Hypothalamic regulation of animal reproductive behavior

项目摘要。性欲障碍是患者不依从的主要原因，在很大程度上- 增加了精神和身体健康的风险此外，性欲下降与以下疾病高度共病： 神经、心血管和代谢疾病，高达20%的美国人口报告长期， 性动机方面令人痛苦的障碍。这是一个重大的公共卫生问题， 性功能障碍通过降低生活质量，减少自我， 人际关系紧张，人际关系紧张。迫切需要进一步调查 性动机的神经基质，以促进发展有效的治疗方法， 认祖归宗功能障碍下丘脑外侧神经元产生神经肽下丘脑泌素（Hcrt，也称为 食欲素）是调节性欲的强有力的候选者。Hcrt神经元促进唤醒和奖赏寻求 该提案的初步数据表明，Hcrt神经元活动与以下因素高度相关： 性动机的表达。然而，Hcrt调控性行为的电路机制尚不清楚。 活化仍不清楚。下丘脑内侧视前区（mPOA）是生殖系统的重要组成部分， 行为跨越脊椎动物，并接受Hcrt神经元的密集神经支配，使其成为一个理想的候选人， 介导Hcrt对性动机的作用。因此，本提案的核心假设是， mPOA投射Hcrt神经元（HcrtmPOA）促进男性和女性的性动机。这一假设 将在三个目标中进行测试：目标1将定义社会性背景中的内源性HcrtmPOA神经元活性。 将使用纤维光度法记录HcrtmPOA钙活性，因为雄性和雌性动物暴露于 各种社会和非社会刺激和交配期间。HcrtmPOA神经元活动之间的关系 具体的刺激，性行为和动机转变将被评估。目标2将决定 HcrtmPOA活性是否是性动机的自然表达所必需的。HcrtmPOA活动将是 化学基因抑制和对性动机的影响，焦虑样行为，寻求奖励， 将评估睡眠和生理唤醒（通过同步EEG/EMG记录）。目标3将阻止- 我认为刺激HcrtmPOA神经元活动是否足以挽救激素水平的性动机， 缺陷的动物或增强有能力的动物的性动机。HcrtmPOA神经元将 光遗传学刺激并如目的2中评估对行为的影响。HcrtmPOA活性预计为 与性动机的表达相关，并专门调节性动机而不影响 其他行为指标。成功完成拟议的研究将提供出色的技术 培训，传授纤维光度测定、化学遗传学、光遗传学和EEG/EMG记录方面的技能。这项工作 将在斯坦福大学的de Lecea和Shah实验室内完成，这将提供一个示范性的 培训环境和概念和专业技能的全面发展。

PROJECT SUMMARY. Disruptions to sexual desire are a leading cause of patient noncompliance, greatly in- creasing risk to mental and physical wellbeing. Furthermore, reduced sexual desire is highly comorbid with neurological, cardiovascular, and metabolic diseases, with up to 20% of the US population reporting long-term, personally-distressing impairments in sexual motivation. This represents a significant public health concern as sexual dysfunction contributes to the etiology of mood disorders via decreased quality of life, reduced self- esteem, and increased strain on interpersonal relationships. There is a critical need for further investigation into the neural substrates of sexual motivation to facilitate development of efficacious treatments for sexual de- sire dysfunctions. Lateral hypothalamic neurons that produce the neuropeptide hypocretin (Hcrt, also known as orexin) are strong candidates to mediate sexual drive. Hcrt neurons promote arousal and reward-seeking be- havior, and this proposal’s preliminary data demonstrates that Hcrt neuronal activity is highly associated with the expression of sexual motivation. However, the circuit mechanisms underlying Hcrt regulation of sexual mo- tivation remain unclear. The medial preoptic area of the hypothalamus (mPOA) is essential for reproductive behavior across vertebrates and receives dense innervation by Hcrt neurons, making it an ideal candidate to mediate Hcrt actions on sexual motivation. Therefore, the central hypothesis of the present proposal is that mPOA-projecting Hcrt neurons (HcrtmPOA) promote sexual motivation in males and females. This hypothesis will be tested in three aims: Aim 1 will define endogenous HcrtmPOA neuronal activity in sociosexual contexts. HcrtmPOA calcium activity will be recorded using fiber photometry as male and female animals are exposed to a variety of social and nonsocial stimuli and during mating. The relationship between HcrtmPOA neuronal activity and specific stimuli, sexual behaviors, and motivational transitions will be assessed. Aim 2 will determine whether HcrtmPOA activity is necessary for the natural expression of sexual motivation. HcrtmPOA activity will be chemogenetically suppressed and the impact on sexual motivation, anxiety-like behavior, reward-seeking be- havior, and physiological arousal (via simultaneous EEG/EMG recording) will be assessed. Aim 3 will deter- mine whether stimulation of HcrtmPOA neuronal activity is sufficient to rescue sexual motivation in hormone- deficient animals or to escalate sexual motivation in hormone-competent animals. HcrtmPOA neurons will be optogenetically stimulated and the impact on behavior assessed as in Aim 2. HcrtmPOA activity is expected to be associated with expression of sexual motivation, and to specifically regulate sexual motivation without impacts on other behavioral metrics. Successful completion of the proposed studies will provide outstanding technical training, imparting skills in fiber photometry, chemogenetics, optogenetics, and EEG/EMG recording. This work will be completed within the de Lecea and Shah labs at Stanford University, which will provide an exemplary training environment and comprehensive development of conceptual and professional skills.