Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior

项目摘要 任何开始学习一门新外语的人都可以证明：像语言这样的感官刺激， 歌曲是近乎连续复杂声音流。通过练习，听众可以学会解析 普通话或斯特拉文斯基的音乐中的含义。不同的交流声音 毫秒的过程（例如，歌曲和语音）通过高精度、低成本的 抖动神经元活动。处理和响应复杂密集声音流的神经元 因此表现出动作电位的快速和精确计时。感觉神经元的发放时间 也受到当前环境的影响，例如注意力的转移以及外部或内部环境的变化。 states.我们的感官和认知能力之所以如此丰富， 经验越来越清晰。在大脑皮层，快速抑制性中间神经元是必不可少的 来编码和学习感官刺激。快速发放的中间神经元的活动是由 通过神经调节剂如催产素，多巴胺，血清素， 儿茶酚胺这些机制可以帮助解释生物如何分配不同的价值观， 对感官刺激的效价和显著性取决于诸如养育，攻击，交配， 和压力最近发现的一种神经调节系统： 大脑中的“神经雌激素”-现在有很大的希望更深入地了解 感觉处理和认知。雌激素治疗可以改善多种神经系统疾病， 帕金森氏病、阿尔茨海默氏病和癫痫等疾病。然而，由于 脑雌激素合成的神经调节观点是相对较新的， 神经雌激素信号本身的潜力目前尚未开发。这个研究项目 这项提案将揭示超精确的，快速抑制性中间神经元对神经元的具体贡献。 皮质中神经雌激素的调节作用。我们将检验这个假设， 神经雌激素直接调节皮层中快速发放的中间神经元以调节发放时间 精确和行为辨别学习。拟议项目将利用 最近的分子和技术进展，以遗传为目标的快速尖峰抑制 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，并可能最终告知人类的行为。 开发针对认知和神经系统疾病的高靶向雌激素疗法。

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.