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

项目总结/摘要 中风后，许多幸存者经历一段时间的神经修复和功能的自发恢复。然而，在这方面， 这一过程通常是不完整的，无法避免长期残疾。修复后的潜在机制 人们对创伤的了解很少，也没有足够的药物治疗来刺激这一过程。先前 研究表明，成功的恢复与分子、细胞和神经可塑性有关。 网络水平，并与其他形式的活动依赖性可塑性，如学习共享功能。客观 这个建议是为了了解中风后可塑性的细胞基础，它如何有助于网络的恢复。 连接性和行为功能，以及它如何成为治疗目标。具体而言，该提案将 探索一类特殊的神经元--小清蛋白抑制性中间神经元--在调节可塑性 中风后神经网络的重塑。小清蛋白中间神经元已被证明门可塑性， 学习，发展和其他活动依赖的可塑性范式，但从来没有研究过， 中风恢复的设置。我们将评估如何药物遗传学操纵小白蛋白中间神经元放电 心率改变健康的活动依赖性可塑性（触须感觉剥夺），以及局灶性脑损伤后的可塑性。 成年小鼠体感皮层的缺血性损伤（光血栓形成）。利用这些可塑性模型，我们 将评估微观结构重新布线与组织学，网络连接与尖端的体内光学 神经成像平台，以及具有行为表型的功能恢复。这一综合办法将使 我们证明，如果小清蛋白抑制电路是中风后可塑性的关键调解人和潜在的 治疗目标，以促进中风幸存者的功能恢复。因此，本建议将侧重于两个具体的 目的： 目的1：研究小白蛋白中间神经元在成年大鼠活动依赖性可塑性中的作用 小鼠躯体感觉皮层 目的2：确定小白蛋白中间神经元在皮质重映射、功能连接和神经元功能重建中的作用。 以及局灶性缺血后的行为恢复。

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.