Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism?

Abstract

The hippocampus is a key brain region regulating complex cognitive and emotional responses, and is implicated in the etiology of depressive and anxiety disorders, many of which exhibit some degree of sex difference. The male rat hippocampus is consistently reported to be slightly but significantly larger than the female. The majority of studies on the development of volumetric sex differences have focused on the effects of estradiol (E 2 ), with relatively few focusing on androgens. We examined the impact of both E 2 and androgens on newly born cells in the developing rat hippocampus, and report that neonatal males have significantly more 5-bromo-2′-deoxyuridine-5′-monophosphate (BrdU)+ cells than females. Both testosterone (T) and dihydrotestosterone treatment of females significantly increased the number of BrdU+ cells, an effect blocked by the androgen receptor antagonist, flutamide. However, only T significantly increased the number of neuronal nuclear antigen+ neurons in the female rat hippocampus. Interestingly, E 2 treatment also increased BrdU+ cells in females, but had no effect on neuron number. Instead, E 2 and T significantly increased the number of newly born glial fibrillary acidic protein or glutamine synthetase+ glial cells in females, indicating that androgens and E 2 may act independently to achieve distinct endpoints. Quantification of pyknotic cells at two different developmental time points indicates no sex difference in the number of cells dying, suggesting, but not proving, that gonadal steroids are promoting cell genesis.

Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior

“…To date, the majority of sex differences in the size of a particular brain region have been attributed to differences in the total number of neurons as a result of differential cell death (5). The findings reported here are surprising because the bias is toward more cell proliferation in females and because very few sex differences in cell proliferation have been reported (21), suggesting that sex differences in proliferation may not mediate the establishment of sex differences in volume of particular brain regions. Moreover, sex differences in cell proliferation during the early postnatal and juvenile period could be specific to those developmental ages and underlie functional differences associated with development, such as the correlation we observed here between cell proliferation and juvenile play behavior.…”

Female rats learn trace memories better than male rats and consequently retain a greater proportion of new neurons in their hippocampi

“…Other sex differences in learning are mediated by the presence of sex hormones and sex differences in the structure of the brain (27,28,(39)(40)(41). As presented here, the total volume of the dentate gyrus is greater in males than in females (27,42).…”

“…Thus, more cells may die in females than in males across time. The second issue is that the female hippocampus is smaller than the male hippocampus (27,28). To account for these sex differences, we calculated the density of new cells in the DG (cells per mm 3 ).…”

“…In the next analyses, we compared the effects of training on the absolute number versus density of surviving cells. This analysis was necessary because the female hippocampus is significantly smaller in volume than the male hippocampus (27,28). To conduct the analysis, all animals were included, regardless of their performance on the trace memory task.…”

Effect of testosterone propionate on hippocampal pyramidal neuron number in female rats

“…(3) Zhang et al showed that the number of bromodeoxyuridine positive cells in female rats were increased with TP and dihydrotestosterone treatment. (8) Xiao and Jordan reported a higher number of androgen receptors and hippocampal CA1 pyramidal cells in the left hemisphere than in the right, but only in gonadally intact male rats, and in female rats given TP. (9) All these studies indicate that experimental hormonal manipulations of laboratory rodents alter not only the functions but also the number of neurons.…”