Hypothalamic regulation of animal reproductive behavior

下丘脑对动物生殖行为的调节

基本信息

批准号：
10457791
负责人：
Kimberly J Jennings
金额：
$ 2.35万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457791
关键词：
Address Animals Antidepressive Agents Antipsychotic Agents Arousal Automobile Driving Behavior Behavioral Calcium Cardiovascular Diseases Data Development Distress Electroencephalography Environment Etiology Exposure to Female Fiber Functional disorder Goals Gonadal Hormones Gonadal Steroid Hormones Hormonal Hormones Hypothalamic structure Impairment Infusion procedures Institution Interpersonal Relations Investigation Lateral Lateral Hypothalamic Area Libido Literature Medial Mediating Mental disorders Metabolic Diseases Methodology Mood Disorders Mood stabilizers Motivation Mus Neurobiology Neuroendocrinology Neurons Neuropeptides Neurosecretory Systems Partner in relationship Patient Noncompliance Patients Pattern Personal Satisfaction Photometry Physiological Population Population Dynamics Preoptic Areas Psyche structure Psychiatric therapeutic procedure Public Health Quality of life Regulation Reporting Reproductive Behavior Research Personnel Rewards Risk Role Sex Behavior Sexual Dysfunction Social Behavior Social Interaction Stimulus System Technology Testing Training Treatment Side Effects Tweens Universities Vertebrates Work anxiety-like behavior cell type comorbidity effective therapy efficacious treatment hormone regulation hypocretin insight male nerve supply nervous system disorder neural correlate optogenetics relating to nervous system reproductive response self esteem skills social

项目摘要

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.

项目摘要。对性欲的破坏是患者不遵守患者的主要原因，很大对精神和身体健康的风险折磨。此外，减少的性欲与神经，心血管和代谢疾病，多达20％的美国人口报告长期报告性动机的个人分发障碍。这代表了一个重大的公共卫生问题性功能障碍通过降低的生活质量，自我降低，有助于情绪障碍的病因尊重和增加人际关系的压力。迫切需要进一步调查进入性动机的神经结构，以促进有效的性治疗父亲功能障碍。下丘脑外侧神经元，产生神经肽下胚素（HCRT，也称为HCRT） Orexin）是介导性驱动力的强大候选人。 HCRT神经元促进了唤醒和回报 - Havior，该提议的初步数据表明，HCRT神经元活动与性动机的表达。然而，性行为的HCRT调节的基础电路机制潮流尚不清楚。下丘脑（MPOA）的介质前区域对于生殖至关重要跨脊椎动物的行为并通过HCRT神经元接收密集的神经支配，使其成为理想的候选者调解HCRT对性动机的行动。因此，本提议的核心假设是 MPOA投射HCRT神经元（HCRTMPOA）促进男性和女性的性动机。这个假设将在三个目标中进行测试：AIM 1将在社交环境中定义内源性HCRTMPOA神经元活动。 HCRTMPOA钙活性将使用纤维光度法记录，因为男性和雌性动物暴露于各种社会和非社交刺激以及交配期间。 HCRTMPOA神经元活动之间的关系将评估特定的刺激，性行为和动机过渡。 AIM 2将确定 HCRTMPOA活动是否对于性动机的自然表达是必需的。 HCRTMPOA活动将是在化学上抑制了性动机，动画行为，寻求奖励的影响 - 将评估Havior和身体唤醒（通过同时进行脑电图/EMG记录）。 AIM 3将确定 - 挖掘HCRTMPOA神经元活动的刺激是否足以挽救马匹的性动机 - 不足的动物或升级能力动物的性动机。 HCRTMPOA神经元将如AIM 2中所评估的对行为的影响。与性动机的表达相关，并专门调节性动机而没有影响关于其他行为指标。成功完成拟议的研究将提供出色的技术训练，授予纤维光度法，化学遗传学，光遗传学和EEG/EMG记录的技能。这项工作将在斯坦福大学的De Lecea和Shah实验室内完成，该实验室将提供一个典范培训环境以及概念和专业技能的全面发展。