ANDROGEN MODULATION OF BRAIN FUNCTION

雄激素对脑功能的调节

基本信息

批准号：
6387582
负责人：
Marilyn Y MCGINNIS
金额：
$ 27.73万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-02-01 至 2003-07-31
项目状态：
已结题

项目摘要

The ultimate objective of this research program is to understand how androgens modulate brain function and regulate the expression of male sexual behavior (MSB). Our approach is to employ biochemical and molecular techniques in combination with behavioral studies to address questions on androgen action in male rat brain. We have expanded our behavioral investigations to include androgen-dependent measures such as partner preference, vocalization and anogenital investigation. All of these behaviors, along with copulation itself, are influential in the expression of MSB and will be referred to herein as androgen-dependent sexual behaviors. To achieve our goals, we will investigate three questions. Question l focusses on the neural sites of androgen action in regulating androgen-dependent sexual behaviors. The androgen receptor (AR) blocker, hydroxyflutamide (OHF), will be used to assess the role of AR in mediating androgen-dependent sexual behaviors in two previously unstudied androgen- concentrating brain sites: the ventromedial hypothalamic nucleus (VMN) and cranial nerve motor nuclei (n. ambiguous, hypoglossal n., facial motor n.). Question 2 focusses on the controversy over whether MSB is mediated by testosterone (T) acting via AR, or by aromatization to estradiol (E2). We will extend our recent results showing that both T and E2 are essential for MSB, by employing a newER blocker, RU58668, to assess the role of estrogen receptors (ER) in mediating androgen-dependent sexual behaviors. The site specificity of E2 action will be determined by implanting RU58668 directly into the medial preoptic area (MPOA), VMN or medial amygdala. Question 3 focusses on the identification of androgen-dependent genes in the hypothalamus-preoptic area (HYP-POA). We will use a subtractively hybridized probe to screen our HYP-POA cDNA library from T-treated adult male rats. RNAse protection assays will be used to verify that the isolated clones are androgen-dependent. Confirmed androgen- dependent clones will be sequenced to establish their identity. The answers to the three questions posed above are central to determining the consequences of T exposure in critical brain sites necessary for MSB, to resolving the controversy over the specificity of T action in the expression of androgen-dependent sexual behaviors, and will provide new insights into the cellular effects of T exposure. The results will also provide important knowledge on the effects of AR and ER blockers on behavior, which has clinical relevance for treating patients suffering from hormone-dependent tumors or from hormonal or sexual dysfunction.

该研究计划的最终目标是了解雄激素如何调节大脑功能并调节男性性行为的表达（MSB）。我们的方法是结合使用生化和分子技术行为研究以解决男性雄激素作用的问题大鼠大脑。我们已经将行为调查扩展到包括依赖雄激素的措施，例如伴侣偏好，发声和肛门生态研究。所有这些行为，与交配本身一起，在表达中具有影响力 MSB并将在此称为雄激素依赖性性行为。为了实现我们的目标，我们将调查三个问题。问题l专注于雄激素的神经部位调节依赖雄激素的性行为的作用。这雄激素受体（AR）阻滞剂，羟氟氨酰胺（OHF）将是用于评估AR在介导雄激素依赖性中的作用在两个以前未研究的雄激素中的性行为浓缩脑部位：腹侧下丘脑核（VMN）和颅神经运动核（n。 n。，面部电动机n。）。问题2的重点是争议 MSB是通过AR作用的睾丸激素（T）介导的，还是由芳香化雌二醇（E2）。我们将扩大最新结果表明T和E2对MSB都是必不可少的较新的阻滞剂RU58668，以评估雌激素的作用介导雄激素依赖性性行为的受体（ER）。 E2动作的场地特异性将通过植入来确定 RU58668直接进入内侧前区域（MPOA），VMN或内侧杏仁核。问题3的重点是识别下丘脑流行区域中的雄激素依赖基因（HYP-POA）。我们将使用减去杂交探针从T处理的成年男性中筛选我们的Hyp-Poa cDNA库老鼠。 RNase保护分析将用于验证孤立的克隆依赖雄激素。确认的雄激素 - 依赖克隆将进行测序以建立其身份。这上面提出的三个问题的答案是确定关键大脑部位暴露的后果 MSB所必需的，解决有关 t作用在雄激素依赖性表达中的特异性性行为，并将为细胞提供新的见解暴露的影响。结果也将提供重要了解AR和ER阻滞剂对行为的影响，这对于治疗患者的临床意义激素依赖性肿瘤或激素或性功能障碍。