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， “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 可以在修复的回路和远端脑之间的功能连接（fc）的恢复中观察到 网络. Fc可能有助于更复杂的恢复。然而，人们对这些机制知之甚少， 潜在的网络可塑性在重新映射和fc。本提案的首要目标是了解 中风后大脑网络的可塑性机制。增强这些修复机制可能是 设计治疗方法以改善中风后的恢复和减轻残疾。 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。这种可塑性在成年期消失 由于V1中抑制性小清蛋白中间神经元（PV-IN）的成熟。PV-IN是最常见的 大脑中的抑制性神经元，并作为“刹车”关闭发育可塑性的关键时期， 巩固大脑活动的成熟时空模式。然而，最近的研究表明， 在成年小鼠中，通过选择性降低PV-IN的放电率，或通过 减弱PV-IN上的兴奋性突触的强度（从而减弱它们的前馈抑制 活动）。PV-IN进一步涉及限制海马、纹状体、前额叶皮层和海马中的可塑性。 皮层和听觉皮层。考虑到PV-IN在整个大脑中的普遍存在，这些发现邀请了 令人兴奋的可能性是PV-IN是神经元可塑性的“守门人”，并且是治疗的潜在靶点。 对受伤的大脑进行干预。 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 针对PV-IN，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：确定是否调节 PV-IN活性可增强触须感觉剥夺和缺血后恢复过程中的皮层可塑性 损伤目的2：探讨室旁核-内侧核上兴奋性突触对皮层神经元兴奋性调节的机制。 在触须感觉剥夺和缺血损伤后恢复过程中的可塑性。目标3：确定 在须剥夺和缺血性损伤后PV和锥体神经元可塑性的翻译组。

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: Todetermine 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.