Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior

项目摘要 雌激素是一类类固醇激素，可以帮助从脑损伤中恢复，并减少脑损伤的影响。 某些神经系统疾病最近，人类和其他动物的中枢神经系统被 显示能够产生自己的雌激素本地供应，为目标提供新的机会， 治疗脑部疾病。从历史上看，雌激素的临床应用取得了好坏参半的成功，可能 因为雌激素药物治疗旨在模拟雌激素的长期作用（数天-数周） 而认知功能可能主要取决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反应有关。 影响和降低患者依从性。这项研究计划的目标是表征机制， 在离散的大脑区域内快速产生和作用雌激素（“快速雌激素信号”）， 了解这些事件对感觉运动整合和行为的后果。利用 最近的方法学进展，这些研究将结合联合收割机敏感的实时测量大脑雌激素 浓度，识别神经元的急性记录，以及当代行为评估， 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 我们对大脑中雌激素的产生如何指导复杂行为的理解存在根本性的差距， 并将最终为认知和神经系统的高度靶向雌激素疗法的发展提供信息。 紊乱

PROJECT SUMMARY 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.