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

基本信息

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
项目类别：
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

项目摘要

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疾病在两性中都非常普遍。生殖功能障碍，而低雄激素会扰乱性行为，降低性欲和生育能力，使用小鼠遗传学（例如雄激素）进行的研究会导致两性疲劳、抑郁和骨质流失。受体敲除）复制了由低雄激素或 AR 不敏感引起的男性生殖功能障碍。女性，AR不敏感会导致生育力低下，子宫形态被破坏，黄体减少，发情周期异常和生殖衰老加速 AR 在多个大脑中高表达。位点，但特定神经回路或个体亚群的作用尚未得到证实，并且脑AR介导的雄激素失衡疾病的原因和机制仍然存在未知，这对于雄激素滥用和性别不安/性别不一致尤为重要。寻求性别确认激素治疗的个体的后果和潜在影响。超生理性雄激素对大脑功能的影响在很大程度上是未知的，我们在此应用中的主要目标是。确定雄激素在表达低或几乎表达的高度互连的大脑部位中的直接作用的作用没有芳香酶，即神经元电路在位点特异性转化后不易受雌激素作用的影响睾酮到雌二醇的回路由杏仁核 (PA) 和腹侧核组成。 PA 传递同种嗅觉信号，与人类的嗅觉高度相关。功能性神经影像学研究、神经损伤或脑损伤已表明。 PA 在性冲动、性欲亢进或性欲减退以及性障碍（例如性欲倒错）中发挥着关键作用 PA 密集投射到 PMv，PMv 在调节中起着基本作用。我们的目标是确定 AR 在男性特定脑核中的作用。雌性小鼠则专注于环境信号、性行为和神经内分泌的整合我们认为 PA 神经元中的 AR 对于性别识别和性唤起是必需的。 PA 对 PMv AR 神经元的输入将性唤起与神经内分泌（促性腺激素）和行为联系起来我们将采用 Cre-loxP 和 FlpO-Frt 方法有条件地删除这些神经中的 Ar。群体、病毒载体、TeTox 和 DREADDs 技术可远程沉默或激活 AR 表达神经元、不同类固醇环境以及两种化学定义的 AR 神经元的分子图谱我们的研究结果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。 AR 在确定的神经回路中的作用是预防不良健康的重要一步雄激素过多或过低以性别特异性方式引起的后果。