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 雄激素失衡的疾病在两性中都非常普遍。高雄激素女性经验 生殖功能障碍，而低雄激素干扰性行为，降低性欲和生育能力， 导致疲劳、抑郁和骨质流失。使用小鼠遗传学的研究（例如，雄激素 受体敲除）复制由低雄激素或AR不敏感性引起的雄性生殖功能障碍。在 雌性，AR不敏感性导致生育力低下，子宫形态破坏，黄体减少， 异常的发情周期和加速的生殖衰老。AR在多个大脑中高度表达 位点，但特定神经元回路或个体亚群的作用尚未得到证实， 由脑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/性别不一致中尤为重要 寻求性别肯定激素治疗的个人。的后果和潜在影响 超生理性雄激素对脑功能的影响在很大程度上是未知的。我们在这个应用程序中的主要目标是 确定直接雄激素作用在高度互连的大脑部位中的作用，这些部位表达低或几乎不表达雄激素。 没有芳香化酶，即，神经元回路对雌激素作用不敏感， 睾酮到雌二醇该回路由杏仁核（PA）的后核和腹侧核组成。 乳头体前核（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。功能性神经影像学研究、神经损伤或脑损伤显示 PA在性欲、性欲亢进或性欲减退以及性障碍（例如，性欲倒错） 在特定性别模式下。PA密集地投射到PMv，PMv在以下调制中具有基本作用： 神经内分泌生殖轴我们的目标是确定AR在男性特定脑核团中的作用， 而雌性小鼠则专注于环境信号、性行为和神经内分泌的整合 控制我们假设PA神经元中的AR是性别识别和性唤起所必需的， 到PMv AR神经元的PA输入将性唤起与神经内分泌（促性腺激素）和行为（性兴奋）联系起来。 应答我们将采用Cre-loxP和FlpO-Frt方法来有条件地删除这些神经元中的Ar 群体、病毒载体、TeTox和DREADD技术来远程沉默或激活AR表达 神经元，不同的类固醇环境，和化学定义的AR神经元在两个 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相关。Unraveling the AR在确定的神经元回路中的作用是预防不良健康的重要步骤 雄激素过多或过少以性别特异性方式引起的后果。