Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior

项目总结 任何开始学习一门新外语的人都可以证明：感觉刺激，比如演讲和 歌曲是近乎连续的复杂声音的串流。通过练习，监听者可以学习解析 普通话或斯特拉文斯基语流中的意义。通信声音随时间而变化 毫秒进程(例如，歌曲和语音)的最佳编码方式是高精度、低成本 抖动神经元活动。处理复杂、密集声流并对其做出反应的神经元 因此表现出快速而精确的动作电位计时。感觉神经元的棘波时序 也受到当前环境的影响，例如注意力的转移和外部或内部的变化 各州。解释我们感官和认知中这种动态丰富的机制 经验正变得越来越清晰。在大脑皮层，快速放电抑制性中间神经元是必不可少的。 对感官刺激进行编码和学习。快速放电的中间神经元的活动被塑造 通过神经调节剂如催产素、多巴胺、5-羟色胺和 儿茶酚胺。这些机制可以帮助解释生物体如何将不同的价值观 对感觉刺激的效价和显著程度取决于父母教养、攻击性、交配、 和压力。一种新近发现的神经调节系统--神经递质的合成和作用 大脑中的神经雌激素--现在为更深入地了解 感觉处理和认知。雌激素治疗可以改善多种神经系统疾病。 疾病，包括帕金森氏症、阿尔茨海默氏症和癫痫。然而，因为 大脑雌激素合成的神经调节角度是相对较新的，治疗性的 神经雌激素信号本身的潜力目前尚未开发。这个项目的研究项目 该提案将揭示超精密、快速抑制性中间神经元对 神经雌激素在大脑皮层的调节作用。我们将检验这一假设 神经雌激素直接调节皮层中的快速放电中间神经元以调节放电时序 精确度和行为辨别学习。拟议中的项目将利用 基因靶向快速放电抑制的分子和技术研究进展 中间神经元。因此，这项工作将解决我们在理解如何 大脑中雌激素的产生指导着复杂的行为，并可能最终告知 开发针对认知和神经障碍的高针对性雌激素疗法。

PROJECT SUMMARY Anyone who starts learning a new foreign language can attest: sensory stimuli like speech and song are near-continuous streams of complex sounds. With practice, listeners can learn to parse the meaning in streams of Mandarin or Stravinsky. Communication sounds that vary over the course of milliseconds (e.g., songs and speech) are optimally encoded by high-precision, low- jitter neuronal activity. The neurons that process and respond to complex, dense sound streams therefore exhibit fast and precise timing of action potentials. The spike timing of sensory neurons is also shaped by the current context, such as shifts in attention and changes in external or internal states. Mechanisms that account for this dynamic richness in our sensory and cognitive experience are becoming clearer. In the cortex, fast-spiking inhibitory interneurons are essential for coding and learning about sensory stimuli. The activity of fast-spiking interneurons is shaped by the moment-by-moment actions of neuromodulators like oxytocin, dopamine, serotonin, and catecholamines. These mechanisms can help explain how organisms assign different values of valence and salience to sensory stimuli depending on contexts like parenting, aggression, mating, and stress. A recently-discovered neuromodulatory system - the synthesis and action of ‘neuroestrogens’ within the brain - now holds a great deal of promise for deeper understanding of sensory processing and cognition. Estrogen treatments can ameliorate a variety of neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and epilepsy. Yet because the neuromodulatory perspective of brain estrogen synthesis is relatively new, the therapeutic potential of neuroestrogen signaling itself is currently untapped. The research program in this proposal will unpack the specific contribution of ultraprecise, fast inhibitory interneurons to the modulatory actions of neuroestrogens in the cortex. We will test the hypothesis that neuroestrogens directly modulate fast spiking interneurons in the cortex to regulate spike timing precision and behavioral discrimination learning. The proposed projects will take advantage of recent molecular and technological advances to genetically target fast-spiking inhibitory interneurons. This work will therefore address a fundamental gap in our understanding of how estrogen production within the brain guides complex behavior, and could ultimately inform the development of highly-targeted estrogen therapies for cognitive and neurological disorders.