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）：美国成年残疾的主要原因，中风的年发病率为780,000，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发恢复，通常发生在中风后的头几周至几个月中。但是，这种恢复是高度可变的，在许多情况下，不完整。我们对恢复机制的大部分理解都集中在局部细胞和分子机制上，涉及大脑重塑。最近的工作检查了在网络级别的中风后的恢复 - 在休息期间检查了整个大脑的同步神经活动的分布模式，并揭示了局灶性中风后功能网络连接的全局模式发生了改变。此外，在缺血性中风后不久，尤其是在半球间的同型功能连通性（FC）中，尤其是预测性能差。在大鼠局灶性缺血模型中，发现同型FC与行为改善并行恢复。有大量间接证据表明，同型间球间FC可能对恢复很重要，并引起了“半球间竞争”的概念。该假设认为，跨半球的激发与抑制之间的平衡对于正常的单侧功能可能很重要（例如，单侧手动运动）。如果这种半球间的平衡受到破坏（例如，通过中风），局部iPsilesials的抑制作用可能会加剧缺陷，从而加剧功能障碍。这个概念很好地解释了重复的经颅磁刺激（RTMS）和经颅直流电流刺激（TDC）的潜在疗效，以恢复半球间平衡并改善感觉运动功能。但是，在人类和动物模型中有关于对侧同位影响对功能恢复的影响的报道。在这笔赠款中，我们将测试 局灶性缺血后，半球间连通性直接影响大脑可塑性和行为恢复的假设。为了可视化FC，我们将利用Culver博士（CO-PI）开发的新型成像方式，FCOI（功能连通性光学信号成像），该模式首次允许小鼠FC成像。我们将使用光遗传激发/抑制作用和Acallosal小鼠的I/LNJ菌株来操纵半球间的连通性，以检查其对皮质可塑性（大脑重新映射）和行为恢复的影响，在以下目的中：1。确定FC，皮质重新映射和行为恢复小鼠的局灶性恢复之间的关系。 2。确定近视间连通性对局灶性缺血后皮质映射和行为恢复的影响。 3。确定同位淋巴结激发/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/剥夺是否改变了皮质重映射和半球间FC。