INFLUENCE OF INTERHEMISPHERIC CONNECTIVITY ON RECOVERY AFTER FOCAL ISCHEMIA

半球间连接对局灶性缺血后恢复的影响

• 批准号: 8563038
• 负责人: Jin-Moo Lee
• 金额: $ 42.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8563038
• 关键词: Adult; Animal Model; Behavior; Behavioral; Brain; Characteristics; Chronic; Conflict (Psychology); Contralateral; Equilibrium; Evolution; Grant; Hand; Human; I/LnJ Mouse; Image; Incidence; Infarction; Ischemia; Ischemic Stroke; Lesion; Mediating; Middle Cerebral Artery Occlusion; Modeling; Molecular; Molecular Genetics; Motor; Movement; Mus; Nodal; Optics; Pattern; Performance; Physiological; Rattus; Recovery; Recovery of Function; Reporting; Rest; Role; Sensorimotor functions; Signal Transduction; Somatosensory Cortex; Stroke; Survivors; Testing; Therapeutic; Time; Work; barrel cortex; brain remodeling; deprivation; disability; functional disability; imaging modality; improved; injured; mouse model; neurogenesis; novel; optogenetics; public health relevance; relating to nervous system; repetitive transcranial magnetic stimulation; somatosensory; stroke recovery; synaptogenesis; therapy development

DESCRIPTION (provided by applicant): The leading cause of adult disability in the US, stroke has an annual incidence of 780,000 with over 5.8 million stroke survivors. Most stroke survivors have some degree of spontaneous recovery, typically occurring in the first weeks to months after stroke; however this recovery is highly variable and in many cases incomplete. Much of our understanding of recovery mechanisms has focused on local cellular and molecular mechanisms involved in brain remodeling. More recent work has examined recovery after stroke at the network level- examining distributed patterns of synchronized neural activity throughout the brain during rest-and has revealed that global patterns of functional network connectivity are altered after focal stroke. Moreover, shortly after ischemic stroke, disrupted interhemispheric homotopic functional connectivity (fc), in particular, predicted poor performance. In a rat focal ischemia model, homotopic fc was found to recover in parallel with behavioral improvement. There is substantial indirect evidence that homotopic interhemispheric fc may be important to recovery, and has given rise to the concept of "interhemispheric competition". This hypothesis holds that an equilibrium between excitation and inhibition across hemispheres may be important for normal unilateral function (e.g. unilateral hand movement). If this interhemispheric balance is disrupted (for example by stroke), local ipsilesional inhibitory influences may exacerbate deficits, worsening functional impairment. This concept has served well to explain the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to restore interhemispheric balance and improve sensorimotor function. However, there are conflicting reports in humans and animal models regarding the impact of contralateral homotopic influence on functional recovery. In this grant, we will test the hypothesis that interhemispheric connectivity directly influences brain plasticity and behavioral recovery after focal ischemia. To visualize fc, we will take advantage of a novel imaging modality, fcOIS (functional connectivity optical intrinsic signal imaging) developed by Dr. Culver (Co-PI), which for the first time permits fc imaging in mice. We will manipulate interhemispheric connectivity using optogenetic excitation/inhibition and the I/LnJ strain of acallosal mice, to examine their effects on cortical plasticity (brain remapping) and behavioral recovery, in the following aims: 1. To determine the relationship between fc, cortical remapping, and behavioral recovery following focal ischemia in mice. 2. To determine the influence of transcallosal interhemispheric connectivity on cortical remapping and behavioral recovery following focal ischemia. 3. To determine the effect of homotopic nodal excitation/inhibition on somatosensory cortical remapping following focal ischemia. 4. To determine if chronic physiological stimulation/deprivation using vibrissal manipulation alters cortical remapping and interhemispheric fc.

描述（由申请人提供）：中风是美国成人残疾的主要原因，年发病率为 780,000 例，其中中风幸存者超过 580 万。大多数中风幸存者都有一定程度的自然恢复，通常发生在中风后的最初几周到几个月内；然而，这种恢复变化很大，而且在许多情况下是不完全的。我们对恢复机制的大部分理解都集中在参与大脑重塑的局部细胞和分子机制。最近的工作在网络水平上检查了中风后的恢复情况——检查休息期间整个大脑同步神经活动的分布模式——并揭示了功能网络连接的全局模式在局灶性中风后发生了改变。此外，缺血性中风后不久，半球间同伦功能连接（fc）的破坏尤其预示着表现不佳。在大鼠局灶性缺血模型中，发现同位 fc 的恢复与行为改善同时进行。有大量间接证据表明同伦半球间 fc 可能对恢复很重要，并产生了“半球间竞争”的概念。该假设认为，半球兴奋和抑制之间的平衡对于正常的单侧功能（例如单侧手部运动）可能很重要。如果这种半球间平衡被破坏（例如由于中风），局部同病灶抑制影响可能会加剧缺陷，使功能障碍恶化。这个概念很好地解释了重复经颅磁刺激（rTMS）和经颅直流电刺激（tDCS）恢复半球间平衡和改善感觉运动功能的潜在功效。然而，关于对侧同伦影响对功能恢复的影响，人类和动物模型中存在相互矛盾的报道。在这笔赠款中，我们将测试 假设半球间连接直接影响局灶性缺血后的大脑可塑性和行为恢复。为了可视化 fc，我们将利用由 Culver 博士 (Co-PI) 开发的一种新颖的成像方式 fcOIS（功能连接光学固有信号成像），它首次允许在小鼠中进行 fc 成像。我们将使用光遗传学激发/抑制和无胼胝体小鼠的 I/LnJ 品系来操纵半球间连接，以检查它们对皮质可塑性（大脑重映射）和行为恢复的影响，目的如下： 1. 确定小鼠局灶性缺血后 fc、皮质重映射和行为恢复之间的关系。 2. 确定经胼胝体半球间连接对局灶性缺血后皮质重映射和行为恢复的影响。 3. 确定同位节点兴奋/抑制对局灶性缺血后体感皮质重映射的影响。 4. 确定使用振动操纵的慢性生理刺激/剥夺是否会改变皮质重映射和半球间 fc。