Sex and stress: effects on the brain - gut axis

项目摘要 女性表现出更高的胃肠道疾病发病率，包括功能性消化不良（FD）， 报告消化不良症状的严重程度高于男性。虽然生理机制， 介导胃肠道（GI）疾病的性别差异尚未完全了解，有人建议， 它们可能由循环雌激素介导。 胃运动受迷走神经背侧运动核（DMV）神经元的调节， 这些神经元由强的紧张性GABA能输入调节。雌激素已被证明增加GABA 在中枢神经系统（CNS）的几个区域中的表达和释放，以及调节 神经元形态和突触活性。 基于我们的初步研究，表明迷走神经输出的雌激素依赖性调制， 胃，我们将测试以下新的假设：“功能性胃肠疾病增加， 在女性中，部分由于雌激素介导的迷走神经流出减少， 胃”。为了研究这一新的假设，我们将使用体外和体内相结合的方法， 电生理学、行为学、化学遗传学和解剖学方法， 探究压力和雌激素在脑-肠轴中的作用。 本提案中概述的实验结果将提供对细胞生物学的更深入理解。 以及雌激素影响FD病因的神经机制，有助于确定 更有效的治疗干预措施，专门针对妇女，并提供新的见解， 围绝经期发生的GI功能变化。

PROJECT SUMMARY Women display higher incidence of gastrointestinal disorders, including functional dyspepsia (FD), and report a higher severity of dyspeptic symptoms compared to men. Although physiological mechanisms that mediate this sex disparity in gastrointestinal (GI) disorders are not fully understood, it has been suggested that they may be mediated by circulating estrogen. Gastric motility is modulated by neurons of the dorsal motor nucleus of the vagus (DMV) and the activity of these neurons is regulated by a robust tonic GABAergic input. Estrogen has been shown to increase GABA expression and release in several regions of the central nervous system (CNS), as well as to modulate neuronal morphology and synaptic activity. Based on our preliminary studies that indicate an estrogen-dependent modulation of vagal output to the stomach, we will test the following novel hypothesis: “Functional gastrointestinal disorders are increased in severity and incidence in females due, in part, to an estrogen mediated decrease in vagal outflow to the stomach”. To investigate this novel hypothesis, we will use a combination of in vitro and in vivo electrophysiological, behavioral, chemogenetic, and anatomical approaches in a rodent model aimed at interrogating the role of stress and estrogen on the brain-gut axis. The results of the experiments outlined in this proposal will provide a deeper understanding of the cellular and neural mechanisms by which estrogen influences the etiology of FD, help identify potential targets for more effective therapeutic interventions directed specifically towards women, and provide novel insights into changes in GI functions that occur in the perimenopausal period.