The Role of Homotopic Functional Connectivity in Cortical Remapping after Focal Ischemia

 描述（由申请人提供）：中风是美国残疾的主要原因，每年的发病率为78万，存活者超过580万。大多数中风幸存者在受伤后的最初几周到几个月内经历了有限程度的自发恢复，但这种恢复通常是不完全的。几十年来，动物模型暗示细胞和分子事件，包括突触发生，树突和轴突发芽，作为恢复的重要因素。虽然人们认为这些细胞程序参与了对恢复至关重要的新连接的形成，但最近的系统水平分析揭示了脑网络可塑性如何参与恢复。 局灶性缺血导致映射到梗死脑组织上的模态的功能急性丧失。有趣的是，行为恢复发生在丢失的模式重新映射到梗死周围皮层，这表明重新映射可能对行为恢复至关重要。除了检查局部病变周围的变化，最近的工作已经检查了中风后全球脑网络的变化。通过检查"静息状态"脑中的神经同步模式，称为功能连接（fc），很明显，局灶性缺血后功能连接的整体模式发生了改变。在缺血性中风后，大脑半球间的同向fc弱（在健康个体中很强）预示着人类的运动和注意力表现较差。在大鼠局灶性脑缺血恢复模型中，半球间同源fc在损伤后降低，并与感觉运动行为表现平行恢复。这些研究表明，重新映射可能涉及长距离的网络变化。事实上，分子分析已经揭示了损伤后对侧皮层中发生的突触发生和神经可塑性。然而，对侧病变对重新定位和恢复的影响作用还没有很好的定义。 有一些证据表明，同伦半球间fc可能反映了同伦视皮层区域之间的兴奋/抑制平衡，这种平衡对正常的单侧功能很重要15。缺血性损伤被认为会破坏网络结构，并导致病灶周围皮质中抑制性张力增加，从而加剧缺陷并限制恢复。这可以解释重复经颅磁刺激（rTMS）和经颅直流电刺激（tDCS）在恢复半球间平衡和改善感觉运动功能方面的潜在疗效。然而，在人类和动物模型中，关于对侧同向影响对功能恢复的影响有相互矛盾的报道，目前还不清楚大脑半球间的交流是有益还是抑制恢复。动物模型可以更好地理解缺血后的对侧皮层生理学，从而更好地针对中风患者进行治疗。 在本研究中，我将检验大脑半球间的功能连接直接影响局部缺血后皮层的重新映射和行为恢复的假设。为了在小鼠局灶性脑缺血模型中可视化皮层地图和fc，我将利用成像模式，fc光学固有信号（fc optical intrinsic signal，fcOIS）来解决以下目标：目标1：确定小鼠局灶性脑缺血后纵裂fc，皮层重新映射和行为恢复之间的关系。目标二：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。

 DESCRIPTION (provided by applicant): Stroke is the leading cause of disability in the US, with an annual incidence of 780,000 and over 5.8 million survivors. Most stroke survivors experience a limited degree of spontaneous recovery in the first weeks to months following injury, but this recovery is often incomplete. For decades animal models have implicated cellular and molecular events including synaptogenesis, dendritic and axonal sprouting, as being important for recovery. While it was believed that these cellular programs are involved in the formation of new connections important for recovery, more recent systems-level analysis have revealed how brain-network plasticity may be involved in recovery. Focal ischemia results in the acute loss of function to modalities mapped onto infarcted brain tissue. Interestingly, behavioral recovery occurs as lost modalities remap onto the peri-infarct cortex suggesting remapping may be critical for behavioral recovery. In addition to examining local peri-lesional changes, more recent work has examined alterations in global brain networks following stroke. By examining patterns of neural synchronization in the "resting state" brain, termed functional connectivity (fc, it is clear that global patterns of functional connectivity are altered following focal ischemia. Immediately following ischemic stroke, weak interhemispheric homotopic fc (which is robust in healthy individuals) predicted poor motor and attentional performance in humans. In a rat focal ischemia recovery model, interhemspheric homotopic fc decreased following injury and recovered in parallel with sensorimotor behavioral performance. These studies suggest that remapping may involve long range network changes. Indeed, molecular profiling has revealed synaptogenesis and neuroplasticity occurring in the contralesional cortex after injury. However, the role the contralesional influence on remapping and recovery is not well defined. There is some evidence that homotopic interhemispheric fc may reflect the excitatory/inhibitory balance between homoptic cortical regions and that this balance is important for normal unilateral functionality 15. Ischemic injury is thought to disrupt network architecture and result in increase inhibitory tone in the perilesional cortex that exacerbates deficits and limits recovery. This coul 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, and it is unclear if interhemispheric communication benefits or inhibits recovery. Animal models may enable a better understanding of contralesional cortex physiology after ischemia allowing better targeting of therapies for stroke patients. In this grant, I will test the hypothesis that interhemispheric functional connectivity directly influences cortical remapping and behavioral recovery after focal ischemia. To visualize cortical maps and fc in a mouse focal ischemia model, I will utilize imaging modalitiy, fc optical intrinsic signal (fcOIS) to address the followig aims: Aim 1: To determine the relationship between interhemispehric fc, cortical remapping, and behavioral recovery following focal ischemia in mice. Aim 2: To determine the influence of transcallosal interhemispheric connectivity on cortical remapping and behavioral recovery following focal ischemia.