Sex-specific role of androgen signaling in neuroendocrine-behavior interface

雄激素信号在神经内分泌行为界面中的性别特异性作用

• 批准号: 10659301
• 负责人: Carol Fuzeti Elias
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659301
• 关键词: Acceleration; Accessory Olfactory Bulbs; Aggressive behavior; Amygdaloid structure; Androgen Receptor; Androgens; Anxiety; Appearance; Aromatase; Athletic; Behavior; Bilateral; Binding; Brain; Cardiovascular Diseases; Cell Nucleus; Chemicals; Collection; Complete Androgen-Insensitivity Syndrome; Cre-LoxP; Cues; Decreased Libido; Disease; Estradiol; Estrogens; Estrous Cycle; Experimental Models; Fatigue; Feedback; Female; Fertility; Functional disorder; GNRH1 gene; Gender; Genes; Genetic; Goals; Gonadal Steroid Hormones; Gonadotropins; Health; Human; Hyperandrogenism; Hypothalamic structure; Individual; Infertility; Knock-out; Lesion; Libido; Maps; Mediating; Mental Depression; Modeling; Molecular; Morphology; Mus; Neurologic; Neurons; Neurosecretory Systems; Odors; Paraphilias; Partner in relationship; Pathway interactions; Performance; Play; Polycystic Ovary Syndrome; Population; Prevention; Regulation; Reproductive Physiology; Role; Sex Behavior; Sex Discrimination; Sexual Arousal; Sexual Health; Shapes; Signal Transduction; Site; Steroids; System; Technology; Territoriality; Testing; Testosterone; Tetanus Toxin; Uterus; Viral Vector; Woman; behavioral response; bone loss; density; designer receptors exclusively activated by designer drugs; experience; experimental study; gender affirming hormone therapy; gender dysphoria; human model; male; mouse genetics; mouse model; mutant; nerve supply; neural circuit; neuroimaging; neuromechanism; neuronal circuitry; neurotransmission; physical conditioning; receptor; reproductive; reproductive axis; reproductive senescence; response; sex; subfertility; tool; virtual

Abstract/Project Summary Disorders of androgens imbalance are highly prevalent in both sexes. Hyperandrogenic females experience reproductive dysfunction, whereas low androgens disrupt sexual behavior, decrease libido and fertility, and induce fatigue, depression, and bone loss in both sexes. Studies using mouse genetics (e.g., androgen receptor knockout) replicate male reproductive dysfunctions caused by low androgens or AR insensitivity. In females, AR insensitivity results in subfertility, with disrupted uterine morphology, fewer corpora lutea, abnormal estrous cycles and accelerated reproductive senescence. AR is highly expressed in multiple brain sites, but the role of specific neuronal circuitry or individual subpopulations has not been demonstrated, and the causes and mechanisms underlying disorders of androgen imbalance mediated by brain AR remain unknown. This is particularly important in androgens abuse and for gender dysphoric/gender incongruent individuals which seek gender-affirming hormone treatment. The consequences and potential effects of supraphysiologic androgens on brain function are largely unknown. Our main goal in this application is to determine the role of direct androgen actions in highly interconnected brain sites that express low or virtually no aromatase, i.e., neuronal circuitry not susceptible to estrogen actions following site-specific conversion of testosterone to estradiol. The circuit is comprised of the posterior nucleus of the amygdala (PA) and the ventral premammillary nucleus (PMv). The PA relays conspecific olfactory signals and is highly relevant for human’s physical and sexual health. Functional neuroimaging studies, neurological insults or brain lesions have shown that the PA has a critical role in sexual drive, hyper- or hyposexuality, and sexual disorders (e.g., paraphilias) in a sex specific mode. The PA densely projects to the PMv which has a fundamental role in the modulation of the neuroendocrine reproductive axis. Our goal is to determine the role of AR in specific brain nuclei of male and female mice focused on the integration of environmental signals, sexual behavior, and neuroendocrine control. We hypothesize that AR in PA neurons is necessary for sex recognition, and sexual arousal, and that PA inputs to PMv AR neurons connect sexual arousal to neuroendocrine (gonadotropins) and behavioral responses. We will employ Cre-loxP and FlpO-Frt approaches to conditionally delete Ar in these neuronal populations, viral vectors, TeTox and DREADDs technology to remotely silence or activate AR expressing neurons, different steroids milieu, and molecular mapping of chemically defined AR neurons in two independent aims. Our findings will open new opportunities for a better understanding of the mechanisms associated with the pathophysiology of altered levels of androgens mediated by neuronal AR. Unraveling the role of AR in defined neuronal circuitry is an essential step toward the prevention of adverse health consequences caused by hyper- or hypoandrogenism in a sex-specific manner.

摘要/项目摘要 雄激素失衡的紊乱在两性中都非常普遍。高雄激素性女性体验 生殖功能障碍，而低雄激素扰乱性行为，降低性欲和生育力，以及 无论男女，都会导致疲劳、抑郁和骨质流失。使用小鼠遗传学(例如，雄激素)的研究 受体敲除)复制由低雄激素或AR不敏感引起的男性生殖功能障碍。在……里面 女性，AR不敏感会导致不育，子宫形态紊乱，黄体减少， 发情周期异常，生殖衰老加速。AR在多发性脑中的高表达 部位，但特定的神经元回路或个别亚群的作用尚未被证明，以及 脑AR介导的雄激素失衡的原因和机制仍然存在 未知。这在雄激素滥用和性别焦虑症/性别不一致方面尤其重要。 寻求性别肯定荷尔蒙治疗的个人。的后果和潜在影响 超生理雄激素对大脑功能的影响在很大程度上是未知的。我们在此应用程序中的主要目标是 确定直接雄激素作用在低表达或虚拟表达的高度相互连接的大脑部位中的作用 没有芳香酶，即在部位特异性转换后对雌激素作用不敏感的神经元回路 睾丸激素转化为雌二醇。该回路由杏仁核后核(PA)和腹侧核组成 乳房前核(PMV)。PA传递同种嗅觉信号，与人类的嗅觉高度相关 身体和性健康。功能神经成像研究，神经侮辱或脑损伤显示 PA在性冲动、性欲亢进或性欲减退以及性功能障碍(如变态)中起着关键作用 在特定性别模式下。PA密集地投射到PMV，PMV在调节 神经内分泌生殖轴。我们的目标是确定AR在男性特定脑核中的作用 雌性小鼠专注于环境信号、性行为和神经内分泌的整合 控制力。我们假设，PA神经元中的AR是性别识别和性唤醒所必需的，而且 PA传入PMV AR神经元将性唤醒与神经内分泌(促性腺激素)和行为联系起来 回应。我们将使用Cre-loxP和FlpO-FRT方法有条件地删除这些神经元中的AR 群体、病毒载体、TeTox和DREADDS技术远程沉默或激活AR表达 神经元，不同的类固醇环境和化学定义的AR神经元的分子图谱 独立的目标。我们的发现将为更好地理解这些机制提供新的机会 与神经元AR介导的雄激素水平改变的病理生理学有关。解开 AR在明确的神经元回路中的作用是预防不良健康的关键一步 因性别而导致的雄激素过多或过低所造成的后果。