopy by examining changes in neurons, glia, and macrophages following a focal freezing insult on the day of birth (postnatal day [P]0). The destruction of neurons and glia induced by the freezing probe extends through the cortical plate and occasionally through the subplate, but the pial membrane appears undamaged and radial glial cells, while damaged, are not eliminated. Reactive astrocytes and macrophages arrive in the damaged area within 24 hours of the injury, and repair of the damaged tissue peaks within the first week. Damaged radial glial fibers regrow, and supragranular neurons migrate through this damaged area, also within the first week. The newly formed supragranular layer overlies the cell-free area. The damaged cortex begins to assume its adult-like microgyric appearance from P5 to P10. On P15 and P32, long glial fibers, resembling radial glia, are present and are immunoreactive for glial fibrillary acidic protein and radial glial fiber antibodies (vimentin and Rat-401). No such fibers appear at this age in the non-microgyric areas or in normal brains. We conclude that microgyria formation may be the consequence of brain repair mechanisms occurring during neuronal migration to the neocortex, and that it appears to preserve primitive features characteristic of the developing cortex.

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PubMed1991

Effects of the autoimmune uterine/maternal environment upon cortical ectopias, behavior and autoimmunity.

NZB and BXSB mice develop autoimmune disease and learn poorly on avoidance tasks. In addition, many of these mice have ectopic collections of neurons, which occur prenatally, in layer I of the cerebral neocortex. The purpose of these experiments was to evaluate the contribution of the uterine/maternal environment upon these variables by transferring fertilized ova to an autoimmune or a non-autoimmune maternal host. In Experiment 1 fertilized DBA ova were transferred into the uteri of BXSB maternal recipients. Later, these animals and conventionally reared DBAs were tested for paw preference, swimming rotation, water escape learning, and shuttlebox avoidance learning. Blood was taken for measurement of immune parameters, and their brains were examined for cortical ectopias. As compared to conventional DBAs, the ova transfer mice had greater amounts of anti-dsDNA autoantibodies, poorer avoidance learning, and poorer water escape learning; in addition, the females had greater paw asymmetry. There was only 1 ectopia in the 81 ova transfer animals, and none in the 78 control mice. In Experiment 2 fertilized NZB ova were transferred into the uteri of non-autoimmune hybrid females and the same procedures were followed as in Experiment 1. Ova transfer mice had lesser amounts of anti-dsDNA autoantibodies, better avoidance learning scores, and females had less paw asymmetry; in addition, within the ova transfer group males were clockwise swimmers whereas females swam counterclockwise. There were 4 ectopics out of 17 ova transfer mice (23.5%), which did not differ from the 40.5% of the control group. In both experiments the uterine environment did not affect the occurrence of ectopias.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1991

Spatial learning, discrimination learning, paw preference and neocortical ectopias in two autoimmune strains of mice.

NZB and BXSB mice were given a battery of behavioral tests including paw preference, water escape, Lashley III maze, and discrimination learning. Their brains were then evaluated for cortical ectopias. The incidence of ectopias was 40.5% in NZBs and 48.5% in BXSBs. In the NZB strain left-pawed ectopic mice (both male and female) had the fastest swimming time in the water escape test, while right-pawed ectopics were the slowest. The same findings were obtained for left- and right-pawed ectopic BXSB males, but not for the females. However, on discrimination learning the BXSB males had the exact opposite pattern: right-pawed ectopics were the best learners while left-pawed ectopics were the worst. Male BXSBs and both male and female NZBs were manifesting autoimmune disease at the time of testing, while female BXSBs were not, suggesting that autoimmunity is a necessary background condition for the differential expression of ectopias and paw preference upon learning processes. The finding that the left-pawed ectopic BXSB mice, who were the poorest learners in the non-spatial discrimination learning test, learned best in the spatial water escape test is in agreement with the Geschwind hypothesis that pathological events during brain development may, in some instances, produce superiority of function.

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PubMed1991

Ontogenesis of neocortical asymmetry: a [3H]thymidine study.

Previous research has demonstrated that symmetric regions in one brain are, on the whole, larger than their asymmetric counterparts in another brain, and that side differences in the volumes of homologous architectonic areas are the result of a decrease in neuronal number in the smaller of the two areas. Therefore, understanding mechanisms by which neuronal numbers are regulated during development may be essential to the investigation of the ontogeny of asymmetry. The radial unit hypothesis of Rakic postulates four factors that determine the number of neurons within a neocortical region: (i) early progenitor cell division; (ii) late cell division; (iii) the effect of thalamocortical and corticocortical afferents, which govern, in part, boundary placement; and (iv) ontogenetic cell death. We report here on experiments that address the development of anatomical asymmetry in the light of this hypothesis. Pregnant Wistar rats were injected with [3H]thymidine on several dates during embryogenesis and their pups killed at several postnatal ages. An estimate of the total number of neurons contained within area 17 and area 18a of each hemisphere was determined and the percentage of those which were labeled was calculated. There were no side differences in this measure between either symmetric or asymmetric architectonic areas although there were consistent differences between areas 17 and 18a. This indicated that while late neuroblast division may be important for cytoarchitectonic differentiation, it may play little or no role in interhemispheric asymmetry.

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PubMed1991

Freezing lesions of the developing rat brain: a model for cerebrocortical microgyria.

Cerebrocortical microgyri were induced by placing a freezing probe on the skull of P0 and P1 rat pups. Freezing lesions resulted in laminar necrosis of the infragranular layers and the subsequent migration of supragranular neurons through the region of damage. The result was most often a region of four-layered microgyric cortex consisting of a molecular layer, a thickened layer ii, a lamina dissecans (corresponding to the necrotized layers IV, V, and VIa), and a neuronal layer iv which corresponded to layer VIb of the intact cortex. Immunocytochemical investigation of the microgyric cortex with antibodies to neurofilament, glial fibrillary acidic protein and glutamate showed more widespread disruption of neocortical architecture than could be seen from Nissl preparations. In contrast, vasoactive intestinal peptide-containing neuronal bodies appeared to be distributed normally in the microgyric region although their processes were sometimes distorted. These results are considered in the light of previous research on induced microgyria, and possible implications for the behavioral consequences of focal, developmental neuropathologic lesions are discussed.

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PubMed1990

Brain abnormalities in immune defective mice.

Mouse strains with or without immune disorders were examined in order to further assess the incidence of brain anomalies in immune-disordered strains. The brain was examined in Nissl-stained serial sections under a light microscope for the presence of abnormalities, with specific attention to ectopic collections of neurons in layer I of the neocortex, as reported in the autoimmune New Zealand Black (NZB) and BXSB strains. The present study was designed to survey additional strains with immune disorders (Snell dwarf, C57BL/6J-nu/nu, BALB/cByJ-nu/nu, and SJL) and 7 control strains without immune disorders. In addition, we attempted to replicate past findings in the highly affected BXSB strain and the MRL/1 strain, which develops autoimmune disease, but has a low incidence of brain abnormalities. The largest number of brain abnormalities (20-40%) were seen in the C57BL/6J-nu/nu, Snell dwarf and BXSB strains. The anomalies in the C57BL/6J-nu/nu and BXSB mice consisted of ectopic neurons in layer I of the neocortex, whereas the Snell dwarf mice had either neuron-free areas in the cortex, or rippling of cortical layers II-IV, and one case had agenesis of the corpus callosum. Between 4% and 8% of the mice from the SJL, MRL/1, and MRL +/+ strains had either neuron-free areas in the cortex or ectopic neurons in layer I. The BALB/cByJ-nu/nu and control strains did not have any cortical abnormalities. Future studies will be designed to determine whether immune-based alterations to the developing brain are responsible for the brain anomalies present in immune-disordered strains.

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PubMed1990

Neocortical VIP neurons are increased in the hemisphere containing focal cerebrocortical microdysgenesis in New Zealand Black mice.

Twenty to forty percent of New Zealand Black mice, a strain that develops severe autoimmune disease and learning deficits, exhibit focal unilateral collections of ectopic neurons and glia in layer I of the neocortex with underlying laminar dysplasia. This type of anomaly traditionally has been considered to represent disordered neuronal migration. In an attempt to further characterize these abnormalities, we compared counts of immunohistochemically-stained VIP-neurons in cortical regions containing ectopias and in adjacent cortex to homologous regions of the opposite hemisphere. There was an overall increase in the number of these neurons in the hemisphere containing the ectopias, which resulted from an increase in the number of VIP neurons both in the column of cortex within and underlying the ectopias and in the medially adjoining columns. We concluded that the presence of ectopias in the cerebral cortex not only represent abnormal migration, but also an increase in the number of at least one subset of neurons.

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PubMed1990

Abnormal architecture and connections disclosed by neurofilament staining in the cerebral cortex of autoimmune mice.

Routine cell stains disclose abnormal, usually single, nests of ectopic neurons in neocortical layer I of New Zealand Black (NZB) and BXSB autoimmune mice. We have suggested that these anomalies represent only the most visible part of more widespread cortical disorganization. In an attempt to determine the true magnitude of cellular and fiber disruption associated with the presence of ectopias, we stained cortical sections containing ectopias in layer I from NZB and BXSB mice with an antibody directed against the 68 kDa subunit of neurofilament protein. The neurofilament-stained sections revealed substantial disruption of the cortical layers underlying the ectopic neurons. This resulted primarily from the existence of dense, radially oriented fiber bundles spanning the thickness of the cortex underlying the ectopias. In some instances these fiber bundles could be seen to join the corpus callosum. Even in a small ectopia, where standard stains show no associated cortical dysplasia, dense neurofilament staining was present in layers II and III. It was concluded that the brains of autoimmune mice have severe developmental cortical disorganization, which could account for the behavioral differences displayed by these animals.

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