Sex difference and laterality in the volume of mouse dentate gyrus granule cell layer

Abstract

Sex differences in spatial learning have been reported in both humans and rodents. Correspondingly, there have been reports of sexual dimorphism in the morphology of the hippocampal formation (HF), a brain structure implicated in spatial cognition. In Experiment 1, we confirmed earlier reports that the overall volume of the granule cell layer (GCL) of the dentate gyrus (DG) of A/J mice is larger in males than in females. We also found that male A/J mice have a larger GCL volume in the right hemisphere than the left. Female A/J mice displayed no such laterality. A similar pattern of laterality, favoring the right HF, had been reported previously in male, but not female, rats. In Experiment 2, we examined mice with a defective structural gene for androgen receptors (testicular feminization mutant, or tfm mice) on a C57/BL6J background. The C57/J strain had not previously been examined for hippocampal sexual dimorphism. We found no sexual dimorphism in the left, right, or total volume of the GCL in C57/BL6J mice whether they were wildtype or tfm. However, the right GCL volume was greater than the left in wildtype C57/BL6J mice of either sex. No lateralization of GCL volume was found in the androgen-insensitive tfm-affected males or the partially androgen-insensitive tfm-carrier females. These findings confirm earlier reports that sexual dimorphism in mouse HF is found in some inbred strains but not others, and indicate for the first time that mouse HF structures are lateralized. The absence of lateralization in partially or wholly androgen-insensitive mice suggests that androgen receptors may play a role in development of laterality in the GCL independently of any sexual dimorphism in this structure.

Introduction

Studies of neural sexual dimorphism enhance our understanding of sex differences in behavior. By relating neural systems and hormones to behavior, sexual dimorphism studies may one day afford a better understanding of the underlying cellular mechanisms of human behavioral sex differences. There are many reports of neural sexual dimorphisms in various animals, including humans (see Ref. [5] for review). Some of these sexual dimorphisms are observed along with corresponding behavioral sex differences, and sometimes both the behavioral and the morphological differences can be reversed through hormone manipulation 2, 8, 11, 14. A sexually dimorphic behavior that has repeatedly been related to specific neuroanatomical regions is spatial cognition.

Sex differences in spatial cognition have been reported in a variety of mammals including humans 1, 14, 20. Since spatial cognition performance has been attributed to the hippocampal formation (HF) 9, 12, one might expect to find morphological sexual dimorphisms in the hippocampus of species that display sex differences in spatial cognition. Indeed, there have been several reports of sexual dimorphism in the HF, including dimorphisms in the overall volume of the HF in rats 4, 10 and in the number, size, and density of cells in the dentate gyrus (DG) of the HF in mice 17, 18, 19.

Wimer and Wimer (1984) reported that male mice have a higher cell density in the granule cell layer (GCL) of the DG than do females in some inbred strains. Three of the six strains examined had a high granule cell number and three had a low number of cells in the GCL. Within the high cell number strains, males had significantly more granule cells than did females. However, the low cell number strains displayed a sexually monomorphic number of granule cells.

In a follow-up study, Wimer et al. (1988) reported that the sex difference in granule cell number appears around postnatal days 20 and 27, when both sexes begin to exhibit a reduction in granule cell number. Since mouse testosterone levels decline immediately after birth and begin to rise in males at about post-natal day 20, and since androgen concentrating neurons are abundant in the mouse hippocampus [15], the authors hypothesized that androgens may play a role in mediating the development of the dimorphism in the GCL of these mice.

The purpose of the present study was to confirm the sex dimorphism that Wimer and Wimer found in the GCL of mice, to examine whether lateralization of HF structure found in rats is also present in mice, and to explore the role of androgens in the development of the sex difference in the GCL. In Experiment 1, we measured the GCL volume of A/J mice, a strain of mice found to have a high number of granule cells and a sex dimorphism in granule cell number previously. We confirmed the sexual dimorphism of this structure in this strain and report, for the first time, that the GCL is lateralized in male mice. In Experiment 2, we examined C57BL/J mice, which were not examined by Wimer and Wimer. We found that mice of this strain have a relatively small GCL volume and, as with the low GCL cell number strains studied by Wimer and Wimer, there was no sexual dimorphism of GCL volume in this strain. Mutants with a defective gene for the androgen receptor (testicular feminization mutant, or tfm) are available on the C57/BL6J background, so we examined these mutants to investigate the role of androgen receptors on GCL morphology. We found that the laterality of the GCL seen in wildtype C57/BL6J mice is absent in mice of this strain carrying the tfm mutation.