Homeostatic plasticity mechanisms regulate behavior in vivo

稳态可塑性机制调节体内行为

• 批准号: 10674083
• 负责人: Joseph M Santin
• 金额: $ 38.46万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674083
• 关键词: Adaptive Behaviors; Address; Adult; Air; Alzheimer' s Disease; Animals; Behavior; Bioinformatics; Biological Models; Brain; Brain Stem; Breathing; Cells; Data; Disease; Electromyography; Electrophysiology (science); Ensure; Environment; Epilepsy; Exhibits; Failure; Financial compensation; Funding Opportunities; Gene Expression; Goals; Ice Cover; Individual; Intrinsic drive; Lead; Life; Light; Link; Longevity; Lung; Measures; Memory; Modeling; Modernization; Molecular; Motor; Motor Neurons; Nature; Neurobiology; Neurons; Neurophysiology - biologic function; Neurosciences; Output; Performance; Physiological; Physiology; Population; Potassium Channel; Prevalence; Process; Pump; Rana; Regulation; Research; Shapes; Stimulus; Synapses; Synaptic plasticity; System; Temperature; Testing; Time; Walking; Water; Work; base; cold temperature; extracellular; gene regulatory network; improved; in vivo; innovation; insight; motor behavior; nervous system disorder; neuromuscular function; neuron component; patch clamp; programs; relating to nervous system; respiratory; response; santin; single-cell RNA sequencing; trait; ventilation

Abstract A remarkable trait of the healthy brain is that it can generate stable behaviors that last for decades. When this fails to occur, a range of neurological disorders follow. An emerging view is that neurons can sense disturbances in their activity and then make compensatory adjustments to stabilize their function, a process referred to broadly as “homeostatic plasticity.” Insights into homeostatic plasticity have improved our understanding of how neurons may remain stable in an ever-changing environment. Despite much progress, how these mechanisms work in the intact brain to produce behaviors across the lifespan remains largely unknown, and therefore, represents a major gap in basic neurobiology. We address this issue using an innovative model where there exists a direct relationship between homeostatic compensation in neurons and regulation of a tractable behavior during adult life: the respiratory motor system in frogs. For long periods each year, motor circuits that control breathing in these animals are inactive because they hibernate in water and do not breathe air. Our group recently discovered this environment leads to compensatory changes in motoneurons that allow the circuit to work appropriately when animals must breathe again after months of inactivity, thereby linking plasticity that stabilizes neuronal function to a vital and tractable behavior. Here, we exploit this system to test three hypotheses that address the central question of how homeostatic mechanisms arise in vivo to support adaptive behavior. Based on our preliminary data, we hypothesize that (1) this network relies on multiple forms of intrinsic and synaptic motor plasticity to generate appropriate output, (2) intrinsic and synaptic compensation follow unique time courses during inactivity due to distinct gene regulatory networks, and (3) activity and environmental stimuli interact to differentially regulate intrinsic and synaptic compensation. These hypotheses will be tested with an integrative approach that blends patch clamp electrophysiology to measure plasticity at the cellular level, single-cell RNA sequencing and quantitative PCR to link gene expression to physiology, electromyography to measure neuromuscular function in vivo, and extracellular recording to assess function of intact circuits. Overall, this work will inform how neurons integrate multiple types of plasticity to produce essential behaviors, a goal that must be achieved to understand how circuit function remains healthy throughout life in many individuals but fails in others to cause disease.

抽象的 健康大脑的一个显着特征是，它可以产生持续数十年的稳定行为。 如果没有发生，一系列神经系统疾病就会随之而来，一种新的观点是神经元可以感知。 其活动受到干扰，然后进行补偿性调整以稳定其功能的过程 广义上称为“稳态可塑性”。对稳态可塑性的见解改善了我们的研究。 尽管取得了很大进展，但我们仍然了解神经元如何在不断变化的环境中保持稳定。 这些机制如何在完整的大脑中发挥作用并在整个生命周期中产生行为仍然在很大程度上 未知，因此代表了基础神经生物学的一个主要空白，我们使用一个解决这个问题的方法。 创新模型，其中神经元的稳态补偿与 成年期间易驯服行为的调节：青蛙的呼吸运动系统在很长一段时间内。 年，这些动物控制呼吸的运动回路不活跃，因为它们在水中冬眠并且不活动。 我们的小组最近发现这种环境会导致补偿性变化。 当动物在几个月后必须再次呼吸时，运动神经元使电路能够正常工作 不活动，从而将稳定神经功能的可塑性与重要且易于处理的行为联系起来。 利用该系统来测试三个假设，这些假设解决了稳态机制如何实现这一核心问题 根据我们的初步数据，我们发现（1）该网络在体内产生以支持适应性行为。 依赖多种形式的内在和突触运动可塑性来产生适当的输出，（2）内在和突触运动可塑性 由于不同的基因调控网络，突触补偿在不活动期间遵循独特的时间进程， (3)活动和环境刺激相互作用以差异调节内在补偿和突触补偿。 这些假设将通过将膜片钳电生理学与 测量细胞水平的可塑性、单细胞 RNA 测序和定量 PCR 来连接基因 表达生理学、肌电图以测量体内和细胞外的神经肌肉功能 总的来说，这项工作将告诉我们神经元如何整合多个神经元。 产生基本行为的可塑性类型，这是理解电路如何工作必须实现的目标 在许多人的健康一生中，其功能仍然存在，但在其他人中却无法引起疾病。