OVARIAN STEROID REGULATION OF SEROTONIN NEURAL FUNCTION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这是一个新的项目/赠款，研究雄激素对5-羟色胺神经系统中行为和基因表达的作用。5-羟色胺系统调节冲动行为和攻击性。据推测，雄激素作用于5-羟色胺系统，以减少5-羟色胺，从而增加冲动。然而，对男性人类和非人类灵长类动物5-羟色胺神经元中类固醇受体的分布缺乏了解，对雄激素对5-羟色胺神经元基因表达的作用也知之甚少。我们假设雄性灵长类动物的5-羟色胺神经元表达雌激素受体β(Erb)和雄激素受体(AR)，这些受体的活性平衡调节5-羟色胺的合成和神经功能，进而控制攻击性。我们将建立雄性猕猴群体，并使用酶抑制剂来调控Erb和AR的活性。我们将评估行为学和整体5-羟色胺。我们将确定ERb、AR和关键代谢酶是否定位在5-羟色胺神经元中，以及它们是否受睾酮代谢产物的调节。此外，5-羟色胺相关基因TPH2、SERT、5HT1A、MAO-A和MAO-B的调控将通过原位杂交来确定。雄性日本猕猴已经被阉割，目前正在接受安慰剂、睾酮(T)、T+来曲唑(芳香酶抑制剂)和T+Avodart(5a还原酶抑制剂)(n=5/组)的治疗。目前正在监测血清雌激素、睾酮和双氢睾酮水平，以验证治疗效果。芬氟拉明挑战将在两周内确定5-羟色胺的全球可获得性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This is a new project/grant examining the action of androgens on behavior and gene expression in the serotonin neural system. The serotonin system mediates impulsive behavior and aggression. It has been reasoned that androgens act on the serotonin system to reduce serotonin and thereby increase impulsivity. However, knowledge of the steroid receptor profile in serotonin neurons of male human and nonhuman primates is lacking and little is known of the actions of androgens on gene expression in serotonin neurons. We hypothesize that serotonin neurons in male primates express estrogen receptor beta (ERb) and androgen receptors (AR) and that the balance of activity at these receptors governs serotonin synthesis and neural function, which in turn, controls aggression. We will establish groups of male macaques and manipulate the activity of ERb and AR with enzyme inhibitors. Behavior and global serotonin will be assessed.We will determine whether ERb, AR, and pivotal metabolic enzymes are localized in serotonin neurons and whether they are regulated by testosterone metabolites. In addition, the regulation of serotonin-related genes TPH2, SERT, 5HT1A, MAO-A and MAO-B will be determined with in situ hybridization. Male Japanese macaques have been castrated and are currently in treatment with placebo, testosterone (T), T+ Letrozole (aromatase inhibitor) and T+Avodart (5a reductase inhibitor)(n=5/group). Serum levels of estrogen, testosterone and dihydrotestosterone are being monitored to verify the efficacy of treatment. Fenfluramine challenges to determine the global availability of serotonin are scheduled in two weeks.