Androgen-induced Neuroplasticity in Hippocampus

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We have demonstrated that administration of androgens to castrated rats markedly increases the density of synapses on the apical dendritic spines of CA1 pyramidal neurons in the hippocampus. Since increased hippocampal spine synapse density is associated with the control of hippocampal information processing, contributing to learning and memory as well as mood state, we hypothesized that this response might represent the anatomical substrate through which the hormones produced their effects on these behaviors. Attempts to directly correlate the effects of androgens on spine synapse density with changes in hippocampal behavior have, however, been unsuccessful, because the behavioral responses are mixed, including both positive and negative effects. In the first funding period of this grant, we demonstrated that, unexpectedly, removal of the testes (orchidectomy) does not induce major changes in hippocampal dendritic spine density, despite the profound negative effect of this procedure on spine synapse numbers. Moreover, we demonstrated significant regional differences in the effects of androgens within the hippocampus, orchidectomy reducing synapse density in CA1 and the dentate gyrus, without significantly affecting synapse density in CA3. An explanation for this was provided by the observation that orchidectomy increases the BDNF sensitivity of CA3 neurons as well as BDNF protein levels, thereby inducing sprouting of mossy fiber axons in CA3. Golgi analysis of neuronal structure in the hippocampus demonstrated a marked reorganization of the apical dendritic structure in CA3, with an almost twofold increase in dendritic length and the number of dendritic branches. Thus, down-regulation of dendritic spine density via removal of testosterone appears to be at least partially compensated for in area CA3 by increases in the total number of dendritic spine contacts, compared to intact males. In the next grant period, we will test the hypotheses that BDNF release is critical to the observed neuronal remodeling and that testosterone may be exerting its effects not only by altering BDNF synthesis, but by affecting pro-BDNF processing in the mossy fiber system. We will further explore the nature of the sex differences in this response, as well as the contributions from different afferent pathways to the hippocampus. These studies may provide a mechanism to explain the mixed behavioral effects of androgens on hippocampally-mediated behaviors in male mammals, as well as indicating the anatomical basis for the profound differences that exist between males and females in these behavioral responses.**