Androgen-induced Neuroplasticity in Hippocampus

我们已经证明，给去势大鼠注射雄激素显著增加了海马区CA1锥体神经元顶端树突棘上的突触密度。由于海马棘突触密度的增加与海马区信息处理的控制有关，有助于学习和记忆以及情绪状态，我们推测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体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，既有积极的，也有消极的。在这笔赠款的第一个资助期，我们证明了，出乎意料的是，摘除睾丸(睾丸切除)并没有引起海马树突棘密度的重大变化，尽管这种程序对脊突触数量产生了深刻的负面影响。此外，我们还发现在海马区雄激素的影响存在显著的地区差异，切除降低了CA1和齿状回的突触密度，而对CA3区的突触密度没有显著影响。对此的解释是，观察到切除增加了CA3神经元对BDNF的敏感性以及BDNF蛋白水平，从而诱导了CA3内苔藓纤维轴突的萌发。对海马神经元结构的高尔基分析表明，CA3区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增加了近两倍。因此，与正常男性相比，在CA3区，通过去掉睾酮而导致的树突棘密度的下调，似乎至少可以通过增加树突棘接触的总数来部分补偿。在下一个授权期，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的合成，而且通过影响苔藓纤维系统中BDNF的前体处理来发挥其作用。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。这些研究可能提供一种机制来解释雄激素对雄性哺乳动物海马体介导的行为的混合行为影响，并指出雄性和雌性在这些行为反应上存在深刻差异的解剖学基础。

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.**