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

基本信息

  • 批准号:
    10586595
  • 负责人:
  • 金额:
    $ 46.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结/摘要 了解影响大脑可塑性的回路水平操作将为有针对性的干预措施的设计提供信息 中风后本提案中概述的实验将确定兴奋/抑制回路的贡献 局部缺血后的脑修复过程,以及行为表现的变化如何与细胞特异性 连通性的变化。中风导致局部脑回路的直接结构性损伤, 全球网络导致跨越多个领域的行为缺陷。中风恢复与 功能性大脑重组,一个涉及形成新的或替代回路的过程。沿着 行为恢复,受损区域重新映射到邻近组织,而静息状态功能模式 在静止状态网络内和跨静止状态网络的RS-FC连接性逐渐重新正常化。虽然地方和全球 在恢复过程中不断观察到功能性大脑组织的变化,这些过程如何与 与支持功能恢复的潜在神经元回路之间的联系尚不清楚。这种知识差距存在 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, RS-FC的模式可以通过间接途径来协调。了解断开的抑制性 和兴奋回路重新整合到全球网络,以支持恢复需要检查神经 网络连接结构,因为它与电路修复的神经解剖学标记一起进化。虽然综合 细胞可塑性与网络可塑性的联系机制尚未建立,抑制回路已经 被证明发挥了关键作用。中风破坏了大脑兴奋和抑制的平衡。恢复此 通过非侵入性脑刺激技术的平衡可以改善恢复。然而,治疗效果 使用这些方法是非常不同的,部分原因是不精确和不加选择的激活或 抑制刺激部位附近的所有细胞。小清蛋白中间神经元(PV-IN)是所有神经元中最常见的 GABA能中间神经元在形成长距离兴奋性和调节脑功能方面发挥关键作用 反映在RS-FC的连贯模式中的节律。尽管其在卒中后可塑性中的作用尚不清楚, 被认为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 影响中风后的修复过程使用皮质的光遗传学靶向和宽视场光学成像, 在清醒小鼠中的钙动力学,我们将建立兴奋性(基于CamK 2a)和 抑制性(基于PV)回路以及它们在局灶性缺血后如何演变(Aim 1)。我们会好好利用- 在小鼠中表征的运动桶网络,以直接测试皮质中活动的影响, 兴奋性/抑制性节点表现出强(Aim 2)或弱(Aim 3)的半球间或半球内连接, 损伤周围组织,以及这些操作如何影响神经回路修复的神经解剖学标记。在 在这项资助结束后,我们将确定CamK 2a/PV回路对中风后恢复的贡献, 进一步了解更完整的行为恢复所需的连接恢复组件。

项目成果

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ADAM Q BAUER其他文献

ADAM Q BAUER的其他文献

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{{ truncateString('ADAM Q BAUER', 18)}}的其他基金

Imaging and Reversibility of Cellular and Network Metabolic Dysfunction in Alzheimer's Disease
阿尔茨海默病细胞和网络代谢功能障碍的成像和可逆性
  • 批准号:
    10536491
  • 财政年份:
    2022
  • 资助金额:
    $ 46.12万
  • 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
  • 批准号:
    9789702
  • 财政年份:
    2018
  • 资助金额:
    $ 46.12万
  • 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
  • 批准号:
    10201764
  • 财政年份:
    2018
  • 资助金额:
    $ 46.12万
  • 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
  • 批准号:
    10445022
  • 财政年份:
    2018
  • 资助金额:
    $ 46.12万
  • 项目类别:
OPTOGENETIC MAPPING OF CELL SPECIFIC CONNECTIONS IN THE MOUSE BRAIN AFTER STROKE
中风后小鼠大脑中细胞特异性连接的光遗传学图谱
  • 批准号:
    9661800
  • 财政年份:
    2018
  • 资助金额:
    $ 46.12万
  • 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
  • 批准号:
    9037714
  • 财政年份:
    2014
  • 资助金额:
    $ 46.12万
  • 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
  • 批准号:
    9244074
  • 财政年份:
    2014
  • 资助金额:
    $ 46.12万
  • 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
  • 批准号:
    8812912
  • 财政年份:
    2014
  • 资助金额:
    $ 46.12万
  • 项目类别:
MECHANISMS OF FUNCTIONAL AND BEHAVIORAL RECOVERY FOLLOWING ISCHEMIC STROKE
缺血性中风后功能和行为恢复的机制
  • 批准号:
    8700071
  • 财政年份:
    2014
  • 资助金额:
    $ 46.12万
  • 项目类别:

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