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.

项目概要/摘要 了解影响大脑可塑性的回路级操作将为有针对性的干预措施的设计提供信息 本提案中概述的实验将确定兴奋/抑制回路的贡献。 局灶性缺血后的大脑修复过程，以及行为表现的变化如何与细胞特异性相关 中风会导致局部大脑回路的直接结构损伤和间接破坏。 全球网络导致跨多个领域的行为缺陷与中风恢复有关。 功能性大脑重组，涉及新的或替代回路的形成的过程。 行为恢复，受损区域重新映射到邻近组织，而静息态功能模式 静息状态网络内部和之间的连接（RS-FC）逐渐重新正常化。 在恢复期间持续观察到功能性大脑组织的变化，这些过程如何相互关联 支持功能恢复的底层神经回路尚不清楚。 部分原因是刺激诱发和静息状态模式反映了许多细胞类型的整体活动，并且 RS-FC 的模式可以通过间接途径来协调，了解如何断开抑制。 和兴奋性回路重新整合到全球网络以支持恢复需要对神经进行检查 网络连接结构随着电路修复的神经解剖学标记而演变。 细胞可塑性与网络可塑性的相关机制尚未建立，抑制电路已经 中风会破坏大脑的兴奋和抑制平衡。 通过非侵入性脑平衡刺激技术可以提高康复治疗效果。 使用这些方法的方式多种多样，部分原因是不精确和不加区别的激活或 受刺激位点附近的所有细胞（PV-IN）的抑制是最普遍的。 GABA能中间神经元在塑造长距离兴奋性和调节大脑功能方面发挥着关键作用 尽管 PV-IN 在中风后可塑性中的作用尚不清楚，但它们反映在 RS-FC 的连贯模式中。 众所周知，它们可以调节其他几种形式的活动依赖性可塑性，使它们成为引人注目的候选者 使用光遗传学靶向和皮质广域光学成像影响中风后的修复过程。 为了研究清醒小鼠的钙动态，我们将建立兴奋性（基于 CamK2a）和 抑制（基于 PV 的）电路及其在局灶性缺血后如何演变（目标 1）。 表征小鼠运动桶网络，直接测试皮质活动的影响 兴奋/抑制节点表现出强（目标 2）或弱（目标 3）半球间或半球内连接 病灶周围组织，以及这些操作如何影响回路修复的神经解剖学标记。 这笔资助结束后，我们将确定 CamK2a/PV 电路对中风后恢复的贡献，以及 进一步了解更完整的行为恢复所需的连接恢复的组成部分。