Plasticizing the Cortex to Enhance Stroke Recovery

塑化皮质以增强中风恢复

• 批准号: 10456020
• 负责人: Jin-Moo Lee
• 金额: $ 48.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456020
• 关键词: Adolescent; Adult; Affect; Area; Attenuated; Auditory area; Behavior; Behavioral; Binocular Vision; Bioinformatics; Brain; Brain Injuries; Calcium; Complex; Corpus striatum structure; Data; Development; Distant; ErbB4 gene; Excitatory Synapse; Eye; Future; Gatekeeping; Gene Expression; Gene Transfer; Genes; Goals; Grant; Hippocampus (Brain); Human; Infarction; Interneurons; Ischemia; Maps; Mediating; Molecular; Mus; Neuregulin 1; Neuronal Plasticity; Neurons; Ocular Dominance; Ocular dominance columns; Optics; Parvalbumins; Patients; Pattern; Pharmacology; Prefrontal Cortex; Prevalence; Process; Recovery; Role; Sensory; Sensory Deprivation; Signal Transduction; Somatosensory Cortex; Stroke; Surgical sutures; Synapses; Testing; Therapeutic Intervention; Time; Translating; Vibrissae; Viral Genes; Visual Cortex; barrel cortex; brain repair; critical developmental period; deprivation; designer receptors exclusively activated by designer drugs; developmental plasticity; disability; functional restoration; gamma-Aminobutyric Acid; gene network; hippocampal pyramidal neuron; improved; inhibitory neuron; ischemic injury; monocular deprivation; neuroimaging; post stroke; receptor; recruit; repaired; segregation; sensory cortex; stroke recovery; stroke survivor; targeted treatment; therapy design; translatome; visual deprivation

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.

抽象的 中风是导致长期残疾的主要原因，在美国每年影响近 800,000 名患者。最多 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，并且在许多情况下 案例不完整。成功的恢复需要突触和细胞水平的可塑性来共同“重新布线” 在称为重新映射的过程中受损的大脑网络。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，人们对其背后的机制知之甚少 重映射和 FC 中的网络可塑性。该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的关键 改善中风后康复并减轻残疾的疗法。 受伤大脑中可塑性的许多过程反映了发育中大脑中发生的过程。 脑。在发育过程中，在视觉皮层 (V1) 中最明显地表现出来，双眼视觉会导致 将眼睛输入平衡分离到 V1 中的眼优势 (OD) 列中。单眼剥夺（MD， 在发育过程中缝合一只眼睛（闭上一只眼睛）会导致幸存的眼睛的 OD 列竞争性地接管 被剥夺的眼睛的 OD 列，类似于中风后的重新映射。这种可塑性在成年后就会消失，因为 V1 中抑制性小清蛋白中间神经元 (PV-IN) 的成熟。 PV-IN 是最普遍的抑制因子 大脑中的神经元，并充当“刹车”来关闭发育可塑性的关键时期，固定到位 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 的放电率或削弱强度，可以恢复成年小鼠的可塑性 PV-IN 上的兴奋性突触（从而削弱其前馈抑制活性）。 PV-IN 已 进一步涉及限制海马体、纹状体、前额叶皮层和听觉皮层的可塑性。 鉴于 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：PV-IN 是 神经元可塑性的“看门人”，以及受伤大脑治疗干预的潜在目标。 这项资助的核心假设是 PV-IN 的活动在感觉过程中调节网络可塑性 剥夺和中风后。我们将采用最先进的皮质钙非侵入性光学神经成像技术 小鼠动态，结合病毒基因转移，探测局部感觉图和全局 FC 的变化 针对 PV-IN，了解活动（目标 1）和 PV-IN 突触输入（目标 2）在调解中的作用 剥夺引起的皮质可塑性和中风恢复。目标 1：确定是否调节 PV-IN 活动 可以增强胡须感觉剥夺期间和缺血性损伤后恢复期间的皮质可塑性。目标 2： 确定PV-IN上的兴奋性突触在胡须期间调节皮质可塑性中的机械作用 缺血性损伤后的感觉剥夺和恢复。目标 3：确定 PV 和可塑性的翻译组 胡须剥夺期间和缺血性损伤后的锥体神经元。