Rapid Estrogen Signaling in Brain Circuits that Guide Complex Behavior

大脑回路中快速的雌激素信号传导指导复杂的行为

• 批准号: 9755104
• 负责人: LUKE R REMAGE-HEALEY
• 金额: $ 36.34万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755104
• 关键词: Action Potentials; Address; Afferent Neurons; Aggressive behavior; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Attention; Basic Science; Behavior; Behavioral; Biomedical Research; Blood Circulation; Brain; Brain Diseases; Brain region; Catecholamines; Cells; Child Rearing; Clinical; Code; Cognition; Cognition Disorders; Cognitive; Communication; Complex; Dementia; Development; Discrimination; Discrimination Learning; Dopamine; Electrophysiology (science); Engineering; Epilepsy; Estrogen Therapy; Estrogens; Exhibits; Functional disorder; Future; Genetic Transcription; Goals; Human; Impairment; Interneurons; Learning; Link; Membrane; Mission; Molecular; Neuromodulator; Neurons; Organism; Outcomes Research; Oxytocin; Parkinson Disease; Partner in relationship; Patients; Prevention; Process; Production; Property; Regulator Genes; Research; Research Activity; Resolution; Sensory; Serotonin; Shapes; Signal Transduction; Specificity; Speech; Stimulus; Stream; Stress; Stroke; System; Testing; Therapeutic; Translating; United States National Institutes of Health; Viral; Woman; Work; cell type; cognitive function; design; electrical property; experience; flexibility; foreign language; in vivo; insight; men; millisecond; nervous system disorder; neural circuit; neuronal circuitry; neuroprotection; neuroregulation; novel therapeutics; optogenetics; patch clamp; programs; relating to nervous system; response; sensory discrimination; sensory stimulus; sound; tool; treatment strategy

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.

项目摘要 任何开始学习新外语的人都可以证明：感官刺激，例如语音和 歌曲是复杂声音的几乎连续流。通过练习，听众可以学会解析 普通话或斯特拉文斯基的流中的含义。沟通声音随着 毫秒（例如，歌曲和语音）的过程是通过高精度，低 - 的最佳编码 抖动神经元活动。处理并响应复杂而密集的声流的神经元 因此，表现出快速，精确的动作电位时机。感觉神经元的尖峰时间 还根据当前的情况来塑造，例如注意力转移以及外部或内部的变化 国家。说明我们的感觉和认知中这种动态丰富性的机制 经验变得越来越清晰。在皮质中，快速加快抑制性中间神经元是必不可少的 用于编码和学习感官刺激。快速刺激性中间神经元的活性是形状的 到催产素，多巴胺，5-羟色胺和 儿茶酚胺。这些机制可以帮助解释生物如何分配不同的值 价值和显着性对感官刺激，具体取决于育儿，侵略性，交配， 和压力。最近发现的神经调节系统 - 合成和作用 大脑内的“神经雌激素” - 现在拥有更深入了解 感官处理和认知。雌激素治疗可以改善各种神经系统 疾病，包括帕金森氏病，阿尔茨海默氏病和癫痫病。但是因为 脑雌激素合成的神经调节视角相对较新，治疗性 神经雌激素信号传导本身的潜力目前尚未开发。其中的研究计划 提案将解开超抑制，快速抑制性中间神经元对 神经雌激素在皮质中的调节作用。我们将检验以下假设 神经雌激素直接调节皮质中的快速尖峰中间神经元调节峰值时间 精度和行为歧视学习。拟议的项目将利用 近期分子和技术进步以遗传靶向快速刺激性抑制 中间神经元。因此，这项工作将解决我们对如何理解的基本差距 大脑中的雌激素产生引导复杂的行为，并最终可能告知 为认知和神经系统疾病的高靶向雌激素疗法的开发。