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

基本信息

批准号：
10579933
负责人：
LUKE R REMAGE-HEALEY
金额：
$ 33.72万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579933
关键词：
Action Potentials Address Afferent Neurons Aggressive behavior Alzheimer&apos s Disease Alzheimer&apos s disease risk Animals Attention Basic Science Behavior Behavioral Biomedical Research Brain Brain Diseases Brain region Catecholamines Cells Child Rearing Circulation 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 Technology Testing Therapeutic Translating United States National Institutes of Health Viral Woman Work cell cortex cell type cognitive function design electrical property experience flexibility foreign language in vivo insight men millisecond nervous system disorder neural neural circuit neuronal circuitry neuroprotection neuroregulation optogenetics patch clamp programs response sensory discrimination sensory stimulus sound tool treatment strategy

项目摘要

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.

项目概要任何开始学习一门新外语的人都可以证明：诸如言语和语言之类的感官刺激歌曲是近乎连续的复杂声音流，通过练习，听众可以学会解析。普通话或斯特拉文斯基交流声音中的含义随时间而变化。毫秒过程（例如，歌曲和语音）通过高精度、低功耗进行最佳编码处理和响应复杂、密集的声音流的神经元活动。因此表现出快速且精确的动作电位计时。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的变化解释我们的感官和认知的这种动态丰富性的机制。在皮质中，快速放电的抑制性中间神经元至关重要。用于编码和学习感觉刺激快速尖峰中间神经元的活动被塑造。通过催产素、多巴胺、血清素等神经调节剂的每时每刻的作用这些机制可以帮助解释生物体如何分配不同的值。感官刺激的效价和显着性取决于养育、攻击、交配等环境，最近发现的神经调节系统 - 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，包括帕金森病、阿尔茨海默病和癫痫症。大脑雌激素合成的神经调节观点相对较新，治疗神经雌激素信号传导本身的潜力目前尚未开发。该提案将揭示超精确、快速抑制性中间神经元对我们将检验皮质中神经雌激素的调节作用。神经雌激素直接调节皮层中快速尖峰的中间神经元，以调节尖峰时间拟议的项目将利用精确和行为歧视学习。最近的分子和技术进步在基因上靶向快速尖峰抑制因此，这项工作将解决我们对中间神经元如何理解的根本差距。大脑内雌激素的产生指导复杂的行为，并最终可以告知开发针对认知和神经系统疾病的高度针对性的雌激素疗法。