| It is well-known that sex differences of structure and function exist between female and male mammalian brain. For example, males have lager volume of the sexually dimorphic nucleus associated with reproduction in hypothalaums than females, and men's abstract thinking is better but women's imagery thinking is better. Hippocampus is an important brain region which has been profoundly invovled in learning and memory, cognition, emotion and stress, sex-specific differences have also been noticed in these hippocampal-dependent structure and physiological function. For example, the size of male hippocampus is slight but significant larger than the females, and the incidence of Alzheimer's disease, a neurological degenerative disease induced by brain aging, is higher in the females than in the males. So far, the molecular mechanisms underlying these sex differences remain unclear. It is known that steroids, such as androgen and estrogens, can regulate hippocampal structure and synaptic plasticity through their nuclear receptors including androgen receptor (AR), estrogen receptor-αand-β(ERa; ERp), but how do these hormones and their receptors regulate sex difference in brain especially hippocampal structure and function is also unclear.It's clear that the regulation of steroids and their receptors of target gene needs their cofactors including coactivators and corepressors. Steroid receptor coactivator-1(SRC-1) is the most widely distributed steroid receptor coactivator in the brain. It participate the regulation of several kinds of steroid receptors for gene transcription. Studies have shown that SRC-1 gene deficiency results in delayed development of cerebellar Purkinje cells, motor function disorder and significant longer escape latency in Morris maze test. Additionally, infusion SRC-1 antisense nucleotide into hypothalamus significantly changes neural plasticity and reproductive behavior. Previously we have demonstrated high levels of SRC-1 in the adult female rat brain, indicating its multiple function in mediating steroids action in the regulation of brain structure and function. But whether there is any sex difference in the distribution of SRC-1 in the female and male brain and, if so, how about its relationship with brain dimorphism remains to be elucidated.Hippocampus is the most important functional brain region and deeply affected by circulating and/or local steroids. Some sex differences of the structure and function of hippocampus have been noticed by previous studies. Whether there is any sex difference of SRC-1 expression in the hippocampus during postnatal development and whether this difference is associated with the hippocampal synaptogenesis is not clear. Since sex hormones affect hippocampus in a sex-dependant manner, how about the effects of circulating sex hormones on hippocampal SRC-1 expression and what is the relationship between these effects and hippocampal synaptic plasticity is also unclear.In order to address these questions, we first used immunohistochemistry to examine the distribution of SRC-1 in the brain of adult female and male mice. Then, we studied the ontogeny of hippocampal SRC-1 and some important synaptic proteins including synaptophysin (SYN), AMPA receptor subtype GluR-1 and postsynaptic density-95 (PSD-95) at different postnatal stages in the female and male mice and explored the correlation between the profile of SRC-1 and synaptic proteins in each sex. Finally, by using the classic steroids-deficiency gonadectomy model to mimic the decline of circular hormone level during aging we examined the expression of hippocampal SRC-1, SYN, GluR-1, PSD-95 at 1-,2- and 4-week after surgery of both sexes and evaluated the correlation of changes between SRC-1 and each synaptic protein.Main results:1. SRC-1 immunopositive materials were widely detected in the brain of adult female and male mice. High levels were detected in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, cerebellum and some nuclei of brainstem. Moderate levels were detected in the thalamus and most nuclei of brainstem, and no or lower levels of SRC-1 were also detected in some specific brain regions.2. SRC-1 immunopositive materials were predominantly detected in the cell nucleus of mice brain, but in some limited regions associated with motion regulation, it seemed they were also detected in neuritis fiber-like structure of motor root of trigeminal nerve of the brainstem. 3. Male brain showed statistically significant higher levels of SRC-1 immunoreactivities when compared with that of the diestrus females, in very limited regions female brain showed higher levels of SRC-1 immunoreactivities than males but without statistically significance.4. The expression of SRC-1 in the hippocampus of female was very low at PO.It significantly increased with development and reached the peak at P14, and significantly decreased at P30 and sustained a high level at P60. However, the developmental change of SRC-1 in hippocampus of male was increased from PO to P30, and reached the peak at P30 and then sustained a high level at P60.5. As to the postnatal developmental profile of hippocampal SYN, GluR-1 and PSD-95, the results showed that females and males shared similar patterns. The levels of SYN and GluR-1 were the lowest at PO but gradually increased with development and reached the peak at P30 and then maintained a high level, levels of PSD-95 were also increased from PO but the peak expression was found at P60.6. The developmental profile of SRC-1 in hippocampus of female and male mice showed high consistent linear correlation with that of SYN, GluR-1 and PSD-95, respectively, in each sex. The highest correlation was detected between SRC-1/GluR-1 in females and SRC-1/SYN in males.7. Circulating sex hormones affected hippocampal SRC-1 in a sex-dependant manner, as demonstrated by gonadectomy. Hippocampal SRC-1 levels decreased significantly 2 weeks after ovariectomy but recovered to normal at 4 weeks in females, while in males it decreased right after orchiectomy. GluR-1 showed identical alterations to SRC-1 after gonadectomy,8. Although hippocampal SYN was not affected by gonadectomy, significant changes of GluR-1 and PSD-95 after gonadectomy were noticed. GluR-1 showed identical changes as that of SRC-1 in both sexes, levels of PSD-95 in female only decreased significantly at 4weeks after ovariectomy but in the males it gradually decreased after orchiectomy.9. The highest linear correlation was found between SRC-1 and GluR-1 in the female after ovariectomy; and this was found between SRC-1/GluR-1 and SRC-1/PSD-95 after orchiectomy.Main conclusion: 1. SRC1-is widely distributed in the brain of both female and male mice, significant male-predominance was detected, indicating a multi-function role of SRC-1 in the regulation of various brain function and this sex-dependant distribution may contribute to the sex-difference of some steroid-related brain structure and function.2. Different extent of sex differences in regarding of the postnatal developmental profiles of hippocampal SRC-1, SYN, GluR-1 and PSD-95 of female and male mice were noticed, correlation analysis showed that SRC-1 is highly related to that of the synaptic proteins, and these results strongly imply a potential role that SRC-1 play in the regulation of hippocampal synaptogenesis in a sex-specific manner.3. Circulating sex hormones regulate hippocampal SRC-1 in a sex-dependant manner, as demonstrated by gonadectomy. Some synaptic proteins were also regulated by sex hormones as that of SRC-1. Furthermore, correlation analysis revealed that change of SRC-1 is highly with that of some of the synaptic proteins. All these strongly suggest that age-related decrease of SRC-1 may contribute the decreased synaptic plasticity in the hippocampus of female and male mice, in a sex-dependant manner.In short, the results of our study demonstrate that SRC-1, which widespreads in the brain and expresses differently between females and males, is potentially involved in the regulation of a variety of brain function and mediate the sex difference of brain structure and function. Sex difference in the developmental expression of SRC-1 in hippocampus and being highly correlated with the developmental model of several synaptic proteins suggest the sex difference of SRC-1 may possibly mediate the sex difference of hippocampal synaptogenesis. Moreover, gonad hormones affect hippocampal SRC-1 in a sex-dependant manner, and this change is also highly related with that of these synaptic proteins,implying the sex difference of SRC-1 may further participate in the changes based on sex difference of hippocampal synaptic plasticity and finally effect sex difference of hippocampus-dependent structure and function during the process of aging. Therefore, this study provides some reliable clues for advanced understanding of the mechanisms in sex difference of structure and functions involved in the brain especially in the hippocampus. |
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