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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.

抽象/项目总结