Homeostatic plasticity mechanisms regulate behavior in vivo

稳态可塑性机制调节体内行为

• 批准号: 10385768
• 负责人: Joseph M Santin
• 金额: --
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385768
• 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.

摘要 健康大脑的一个显著特征是它可以产生持续数十年的稳定行为。当这个 如果没有发生，一系列神经系统疾病就会随之而来。一个新兴的观点是神经元可以感知 干扰他们的活动，然后进行补偿调整，以稳定他们的功能，这是一个过程， 广义上称为“稳态可塑性”对稳态可塑性的深入了解提高了我们的 了解神经元如何在不断变化的环境中保持稳定。尽管取得了很大进展， 这些机制如何在完整的大脑中发挥作用，从而在整个生命周期中产生行为， 未知，因此代表了基础神经生物学的一个重大空白。我们使用一个 创新模型，其中神经元中的稳态补偿与 在成年生活中对一种易于控制的行为的调节：青蛙的呼吸运动系统。在很长一段时间里， 一年来，这些动物控制呼吸的运动回路是不活跃的，因为它们在水中冬眠， 不要呼吸空气。我们的团队最近发现这种环境会导致 运动神经元，使电路正常工作时，动物必须呼吸后，几个月的 不活动，从而将稳定神经元功能的可塑性与重要和易处理的行为联系起来。这里我们 利用这个系统来测试三个假设，解决了自我平衡机制如何 支持适应性行为。根据我们的初步数据，我们假设（1）这个网络 依赖于多种形式的内在和突触运动可塑性，以产生适当的输出，（2）内在和 由于不同基因调节网络， 和（3）活动和环境刺激相互作用以差异调节内在和突触补偿。 这些假设将用一种综合方法进行检验，该方法将膜片钳电生理学与 在细胞水平上测量可塑性，单细胞RNA测序和定量PCR连接基因 表达生理学，肌电图测量体内神经肌肉功能，和细胞外 记录以评估完整电路的功能。总的来说，这项工作将告知神经元如何整合多个 类型的可塑性，以产生基本的行为，一个目标，必须达到了解如何电路 在许多个体中，功能在整个生命中保持健康，但在其他人中则无法引起疾病。