Androgen-induced Neuroplasticity in Hippocampus

我们已经证明雄激素给去势大鼠显著增加海马CA1锥体神经元顶端树突棘的突触密度。由于海马棘突触密度的增加与海马信息处理的控制有关，有助于学习和记忆以及情绪状态，我们假设这种反应可能代表了激素对这些行为产生影响的解剖学基础。然而，试图将雄激素对脊柱突触密度的影响与海马行为的变化直接联系起来的尝试并不成功，因为行为反应是混合的，包括积极和消极的影响。在该基金的第一个资助期，我们意外地证明，尽管该手术对脊柱突触数量产生了深远的负面影响，但睾丸切除（睾丸切除术）并不会引起海马树突棘密度的重大变化。此外，我们证明了雄激素在海马、兰花切除术降低CA1和齿状回突触密度的作用存在显著的区域差异，而对CA3突触密度没有显著影响。对此的解释是，观察到兰花切除术增加了CA3神经元对BDNF的敏感性以及BDNF蛋白水平，从而诱导CA3苔藓纤维轴突的发芽。海马神经元结构高尔基体分析显示，CA3的顶端树突结构发生了明显的重组，树突长度和树突分支数量几乎增加了两倍。因此，与完整的雄性相比，通过去除睾丸激素而下调的树突脊柱密度似乎至少部分地补偿了CA3区树突脊柱接触总数的增加。在下一个资助期，我们将测试BDNF释放对观察到的神经元重塑至关重要的假设，以及睾酮可能不仅通过改变BDNF合成，而且通过影响苔藓纤维系统中BDNF前的加工来发挥其作用。我们将进一步探索这种反应中性别差异的本质，以及不同传入途径对海马体的贡献。这些研究可能为解释雄激素对雄性哺乳动物海马调节行为的混合行为效应提供了一种机制，并为这些行为反应在雄性和雌性之间存在的深刻差异提供了解剖学基础。

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.