Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior

说明(申请人提供)：雌激素是一种类固醇激素，可以帮助从脑损伤中恢复，并减少某些神经疾病的影响。最近，人类和其他动物的中枢神经系统被证明能够产生自己的局部雌激素供应，为脑部疾病的靶向治疗提供了新的机会。从历史上看，雌激素的临床应用取得了好坏参半的结果，可能是因为雌激素药物治疗的目的是模仿雌激素的长期作用(天-周)，而认知功能可能严重依赖于雌激素的短期作用(秒-分钟)。事实上，用全身剂量的雌激素治疗神经系统疾病与不良副作用和患者依从性降低有关。这项研究计划的目标是描述离散大脑区域内雌激素快速产生和作用(‘快速雌激素信号’)的机制，并了解这些事件对感觉运动整合和行为的影响。利用最近的方法学进展，这些研究将结合大脑雌激素浓度的灵敏实时测量、已识别神经元的急性记录和当代行为评估，以了解快速雌激素信号在大脑回路中的功能意义。这项工作将解决我们对大脑内雌激素产生如何指导复杂行为的理解中的一个根本空白，并最终将为开发针对认知和神经疾病的高度靶向的雌激素疗法提供信息。

DESCRIPTION (provided by applicant): Estrogens are a class of steroid hormones that can aid recovery from brain injury and reduce the impact of certain neurological disorders. Recently, the central nervous system of humans and other animals has been shown capable of generating its own local supply of estrogens, providing new opportunities for the targeted treatment of brain diseases. Historically, the clinical use of estrogens has produced mixed success, possibly because estrogenic drug treatments are designed to mimic long term actions of estrogens (days-weeks) whereas cognitive function may depend critically on the short-term actions of estrogens (seconds-minutes). Indeed, treating neurological disorders with systemic doses of estrogens is associated with adverse side effects and reduced patient compliance. The goal of this research program is to characterize the mechanisms for rapid estrogen production and action ('rapid estrogen signaling') within discrete brain regions, and to understand the consequences of these events for sensorimotor integration and behavior. Taking advantage of recent methodological advances, these studies will combine sensitive real-time measures of brain estrogen concentrations, acute recordings of identified neurons, and contemporary behavioral assessments to understand the functional significance of rapid estrogen signaling in brain circuits. This work will address a fundamental gap in our understanding of how estrogen production within the brain guides complex behavior, and will ultimately inform the development of highly-targeted estrogen therapies for cognitive and neurological disorders.