Homeostatic plasticity mechanisms regulate behavior in vivo

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。当这件事 如果没有发生，一系列神经疾病就会随之而来。一种新的观点认为神经元可以感知 活动中的干扰，然后进行补偿性调整以稳定他们的功能，这是一个过程 泛指“动态可塑性”。对体内平衡可塑性的洞察提高了我们的 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内产生行为，目前仍在很大程度上仍未得到证实 未知，因此，代表了基础神经生物学的一个重大缺口。我们使用一个 创新模型，在神经元的动态平衡补偿和 成年生活中易驯服行为的调节：青蛙的呼吸运动系统。在很长一段时间内 一年来，这些动物控制呼吸的马达回路处于不活跃状态，因为它们在水中冬眠 而不是呼吸空气。我们团队最近发现，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，运动神经元允许回路正常工作 不活动，从而将稳定神经元功能的可塑性与重要和易驯服的行为联系起来。在这里，我们 利用这个系统来测试三个假设，这三个假设解决了动态平衡机制如何 在体内产生，以支持适应行为。根据我们的初步数据，我们假设(1)这个网络 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 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，以不同的方式调节内源性和突触补偿。 这些假说将通过一种综合的方法进行验证，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测序和定量聚合酶链式反应连接基因 表现为生理学、肌电图以测量体内和细胞外的神经肌肉功能 记录以评估完整电路的功能。总体而言，这项工作将告诉我们神经元如何整合多个 产生基本行为的可塑性类型，这是理解电路如何 在许多人的一生中，功能保持健康，但在另一些人则不会导致疾病。

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.