INFLUENCE OF INTERHEMISPHERIC CONNECTIVITY ON RECOVERY AFTER FOCAL ISCHEMIA

描述(申请人提供)：中风是美国成人残疾的主要原因，每年的发病率为78万，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整的。我们对恢复机制的了解主要集中在参与脑重塑的局部细胞和分子机制上。最近的工作在网络水平上研究了中风后的恢复--检查休息期间整个大脑同步神经活动的分布模式--并揭示了局灶性中风后功能网络连接的整体模式发生了变化。此外，缺血性卒中后不久，大脑半球间同源功能连接(FC)中断尤其预示着表现不佳。在大鼠局灶性脑缺血模型中，发现同源Fc在行为改善的同时恢复。有大量的间接证据表明，同源的半球间Fc可能对恢复很重要，并由此产生了“半球间竞争”的概念。这一假说认为，两个半球之间的兴奋和抑制之间的平衡对于正常的单侧功能(例如，单侧手的运动)可能很重要。如果这种大脑半球间的平衡被破坏(例如，由于中风)，局部的自我抑制影响可能会加剧缺陷，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，关于对侧同源影响对功能恢复的影响，有相互矛盾的报告。在这笔赠款中，我们将测试 假设大脑半球间的连通性直接影响脑的可塑性和局灶性缺血后的行为恢复。为了可视化FC，我们将利用卡尔弗博士(Co-Pi)开发的一种新的成像方式-fcOIS(功能连接光学本征信号成像)，它首次允许在小鼠中进行FC成像。我们将利用光遗传激发/抑制和无足小鼠的I/LnJ品系来操纵大脑半球间的连通性，以考察它们对皮层可塑性(脑重新映射)和行为恢复的影响，目的如下：1.确定FC、皮质重新映射与小鼠局灶性脑缺血后行为恢复的关系。2.研究大脑半球与大脑半球间的连通性对局灶性脑缺血后皮质重定位和行为恢复的影响。3.确定同位结节兴奋/抑制对局灶性脑缺血后躯体感觉皮层重新定位的影响。4.用振动手法确定慢性生理刺激/剥夺是否改变了大脑皮层重映射和大脑半球间的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.