Plasticizing the Cortex to Enhance Stroke Recovery

摘要 中风是长期残疾的主要原因，在美国每年影响近80万患者。最 中风幸存者有一定程度的自发恢复，但这种恢复是不可预测的，在许多情况下， 案件不完整。成功的恢复需要突触和细胞水平的可塑性来集体“重新连接” 受损的大脑网络，这个过程被称为重新映射。在全球范围内，大脑网络的可塑性可以是 在修复的电路和远端大脑网络之间的功能连接（FC）恢复中观察到。 Fc可能有助于更复杂的恢复。然而，人们对这种现象背后的机制知之甚少。 网络可塑性在重新映射和fc.本提案的总体目标是了解 中风后大脑网络的可塑性。增强这些修复机制可能是设计 改善中风后恢复和减轻残疾的治疗。 受伤大脑中的许多潜在可塑性过程反映了那些发生在发育过程中的过程。 个脑袋在发育过程中的视觉皮层（V1）中最显著地证明，双眼视觉导致 在V1中，眼输入到眼优势（OD）列中的平衡分离。单眼剥夺（MD， 在开发过程中关闭一只眼睛）导致备用眼睛的OD列竞争性地接管 剥夺眼的OD列，类似于中风后的重新映射。这种可塑性在成年后消失， 抑制性小清蛋白中间神经元（PV-IN）在V1的成熟。PV-IN是最普遍的抑制性 大脑中的神经元，并作为“刹车”关闭发育可塑性的关键时期， 大脑活动的成熟空间/时间模式。然而，最近的研究表明，青少年样OD 通过选择性降低PV-IN的放电率，或通过减弱PV-IN的强度， 的兴奋性突触到PV-IN（从而削弱其前馈抑制活性）。PV-IN已经 进一步涉及限制海马体、纹状体、前额皮质和听觉皮质的可塑性。 考虑到PV-IN在整个大脑中的普遍存在，这些发现提出了一个令人兴奋的可能性，即PV-IN是 神经元可塑性的“守门人”，以及损伤脑中治疗干预的潜在靶点。 这项研究的中心假设是，PV-IN的活动在感觉神经元活动期间调节网络的可塑性。 剥夺和中风后。我们将采用最先进的非侵入性光学神经成像技术对大脑皮层钙离子进行检测 小鼠中的动力学，以探测局部感觉图和整体fc的变化，与病毒基因转移相结合 以PV-IN为目标，了解活动（目的1）和PV-IN上的突触输入（目的2）在介导 剥夺诱导的皮层可塑性和中风恢复。目的1：确定调节PV-IN活性是否 可以增强胡须感觉剥夺和缺血损伤后恢复期间的皮质可塑性。目标2： 确定PV-INs上的兴奋性突触在晶须形成过程中调节皮质可塑性的机制作用。 缺血损伤后感觉剥夺和恢复。目的3：确定PV中可塑性的翻译基因， 触须剥夺和缺血性损伤后的锥体神经元。

ABSTRACT Stroke is the leading cause of long-term disability, affecting almost 800,000 patients per year in the US. Most stroke survivors have some degree of spontaneous recovery, but this recovery is unpredictable and in many cases incomplete. Successful recovery requires plasticity at the synaptic and cellular level to collectively “rewire” damaged brain networks, in a process called remapping. On a global scale, plasticity in brain networks can be observed in the restoration of functional connectivity (fc) between repaired circuits and distant brain networks. Fc likely contributes to recovery of more complex. However, little is known about the mechanisms underlying network plasticity in remapping and fc. The overarching goal of this proposal is to understand mechanisms of plasticity in brain networks after stroke. Enhancing these mechanisms of repair may be key to designing therapies to improve recovery and attenuate disability after stroke. Many of the processes underlying plasticity in the injured brain mirror those that occur in the developing brain. Most saliently demonstrated in the visual cortex (V1) during development, binocular vision leads to balanced segregation of eye inputs into ocular dominance (OD) columns in V1. Monocular deprivation (MD, suturing one eye shut) during development leads the OD columns of the spared eye to competitively take over the OD columns of the deprived eye, similar to remapping after stroke. This plasticity dissipates in adulthood due to the maturation of inhibitory parvalbumin interneurons (PV-INs) in V1. PV-INs are the most prevalent inhibitory neurons in the brain, and act as ‘brakes’ to close critical periods of developmental plasticity, cementing in place mature spatial/temporal patterns of brain activity. However, recent studies have shown that juvenile-like OD plasticity can be restored in adult mice by selectively reducing firing rates in PV-INs, or by weakening the strength of excitatory synapses onto PV-INs (thus weakening their feed-forward inhibitory activity). PV-INs have been further implicated in restricting plasticity in the hippocampus, striatum, prefrontal cortex, and auditory cortex. Given the prevalence of PV-INs throughout the brain, these findings invite the exciting possibility that PV-INs are “gate-keepers” of neuronal plasticity, and potential targets for therapeutic intervention in the injured brain. The central hypothesis of this grant is that activity in PV-INs regulates network plasticity during sensory deprivation and after stroke. We will employ cutting edge non-invasive optical neuroimaging of cortical calcium dynamics in mice to probe changes in local sensory maps and global fc, in combination with viral gene transfer targeted to PV-INs, to understand the role of activity (Aim 1) and synaptic inputs onto PV-INs (Aim 2) in mediating deprivation-induced cortical plasticity and recovery from stroke. Aim 1: To determine if modulating PV-IN activity can enhance cortical plasticity during whisker sensory deprivation and recovery after ischemic injury. Aim 2: To determine the mechanistic role of excitatory synapses onto PV-INs in regulating cortical plasticity during whisker sensory deprivation and recovery after ischemic injury. Aim 3: To identify the translatome of plasticity in PV and Pyramidal neurons during whisker deprivation and after ischemic injury.