OVARIAN STEROID REGULATION OF SEROTONIN NEURAL FUNCTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目研究雌激素(E)和孕酮(P)对猕猴5-羟色胺神经功能的影响。5-羟色胺控制着许多自主神经和高阶神经功能。5-羟色胺神经传递的增加有望有助于唤醒、提升情绪和改善认知功能。我们现在正在寻求一种假设，即卵巢激素也可以提高5-羟色胺神经元的存活率和5-羟色胺神经元的可塑性。我们用TUNEL法检测了去势雌性猕猴中缝背核5-羟色胺神经元的DNA片段化，发现E？P处理1个月后，雌性猕猴TUNEL阳性细胞明显减少。这表明卵巢类固醇作用于DNA修复机制。随后，我们发现在激光捕获的5-羟色胺神经元中，与DNA修复相关的探针组增加。此外，我们还研究了卵巢类固醇对激光捕捉的5-羟色胺神经元中树突棘突起相关基因表达的影响。我们发现，E？P处理1个月后，RhoA、RAC和CDC42及其下游效应分子在恒河猴基因芯片上的表达显著增加，并用qRT-PCR证实了这些变化。这些表达变化会增加5-羟色胺神经元树突上的棘突增殖。最后，我们发现芬氟拉明，一种增加催乳素分泌的5-羟色胺释放剂，在切除卵巢3年的猕猴中比结扎完整卵巢的对照组效果更差。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project examines the effect of estrogen (E) and progesterone (P) on serotonin neural function in macaques. Serotonin governs many autonomic and higher order neural functions. An elevation in serotonin neurotransmission is expected to benefit arousal, elevate mood and improve cognitive function. We are now pursing the hypothesis that ovarian hormones also improve serotonin neuron survival and serotonin neuronal plasticity. We examined DNA fragmentation in serotonin neurons of the dorsal raphe nucleus with a TUNEL assay and found that E¿P treatment for one month significantly reduced TUNEL positive cells in ovarectomized female macaques. This indicates that ovarian steroids act on DNA repair mechanisms. Subsequently, we found that 64 probe sets related to DNA repair were increased by E¿P in laser-captured serotonin neurons. In addition, we determined the effect of ovarian steroid administration on gene expression related to dendritic spine protrusion in laser-captured serotonin neurons. We found that E¿P treatment for one month significantly increased expression of RhoA, Rac and cdc42 and their downstream effectors on a rhesus macaque microarray and confirmed these changes with qRT-PCR. These expression changes would increase spine proliferation on dendrites of serotonin neurons. Finally, we found that fenfluramine, a serotonin releaser that increases prolactin secretion, was less effective in macaques that were ovariectomized for 3 years compared to tubally ligated ovarian intact controls.