Plasticizing the Cortex to Enhance Stroke Recovery

摘要 中风是导致长期残疾的主要原因，在美国每年影响近80万名患者。多数 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 案件未完成。成功的康复需要在突触和细胞水平上的可塑性，以共同“重新连接” 在一个称为重新映射的过程中，破坏了大脑网络。在全球范围内，大脑网络的可塑性可以 在修复的电路和远程大脑网络之间的功能连接(FC)的恢复中观察到。 FC可能有助于更复杂的疾病的恢复。然而，人们对其背后的机制知之甚少。 重映射和FC中的网络可塑性。这项建议的首要目标是了解 中风后大脑网络的可塑性。加强这些修复机制可能是设计 促进中风后康复和减轻残疾的治疗。 在受伤的大脑中，许多潜在的可塑性过程反映了在发育过程中发生的那些过程 大脑。在发育过程中，最显著的表现在视觉皮质(V1)，双眼视觉导致 在V1中，眼睛输入到眼优势(OD)列的平衡分离。单眼剥夺(MD， 在开发过程中缝合一只眼睛)导致备用眼睛的OD柱竞争性地接管 剥夺眼的OD柱，类似于卒中后的重新定位。这种可塑性在成年后会消失，因为 与V1中抑制性小白蛋白中间神经元(PV-INS)的成熟有关。PV-INS是最普遍的抑制物 大脑中的神经元，起着关闭发育可塑性关键时期的‘刹车’的作用，在适当的地方巩固 大脑活动的成熟空间/时间模式。然而，最近的研究表明，类似青少年的过量饮食 通过选择性地降低PV-INS的放电频率，或通过削弱强度，可以恢复成年小鼠的可塑性 兴奋性突触连接到PV-ins上(从而削弱了它们的前馈抑制活性)。PV-INS已经被 进一步牵涉到限制海马体、纹状体、前额叶皮质和听觉皮质的可塑性。 鉴于PV-INS在大脑中的普遍存在，这些发现引发了PV-INS是令人兴奋的可能性 神经元可塑性的“守门人”，以及在受伤的大脑中进行治疗干预的潜在目标。 这项授权的中心假设是，在感觉过程中，PV-INS中的活动调节网络的可塑性 剥夺和中风后。我们将使用尖端的非侵入性皮质钙的光学神经成像 结合病毒基因转移探测局部感觉图和全局Fc变化的小鼠动力学 以PV-ins为靶点，了解活动(目标1)和突触输入到PV-ins(目标2)在调节 剥夺诱导的皮质可塑性和卒中后的恢复。目标1：确定是否调节PV-IN的活性 在胡须感觉剥夺和缺血损伤后恢复期间，可增强皮质的可塑性。目标2：实现 确定兴奋性突触到PV-INS在胡须期间调节皮质可塑性的机制作用 感觉剥夺与缺血性损伤后的恢复。目的3：鉴定pv和pv可塑性的翻译体。 胡须剥夺和缺血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.