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的疾病在两性中都非常普遍。女性过度女性经历生殖功能障碍，而低雄激素破坏了性行为，减少性欲和生育能力，并且两性诱发疲劳，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不敏感引起的男性复制功能障碍。在女性，不敏感性会导致不差，子宫形态破坏，较少的lutea，异常发情周期和加速生殖感应。 AR在多个大脑中高度表达站点，但是尚未证明特定神经元电路或个体亚群的作用，并且由脑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烦躁/性别不一致中尤其重要寻求性别肯定马龙治疗的个人。后果和潜在影响脑功能上的诊断雄激素在很大程度上尚不清楚。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高度互连的大脑位点中的作用，该位点表达低或虚拟没有芳香酶，即神经元电路不易在现场特异性转化后不受雌激素作用的影响睾丸激素到雌二醇。该电路已完成杏仁核（PA）和腹侧的后核前核核（PMV）。 PA继电器特定的嗅觉信号，与人类高度相关身体和性健康。功能性神经影像学研究，神经系统损伤或脑病变已显示 PA在性驱动，过度或过度疾病和性障碍（例如，菌群）中具有关键作用在性别模式下。 PA的全部项目向PMV投影，该项目在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在男性特定脑核中的作用雌性小鼠着重于环境信号，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对于性别识别和性唤醒是必要的，并且 PA输入到PMV AR神经元将性唤醒连接到神经内分泌（促性腺激素）和行为回答。我们将采用Cre-loxp和flpo-FRT方法在这些神经元中有条件删除AR 种群，病毒载体，四氧毒素和恐惧技术，以远程静音或激活AR表达神经元，不同类固醇环境和化学定义的AR神经元的分子图独立目标。我们的发现将为更好地理解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有关。解开 AR在定义的神经元电路中的作用是预防不良健康的重要一步由性别特异性的方式由超或性低下的后果引起的。