Determining the efficacy of therapeutic interventions after stroke from cell specific functional connectomes

从细胞特异性功能连接组确定中风后治疗干预的功效

• 批准号: 10586595
• 负责人: ADAM Q BAUER
• 金额: $ 46.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586595
• 关键词: Adult; Affect; Axon; Behavior; Behavioral; Brain; Brain Infarction; Brain region; Calcium; Cells; Contralateral; Data; Distant; Equilibrium; Exhibits; Global Change; Grant; Incidence; Interneurons; Intervention; Ipsilateral; Ischemia; Knowledge; Left; Maps; Measures; Mediating; Methods; Microscopic; Monitor; Motor; Mus; Neuroanatomy; Neurons; Nodal; Parvalbumins; Pathway interactions; Pattern; Performance; Play; Population; Prevalence; Process; Recovery; Recovery Support; Recovery of Function; Rest; Role; Shapes; Site; Stimulus; Stroke; Structure; System; Techniques; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Treatment Efficacy; Vertebral column; awake; barrier to testing; brain circuitry; brain dysfunction; brain repair; calcium indicator; cell type; connectome; density; design; disability; efficacy evaluation; experimental study; improved; in vivo; neural network; neurobehavioral; neuroimaging; neuronal circuitry; noninvasive brain stimulation; optical imaging; optogenetics; post stroke; redshift; repaired; restoration; somatosensory; stroke patient; stroke recovery; stroke survivor; tool

PROJECT SUMMARY/ABSTRACT Understanding circuit-level maneuvers that affect brain plasticity will inform the design of targeted interventions after stroke. Experiments outlined in this proposal will determine the contributions of excitatory/inhibitory circuits on brain repair processes after focal ischemia, and how changes in behavioral performance relate to cell-specific changes in connectivity. Stroke causes direct structural damage to local brain circuitry and indirect disruption of global networks resulting in behavioral deficits spanning multiple domains. Stroke recovery is associated with functional brain reorganization, a process involving the formation of new or alternative circuits. Along with behavioral recovery, damaged regions remap to adjacent tissue while patterns of resting-state functional connectivity (RS-FC) within and across resting-state networks gradually renormalize. While local and global changes in functional brain organization are consistently observed during recovery, how these processes relate to the underlying neuronal circuitry supporting recovery of function is unknown. This knowledge gap exists partially because stimulus-evoked and resting-state patterns reflect ensemble activity from many cell types, and patterns of RS-FC can be orchestrated through indirect pathways. Understanding how disconnected inhibitory and excitatory circuits reintegrate into global networks to support recovery requires examination of neural network connectivity structure as it evolves with neuroanatomical markers of circuit repair. While an integrated mechanism relating cellular plasticity with network plasticity has yet to be established, inhibitory circuits have been shown to play a key role. Stroke disrupts the brain’s balance of excitation and inhibition. Restoring this balance through non-invasive brain stimulation techniques can improve recovery. However, treatment efficacy using these methods is extremely varied, partially due to the imprecision and indiscriminate activation or inhibition of all cells near the stimulated site. Parvalbumin interneurons (PV-INs) are the most prevalent of all GABAergic interneurons, play key roles in shaping excitability over long distances, and regulate functional brain rhythms reflected in coherent patterns of RS-FC. Though their role in post-stroke plasticity is unknown, PV-INs are known to mediate several other forms of activity-dependent plasticity, making them compelling candidates for affecting repair processes after stroke. Using optogenetic targeting and wide field optical imaging of cortical calcium dynamics in awake mice, we will establish functional connectomes of excitatory (CamK2a-based) and inhibitory (PV-based) circuits and how they evolve following focal ischemia (Aim 1). We will utilize the well- characterized motor-barrel network in the mouse to directly test the influence of activity in cortical excitatory/inhibitory nodes exhibiting strong (Aim 2) or weak (Aim 3) inter- or intra-hemispheric connectivity with perilesional tissue, and how these manipulations affect neuroanatomical markers of circuit repair. At the conclusion of this grant, we will determine the contributions of CamK2a/PV circuits on post-stroke recovery, and further understand the components of connectivity restoration required for more complete behavioral recovery.

项目摘要/摘要 了解影响大脑可塑性的电路级操作将为目标干预的设计提供信息 中风后。该提案中概述的实验将确定兴奋性/抑制回路的贡献 局灶性缺血后的大脑修复过程，以及与细胞特异性相关的行为性能的变化 连通性的变化。中风会直接造成当地脑电路的结构损害，并间接破坏 导致行为的全局网络定义了跨越多个域。中风恢复与 功能性脑重组，涉及形成新的或替代电路的过程。以及 行为恢复，损坏的区域重现为相邻组织，而静止状态功能的模式 静止状态网络内部和跨静止状态网络内部和跨静息网络的连接性（RS-FC）逐渐重新归一化。而本地和全球 在恢复过程中始终观察到功能性脑组织的变化，这些过程与这些过程如何相关 对于支持功能恢复的基础神经元电路是未知的。这个知识差距存在 部分是因为刺激诱发和静止状态模式反映了许多细胞类型的集合活动，以及 RS-FC的模式可以通过间接途径进行编排。了解如何断开抑制性 兴奋性电路重新融合到全球网络以支持恢复需要检查神经元 网络连通性结构随着电路修复的神经解剖标记而演变。而整合 与网络可塑性有关的机制尚未确定，抑制回路具有 他被证明扮演着关键角色。中风破坏了大脑的兴奋和抑制平衡。还原这个 通过非侵入性大脑刺激技术平衡可以改善恢复。但是，治疗效率 使用这些方法非常多样化，部分是由于影响和不加选择的激活或 抑制刺激位点附近的所有细胞。白蛋白中间神经元（PV-INS）是所有人中最普遍的 GABA能中间神经元，在长距离塑造令人兴奋的过程中发挥关键作用，并调节功能性大脑 RS-FC的相干模式反映的节奏。尽管它们在冲程后可塑性中的作用尚不清楚，但PV-INS 众所周知会介导其他几种与活动相关的可塑性，使其引人入胜的候选人 在中风后影响修复过程。使用光遗传靶向和皮质的宽场光学成像 在清醒小鼠中，我们将建立兴奋性功能连接（基于CAMK2A）和 抑制性（基于PV）电路及其如何在局灶性缺血之后进化（AIM 1）。我们将利用福祉 在小鼠中表征了电动机网络，以直接测试皮质中活性的影响 表现出强的兴奋性/抑制性节点（AIM 2）或弱（AIM 3）与半球内或半球内连接性 周围组织以及这些操作如何影响电路修复的神经解剖标记。在 结论这笔赠款，我们将确定CAMK2A/PV电路对冲程后恢复的贡献，以及 进一步了解更完整的行为恢复所需的连接恢复组成部分。