Search for a gene that may result in fewer neurons in the adult mouse hippocampus.

Experimentally produced C57BL/6J-Pdebrd1 congenic mice carrying this gene for retinal degeneration were previously found to have fewer hippocampal neurons than partner strain C57BL/6J+Pdeb-rd1 mice possessing normal retinas. A linked passenger gene on the inserted chromosome segment containing the Pdebrd1 gene might have been responsible. An inbred strain segregating at the Pdebrd1 locus and with a genetic background on which the gene is normally present has now been examined. No neuron loss was observed. These new results indicate that, while Pdebrd1 was necessary for the occurrence of fewer hippocampal neurons in C57BL/6J-Pdebrd1 mice, it alone was not sufficient to produce this effect. The Pdebrd1 gene was acting in combination with at least one other gene not on the introduced chromosome segment. The results also provide evidence that genetic background effects can minimize or eliminate hippocampal neuron loss in some strains that normally carry the Pdebrd1 gene.

The mouse gene retinal degeneration (rd) may reduce the number of neurons present in the adult hippocampal dentate gyrus.

C57BL/6J and C57BL/6J-rd le Gus-sh mice, congenics at the rd locus, were compared with respect to number of granule cells and presumed pyramidal basket cells in the hippocampal dentate gyrus. Number of both types of neurons were less in rd/rd mice than in +/-/+/- mice. The rd gene may be responsible.

New strains of seizure-prone mice.

The origins of two new strains of seizure-prone mice are provided, and some of their behavioral characteristics are described. Comparison of the hippocampal granule cell layer of one of the new strains with the two inbred strains from which it was derived revealed strain differences in the diameter of granule cell nuclei and in the number of granule cells in the suprapyramidal blade. Basket cell counts did not differ between the strains, but both basket cell and granule cell number were consistently higher for the suprapyramidal blade than for the infrapyramidal blade. The existence of these and other blade differences suggests that the two blades will prove to be functionally distinctive neuronal systems.

On the sources of strain and sex differences in granule cell number in the dentate area of house mice.

The origins of strain and sex differences in the number of granule cells in the dentate area of hippocampus were examined in a breeding study employing two inbred strains of mice that differ substantially in granule cell number. Sources of hereditary variation analyzed included autosomes, sex chromosomes, and maternal factors, including cytoplasmic and environmental. The results corroborated those of an earlier study in finding that 80% of the strain variation is attributable to autosomal differences. In addition, there appears to be a cytoplasmic factor that results in a strain-dependent sex dimorphism. The autosomal contribution is attributed to mechanisms operating during the primary phase of granule cell genesis. The possibility that the sex difference results from strain differences in mitochondrial DNA affecting rate of cell death is considered.

On the development of strain and sex differences in granule cell number in the area dentata of house mice.

Male and female house mice of 6 inbred strains high or low in granule cell number as adults were examined at 3 immature postnatal ages beginning with day 13, and in young adulthood at day 84. The difference between mice of high and of low strains was present by postnatal day 13. Possible contributions of both incremental and decremental developmental events must be considered. Both males and females exhibited a reduction in granule cell number between postnatal days 20 and 27. Competition for efferent target cell sites was considered as a basis for sex-independent granule cell death, but no supporting evidence was obtained. Females displayed a greater reduction in granule cell number than did males. Thus, a sex dimorphism (females lower) appeared at that time. A low-level testosterone effect acting during this period of granule cell death, or a long-term consequence of high perinatal testosterone levels, might be responsible.

Three sex dimorphisms in the granule cell layer of the hippocampus in house mice.

Inbred strains of mice differ in number of neurons in the dentate granule cell layer of hippocampus and in granule cell density. In a study of both sexes in 6 strains, females had significantly lower granule cell density than males of the same strain. Females of strains with high neuron numbers had significantly fewer granule cells than males of the same strain, while males and females of low neuron number strains did not differ from each other. Sizes of neuronal nuclei were examined in males and females of two strains. No significant strain difference was found, but females had significantly smaller nuclei. The results suggest that hippocampal function is associated with the differing adaptive roles of male and female house mice.

An association between granule cell density in the dentate gyrus and two-way avoidance conditioning in the house mouse.

Mice with genetically associated variations in the number and density of granule cells in the dentate gyrus were tested for open-field activity, spatial maze learning, and two-way avoidance conditioning. The number of granule cells was not associated with any behavior measured. Only avoidance conditioning was related to granule cell density, which had a negative correlation with performance on the shuttle box task. This result was replicated in two genetically different stocks of mice. Density of the more caudal portion of the dentate was associated with early stages of avoidance learning, whereas the more rostral portion was associated with later stages. The results are discussed in relation to theories of functional dissociation within the hippocampus.

A biometrical-genetic analysis of granule cell number in the area dentata of house mice.

Considerable variability in the number of granule cells in the area dentata has been found among inbred strains of mice. In this report a simplified triple-test cross breeding design was employed to identify and discriminate between heritable and non-heritable sources of this variability. Granule cell numbers were estimated in two previously identified extreme strains of mice and in their reciprocal F1 hybrids with 3 strains of mice known to be intermediate between the 2 extremes. Analytical techniques of biometrical genetics applied to the neuron number estimates indicated that genetic transmission of this trait involves genes located upon autosomes. Transmission does not involve cytoplasmic factors within the female egg, or maternally-mediated differences in nutrition. Of the total variability in dentate granule cell number, 86% is estimated to be determined by an additive genetic component. A dorsal-to-ventral increase in the size of granule cell nuclei was found for all genotypes; some possible bases for this increase are discussed.

The genetic organization of neuron number in the pyramidal cell layer of hippocampal regio superior in house mice.

This report concerns variations in neuron number within the pyramidal cell layer of hippocampal regio superior in 18 inbred strains of house mice. There is a genetically associated variability in the total number of neurons in this pyramidal layer. Systematic strain variations in the orientation of the pyramidal cell layer are also present. Relations between the numbers of neurons in various experimenter-defined subdivisions of regio superior were examined following statistical corrections for the variations in orientation. This led to a preliminary delineation of 4 genetically-defined subdivisions of the regio superior pyramidal cell layer.

The genetic organization of neuron number in the granule cell layer of the area dentata in house mice.

This report concerns variations in neuron number within the granule cell layer of the area dentata that occur among inbred strains of house mice. There is genetically associated variability in the total number of neurons present, with a very substantial range of estimated values. Systematic strain variations in the orientation of the granule cell layer are also present. When statistical corrections for variations in orientation are made, associations between the neuron numbers of subdivisions of the granule cell layer are consistent with the presence of common genetic determination of neuron number throughout the entire lamina.

Genetically-associated variations in the development of hippocampal pyramidal neurons may produce differences in mossy fiber connectivity.

The neuronal generation patterns of hippocampal pyramids were analyzed in two inbred strains of house mice (SM/J and BALB/cJ) using triated thymidine radioautography. These two strains of mice possess markedly different patterns of mossy fiber synapses upon pyramidal neurons within a specific segment of regio inferior. The results of this study show that this same segment of regio inferior also displays markedly different patterns of pyramidal neuron generation in the two strains. Specifically, the pyramids of this segment of regio inferior are generated according to the typical "inside-out" sequence in SM/J mice, but this pattern is reversed into an "outside-in" sequence in BALB/cJ mice. Remaining segment of regio inferior, and all of regio superior, is formed in an inside-out sequence in both strains. These results strongly suggest that altered temporal patterns of pyramidal neuron generation may play a major role in determining mossy fiber connectivity patterns.

The genetic organization of neuron number in Ammon's horns of house mice.

This study of the Ammon's horns of 20 inbred strains of house mice had 3 primary objectives. The first was to determine whether there was genetically-associated variability in the number of neurons present within a dorsal and a ventral portion of this brain region. If genetically-associated variability proved to be present, there were two additional objectives which we wished to achieve. One was to determine the degree to which genetically-associated variations in neuron number are confined to specific neuronal regions, or shared between neuronal regions. The other was to identify specific extreme strains for further study. A section cut in a coronal plane was selected for a sampling within a dorsal portion of Ammon's horn, and a section cut in a horizontal plane was selected for a sampling within a ventral portion. Counts were made of neuronal nuclei in the granule cell layer of the dentate gyrus and in the pyramidal layers of regio inferior and regio superior of the hippocampus. Cross-sectional areas for these somal laminae were also measured and planimetric neuron densities were obtained by computing the ratios of nuclei counted to the areas of the appropriate somal laminae. Genetically-associated variability in counts of neuronal nuclei was observed for all neuronal regions within both the dorsal and the ventral sampled portions. Genetically-associated variability in planimetric neuron density was clearly present within the dorsal portion. The obtained counts of neuronal nuclei were adjusted statistically for variations in planimetric neuron density to provide the best indices of variation in neuron number presently available. Results for these adjusted neuron counts were as follows. First, there was an indication of substantial genetically-associated variability in neuron number. With the single exception of one neuronal region (dorsal regio superior), adjusted neuron counts exhibited significant genetically-associated variability for all neuronal regions within both portions sampled. Second, there was evidence for both separate and shared genetic determination of neuron number between neuronal regions. Strains were not uniformly high, intermediate, or low in their adjusted neuron counts. Instead, a complex patterning of high and low genetically-associated correlations was observed between neuronal regions and sampled portions. Third, extreme strains for each neuronal region were identified for the sampled dorsal and ventral portions. Differences between the neuron numbers of interconnected neuronal regions imply variations in connectivity. Such variations could provide a morphological basis for 'tuning' associated adaptive characteristics of populations of house mice to enhance the likelihood of their survival in environments with varying ecological requirements.