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（MSB）的表达。我们的方法是结合使用生化和分子技术解决男性雄激素作用问题的行为研究老鼠的大脑。我们已将行为调查范围扩大到包括雄激素依赖性措施，例如伴侣偏好，发声和肛门生殖器检查。所有这些行为，与交配本身一起，对表达有影响 MSB 在本文中称为雄激素依赖性性行为行为。为了实现我们的目标，我们将研究三个问题。问题 l 关注雄激素的神经部位调节雄激素依赖性性行为的作用。这雄激素受体（AR）阻滞剂羟基氟他胺（OHF）将用于评估 AR 在介导雄激素依赖性中的作用两种先前未经研究的雄激素的性行为大脑集中部位：下丘脑腹内侧核 (VMN) 和颅神经运动核（n. 模糊的、舌下神经核 n.，面部运动 n.)。问题2集中于争议 MSB 是由通过 AR 作用的睾酮 (T) 介导的，还是由芳构化为雌二醇（E2）。我们将扩展我们最近的成果通过采用，表明 T 和 E2 对于 MSB 都是必不可少的一种新的 ER 阻滞剂 RU58668，用于评估雌激素的作用受体（ER）介导雄激素依赖性性行为。 E2作用的位点特异性将通过植入来确定 RU58668 直接进入内侧视前区 (MPOA)、VMN 或内侧杏仁核。问题3集中于识别下丘脑视前区的雄激素依赖性基因（HYP-POA）。我们将使用消减杂交探针从 T 处理的成年男性中筛选我们的 HYP-POA cDNA 文库老鼠。 RNAse 保护测定将用于验证分离的克隆是雄激素依赖性的。确认雄激素- 依赖性克隆将被测序以确定其身份。这上述三个问题的答案至关重要确定大脑关键部位暴露于 T 的后果 MSB 有必要解决有关该问题的争议 T作用在雄激素依赖性表达中的特异性性行为，并将提供对细胞的新见解 T暴露的影响。研究结果还将提供重要的关于 AR 和 ER 阻滞剂对行为影响的知识，这对于治疗患有以下疾病的患者具有临床意义激素依赖性肿瘤或来自激素或性的肿瘤功能障碍。