Integration of Stress and Reproductive Axes by Dopamine

多巴胺整合压力轴和生殖轴

• 批准号: 7230277
• 负责人: SIMON J EVANS
• 金额: $ 16.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230277
• 关键词: Adrenal Glands; Adrenalectomy; Affective; Amygdaloid structure; Animals; Brain; Cell Nucleus; Cells; Condition; Control Groups; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Dopamine; Dopamine Agonists; Dopamine Receptor; Drug usage; Feeding behaviors; Glucocorticoids; Goals; Gonadotropin Hormone Releasing Hormone; Health; Hormones; Human; Hypothalamic structure; In Situ Hybridization; Injection of therapeutic agent; Label; Lasers; Measures; Medial; Mediating; Microscopy; Neurons; Neurosecretory Systems; Output; Oxytocin; Parkinson Disease; Pituitary Gland; Polymerase Chain Reaction; Positioning Attribute; Psychotic Disorders; Rattus; Regulation; Relative (related person); Reproductive Behavior; Reproductive system; Research Proposals; Serum; Sexual Dysfunction; Source; Steroids; Stress; System; Testing; Time; Transcript; Variant; Vasopressins; base; biological adaptation to stress; dopamine system; dopaminergic neuron; hypothalamic-pituitary-adrenal axis; magnocellular; paraventricular nucleus; parvocellular; reproductive; reproductive axis; research study; response; restraint stress; zona incerta

DESCRIPTION (provided by applicant): Our overall goal is to determine how the stress response system and the reproductive system interact. This proposal is based on our observation that dopamine neurons in the medial zona incerta (MZI) are sensitive to variations in circulating adrenal steroid levels. These neurons are known to regulate reproductive and feeding behavior but have not previously been implicated in the stress response. However, these neurons are believed to project to corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) and are thus in a position to regulate hypothalamic-pituitary-adrenal (HPA) axis activity, which is increased during stress. We hypothesize that activity of MZI dopamine neurons leads to dopamine release in the PVN and that this simultaneously stimulates reproductive behavior and inhibits the stress response. Furthermore, we hypothesize that this activity is sensitive to glucocorticoid levels, which increase during stress. In specific aim one we will determine if dopamine system transcripts within the MZI are regulated by glucocorticoids and, if so, which ones. This will be accomplished by combining laser- capture microscopy (LCM), to isolate MZI neurons, with quantitative real-time PCR (qRT-PCR) to measure dopamine transcript levels in adrenalectomized rats. In specific aim two we will determine which dopamine receptors are expressed in the PVN and specifically, which, if any, are expressed on CRH neurons. This will also be accomplished by combining LCM of PVN neurons with qRT-PCR followed by double-labeled in situ hybridization. In specific aim three we will inject a dopamine agonist into the PVN and determine the effect of this manipulation on markers of HPA activation, namely, increases in serum adrenocorticotropin hormone and corticosterone. For these studies rats will be cannulated to allow injection into the PVN just prior to either handling or restraint stress. The studies are important to human health because they will help elucidate the function of dopamine activity in the PVN and the factors that regulate this activity. This is relevant because several clinically used drugs that treat conditions as varied as psychosis, sexual dysfunction and Parkinson's disease manipulate brain dopamine and the consequences of this manipulation on stress and HPA activity is not understood.

描述（由申请人提供）：我们的总体目标是确定压力反应系统和生殖系统如何相互作用。该提议基于我们的观察，即内侧未定带 (MZI) 中的多巴胺神经元对循环肾上腺类固醇水平的变化敏感。已知这些神经元可以调节生殖和进食行为，但之前并未涉及应激反应。然而，这些神经元被认为投射到下丘脑室旁核 (PVN) 中的促肾上腺皮质激素释放激素 (CRH) 神经元，因此能够调节下丘脑 - 垂体 - 肾上腺 (HPA) 轴活动，该活动在压力期间会增加。我们假设 MZI 多巴胺神经元的活动导致 PVN 中多巴胺的释放，这同时刺激生殖行为并抑制应激反应。此外，我们假设这种活动对糖皮质激素水平敏感，糖皮质激素水平在压力下会增加。在具体目标一中，我们将确定 MZI 内的多巴胺系统转录是否受糖皮质激素调节，如果是，是哪些。这将通过结合激光捕获显微镜 (LCM) 来分离 MZI 神经元，与定量实时 PCR (qRT-PCR) 相结合来测量肾上腺切除大鼠的多巴胺转录水平。在具体目标二中，我们将确定哪些多巴胺受体在 PVN 中表达，特别是哪些多巴胺受体（如果有的话）在 CRH 神经元上表达。这也将通过将 PVN 神经元的 LCM 与 qRT-PCR 相结合，然后进行双标记原位杂交来实现。在具体目标三中，我们将向 PVN 注射多巴胺激动剂，并确定这种操作对 HPA 激活标志物的影响，即血清促肾上腺皮质激素和皮质酮的增加。对于这些研究，在处理或约束应激之前，将对大鼠进行插管以允许注射到 PVN 中。这些研究对人类健康很重要，因为它们将有助于阐明 PVN 中多巴胺活性的功能以及调节该活性的因素。这是相关的，因为临床上使用的几种治疗精神病、性功能障碍和帕金森病等多种疾病的药物会操纵大脑多巴胺，而这种操纵对压力和 HPA 活性的影响尚不清楚。