Androgen-induced Neuroplasticity in Hippocampus

雄激素诱导的海马神经可塑性

• 批准号: RGPIN-2015-04537
• 负责人: MacLusky, Neil
• 金额: $ 1.75万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=589859
• 关键词: Androgen; induced; Neuroplasticity; Hippocampus

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.

我们已经证明，雄激素去势大鼠的管理显着增加突触的密度在海马CA1锥体神经元的顶端树突棘。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，试图将雄激素对棘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。在该资助的第一个资助期内，我们证明了，出乎意料的是，睾丸切除术（睾丸切除术）不会引起海马树突棘密度的重大变化，尽管该手术对棘突触数量有深刻的负面影响。此外，我们证明了显着的区域差异的影响，雄激素在海马，海马切除术减少突触密度在CA 1和齿状回，而不显着影响突触密度在CA 3。通过观察到小脑扁桃体切除术增加了CA3神经元的BDNF敏感性以及BDNF蛋白水平，从而诱导CA3中苔藓纤维轴突的发芽，对此进行了解释。海马神经元结构的高尔基体分析表明，CA3的顶端树突状结构的显着重组，树突状的长度和树突状分支的数量几乎增加了两倍。因此，通过去除睾酮下调树突棘密度似乎至少部分补偿在CA3区的树突棘接触的总数增加，相比完整的男性。在下一个资助期，我们将测试的假设，BDNF的释放是至关重要的观察到的神经元重塑和睾酮可能发挥其作用，不仅通过改变BDNF的合成，但通过影响前BDNF的苔藓纤维系统的处理。我们将进一步探讨这种反应的性别差异的性质，以及不同传入途径对海马的贡献。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的神经介导的行为的混合行为效应，以及指示这些行为反应中存在于雄性和雌性之间的深刻差异的解剖学基础。