INFLUENCE OF INTERHEMISPHERIC CONNECTIVITY ON RECOVERY AFTER FOCAL ISCHEMIA

描述（由申请人提供）：卒中是美国成人残疾的主要原因，每年的发病率为780，000，超过580万卒中幸存者。大多数中风幸存者有一定程度的自发恢复，通常发生在中风后的前几周到几个月;然而，这种恢复是高度可变的，在许多情况下是不完全的。我们对恢复机制的理解主要集中在参与脑重塑的局部细胞和分子机制上。最近的研究在网络水平上研究了中风后的恢复--研究了休息时整个大脑中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球模式发生了改变。此外，缺血性中风后不久，中断半球间的同源功能连接（fc），特别是预测性能差。在大鼠局灶性脑缺血模型中，发现同型fc恢复与行为改善平行。有大量的间接证据表明，同伦半球间的fc可能是重要的恢复，并引起了“半球间的竞争”的概念。这一假说认为，兴奋和抑制之间的平衡可能是重要的正常单侧功能（如单侧手部运动）。如果这种半球间的平衡被破坏（例如中风），局部同病灶抑制的影响可能会加剧赤字，恶化功能障碍。这一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）恢复大脑半球间平衡和改善感觉运动功能的潜在疗效。然而，在人类和动物模型中，关于对侧同位影响对功能恢复的影响有相互矛盾的报道。在这份研究中，我们将测试 假设大脑半球间连接直接影响脑可塑性和局灶性缺血后的行为恢复。为了可视化fc，我们将利用一种新的成像方式，fcOIS（功能连接光学内在信号成像）由Culver博士（合作PI）开发，这是第一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I/LnJ品系的无胼胝体小鼠来操纵半球间连接，以检查它们对皮层可塑性（大脑重新映射）和行为恢复的影响，目的如下：1.确定小鼠局灶性脑缺血后fc、皮质重映射和行为恢复之间的关系。2.确定胼胝体纵裂连接对局灶性脑缺血后皮质重映射和行为恢复的影响。3.确定局灶性脑缺血后，同位节点兴奋/抑制对体感皮层重映射的影响。4.确定慢性生理刺激/剥夺是否会改变触须操作的皮层重映射和纵裂fc。

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.