Physiology of Hypothalamic Neurosteroidal Progesterone

描述（由申请人提供）：神经类固醇，在大脑中合成的类固醇，涉及从压力，抑郁，焦虑到认知的功能。一种神经类固醇是黄体酮，一种典型的参与生殖调节的性激素。虽然中枢神经系统有能力合成孕酮，但迄今为止，似乎只有来自卵巢和肾上腺的外周孕酮调节生殖。我们的初步研究表明，雌激素诱导的下丘脑孕酮合成足以启动排卵和交配所必需的生殖事件。雌激素刺激卵巢切除和肾上腺切除（ovx/adx）大鼠增加下丘脑孕酮水平。在这些动物中，雌激素诱导的脊柱前凸行为和孕激素依赖的接受行为。同样，雌激素刺激ovx/adx大鼠诱导黄体生成素（LH）激增。在这些大鼠中，阻断3 β-羟基类固醇脱氢酶（3 β-HSD），将双烯醇酮转化为孕酮的酶，阻止了LH激增。雌激素刺激培养的星形胶质细胞合成孕酮，这表明胶质细胞可能介导雌激素的正反馈。这些数据表明，在缺乏外周类固醇生成组织的情况下，雌激素可以通过刺激神经甾体孕酮的合成来诱导孕酮依赖性事件。我们建议检验这一假设：雌激素刺激下丘脑孕酮的合成，激活调节LH峰和性行为的回路。提出了三个实验：首先，使用完整和ovx/adx大鼠模型，我们将直接测试是否雌激素诱导的LH峰是依赖于增加下丘脑神经甾体孕酮。其次，我们建议确定雌激素是否增加类固醇生成酶（P450侧链裂解和3 β-HSD）的表达和/或活性，需要合成孕酮，在体外和体内。第三，使用相同的完整和ovx/adx大鼠模型，我们将确定雌激素诱导的下丘脑孕酮是否足以促进性行为。这些研究将证明神经甾体孕酮的生理学，并提供有关中枢神经系统雌激素正反馈机制的重要新信息。

DESCRIPTION (provided by applicant): Neurosteroids, steroids synthesized in the brain, have been implicated in functions ranging from stress, depression, anxiety, to cognition. One neurosteroid is progesterone, a classic sex hormone involved in the regulation of reproduction. Although the CNS has the capacity to synthesize progesterone, to date it has appeared that only peripheral progesterone, from the ovaries and adrenals, regulates reproduction. Our preliminary studies have demonstrated that estrogen-induced hypothalamic progesterone synthesis is sufficient to initiate reproductive events necessary for ovulation and copulation. Estrogen stimulation of ovariectomized and adrenalectomized (ovx/adx) rats increased hypothalamic progesterone levels. In such animals, estrogen induced lordosis behavior and progesterone dependent proceptive behavior. Similarly, estrogen stimulation of ovx/adx rats induced a luteinizing hormone (LH) surge. In these rats, blocking 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the enzyme that converts pregnenolone to progesterone, prevented the LH surge. Estrogen stimulates astrocytes in culture to synthesize progesterone, suggesting that glial cells may mediate estrogen-positive feedback. These data indicate that, absent the peripheral steroidogenic tissues, estrogen can induce progesterone dependent events by stimulating the synthesis of neurosteroidal progesterone. We propose to test the hypothesis: estrogen stimulates synthesis of hypothalamic progesterone that activates circuits regulating the LH surge and sexual behavior. Three experiments are proposed: First, using intact and ovx/adx rat models we will directly test whether the estrogen-induced LH surge is dependent on increased hypothalamic neurosteroidal progesterone. Second, we propose to determine whether estrogen increases the expression and/or activity of steroidogenic enzymes (P450 side chain cleavage and 3beta-HSD) needed to synthesize progesterone, in vitro and in vivo. Third, using the same intact and ovx/adx rat models, we will determine whether estrogen-induced hypothalamic progesterone is sufficient to facilitate sexual behavior. These studies will demonstrate the physiology of neurosteroidal progesterone and provide important new information about the mechanism of estrogen-positive feedback in the CNS.