The Role of Parvalbumin Interneurons in Cortical Plasticity and Recovery After Stroke

项目摘要/摘要 中风后，许多幸存者经历了一段时间的神经修复和自发的功能恢复。然而， 这一过程通常是不完整的，无法避免慢性残疾。修复后的潜在机制 人们对损伤的了解很少，而且没有足够的药物治疗来刺激这一过程。上一首 研究表明，成功的康复与分子、细胞和 网络水平，并与其他形式的依赖活动的可塑性共享特征，如学习。目标是 这项建议是为了了解中风后可塑性的细胞基础，以及它如何有助于网络的恢复 连接性和行为功能，以及它可能如何成为治疗的靶点。具体地说，这项提议将 探索一类特殊的神经元--小白蛋白抑制中间神经元--在调节可塑性中的作用 中风后神经网络的重塑。小白蛋白中间神经元被证明具有可塑性。 学习、发展和其他依赖活动的可塑性范式，但从未在 中风恢复的设置。我们将评估小白蛋白中间神经元放电的药物遗传学操作 比率改变健康的依赖活动的可塑性(胡须感觉剥夺)，以及病灶后的可塑性 成年小鼠躯体感觉皮质的缺血性损伤(光血栓形成)。使用这些塑性模型，我们 将通过组织学评估微观结构重新布线，利用体内最先进的光学技术评估网络连接 神经成像平台，以及通过行为表型进行功能恢复。这一综合方法将使 美国将证明小白蛋白抑制回路是否是卒中后可塑性的关键介质和潜在的 促进中风幸存者功能恢复的治疗目标。因此，这项提案将侧重于两个具体的 目标： 目的1：确定小白蛋白中间神经元在成人活动性可塑性中的作用 小鼠的体感皮质。 目的2：确定小白蛋白中间神经元在皮质重映射、功能连接中的作用 局灶性脑缺血后的行为恢复。

PROJECT SUMMARY/ABSTRACT After stroke, many survivors undergo a period of neural repair and spontaneous recovery of function. However, this process is usually incomplete and fails to avert chronic disability. The underlying mechanisms of repair after injury are poorly understood, and there is insufficient medical therapy available to stimulate the process. Previous work has demonstrated that successful recovery is associated with neuroplasticity at the molecular, cellular, and network level, and shares features with other forms of activity-dependent plasticity, like learning. The objective this proposal is to understand the cellular basis of plasticity after stroke, how it contributes to recovery of network connectivity and behavioral function, and how it might be targeted therapeutically. Specifically, this proposal will explore the role of a specific class of neurons – parvalbumin inhibitory interneurons – in modulating plastic remodeling of neural networks after stroke. Parvalbumin interneurons have been shown to gate plasticity in learning, development, and other activity-dependent plasticity paradigms, but have never been studied in the setting of stroke recovery. We will assess how pharmacogenetic manipulation of parvalbumin interneuron firing rates alters healthy activity-dependent plasticity (whisker sensory deprivation), as well as plasticity after focal ischemic injury (photothrombosis) in the somatosensory cortex of adult mice. Using these plasticity models, we will assess microscopic structural rewiring with histology, network connectivity with a cutting-edge in vivo optical neuroimaging platform, and functional recovery with behavioral phenotyping. This integrated approach will allow us to demonstrate if parvalbumin inhibitory circuits are a key mediator of post-stroke plasticity and a potential therapeutic target to promote functional recovery in stroke survivors. This proposal will thus focus on two specific aims: Aim 1: To determine the role of parvalbumin interneurons in activity-dependent plasticity in the adult mouse somatosensory cortex. Aim 2: To determine the role of parvalbumin interneurons in cortical remapping, functional connectivity and behavioral recovery following focal ischemia.