Noradrenergic mechanisms of vagus nerve stimulation mediated stroke rehabilitation

项目摘要/摘要 在美国，由中风等神经损伤引起的运动障碍影响着数百万人。 这些损伤通常会导致慢性上肢残疾，这可能会大大降低生活质量。它是 人们普遍认为，运动皮质(M1)的可塑性是中风后功能恢复的基础；因此， 增强神经可塑性的方法的发展保证了患者更好的功能恢复。我们有 开发了一种新的策略来促进运动网络中的突触可塑性和促进运动的恢复 中风后的功能。这项技术使用短暂的迷走神经刺激(VNS)来进行 康复训练中的神经调节回路。当配合运动康复训练时，迷走神经 神经刺激(VNS)诱导M1可塑性并显著促进大鼠前肢功能恢复 中风的临床前模型。此外，基于最近一项成功的关键试验，VNS疗法已获得FDA 批准作为慢性卒中患者上肢功能恢复的首个神经调节疗法。 虽然VNS疗法对慢性中风患者来说是一种潜在的变革性干预措施，但额外的 需要开发来优化这一治疗策略的疗效-以提高 治疗效果和对VNS治疗有反应的参与者数量。成功的关键 开发更有效的方法是对导致 有助于中风康复的神经可塑性。VNS的作用机制被认为是通过增加 M1中的神经调节剂，创造了一种有利于可塑性的新皮质状态。去甲肾上腺素(NE)， 特别是，已知在VNS依赖的神经可塑性中起关键作用，但这是否重要 在卒中康复的背景下，神经调节系统对VNS疗效的关键作用尚不清楚。 在当前的提案中，我们的目标是批判性地检查依赖VNS的参与的功能相关性 去甲肾上腺素能网络在卒中后驱动突触可塑性和功能恢复中的作用。在Aim I中，我们使用一个 光遗传学方法探讨迷走神经刺激是否激活大鼠脑内广泛投射的去甲肾上腺素能神经元 蓝斑是增强皮质脊髓连接和前肢运动的必要条件和充分条件。 中风后的表现。在AIM II中，我们测试了运动皮质内的局部去甲肾上腺素信号是否 是VNS介导的卒中恢复的中枢。在目标III中，我们测试了辅助药理作用 增强中枢去甲肾上腺素能信号可改善卒中后VNS的疗效 康复。 通过因果检验NE信号在VNS驱动的皮质脊髓可塑性和中风恢复中的重要性， 拟议的目标将阐明VNS增强康复的神经生物学基础，并提供信息 为中风患者开发和验证更有效的治疗方案。

PROJECT SUMMARY/ABSTRACT Motor impairments arising from neural injuries such as stroke impact millions of people in the United States. These injuries often result in chronic upper limb disability, which can substantially diminish quality of life. It is widely held that plasticity in the motor cortex (M1) underlies recovery of function following stroke; therefore, the development of methods to enhance neuroplasticity promises greater functional recovery in patients. We have developed a novel strategy to promote synaptic plasticity in motor networks and enhance recovery of motor function following stroke. This technique uses brief bursts of vagus nerve stimulation (VNS) to engage neuromodulatory circuits during rehabilitative exercises. When paired with motor rehabilitation training, vagus nerve stimulation (VNS) induces M1 plasticity and significantly improves recovery of forelimb function in preclinical models of stroke. Moreover, based on a recent successful pivotal trial, VNS therapy has received FDA approval as the first neuromodulation therapy for recovery of upper limb function in chronic stroke. While VNS therapy represents a potentially transformative intervention for chronic stroke patients, additional development is needed to optimize the efficacy of this treatment strategy—to improve both the magnitude of the therapeutic effect and the number of participants that respond to VNS treatment. Key to the successful development of more effective approaches is a clear understanding of the mechanisms that give rise to neuroplasticity that subserves stroke recovery. VNS is thought to work by increasing the activity of neuromodulators in M1, creating a neocortical state conducive to plasticity. Noradrenaline (norepinephrine, NE), in particular, is known to play a key role in VNS-dependent neuroplasticity, but whether this important neuromodulatory system critically contributes to VNS efficacy in the context of stroke recovery remains unknown. In the current proposal, we aim to critically examine the functional relevance of VNS-dependent engagement of the noradrenergic network in driving synaptic plasticity and functional recovery after stroke. In Aim I, we use an optogenetic approach to ask whether VNS-driven activation of broadly-projecting noradrenergic neurons in the locus coeruleus is necessary and sufficient to enhance corticospinal connectivity and forelimb motor performance following stroke. In Aim II, we test whether local noradrenergic signaling within the motor cortex is central to VNS-mediated stroke recovery. And in Aim III, we test whether adjunctive pharmacological enhancement of central noradrenergic signaling can improve the effectiveness of VNS during stroke rehabilitation. By causally examining the importance of NE signaling in VNS-driven corticospinal plasticity and stroke recovery, the proposed Aims will elucidate the neurobiological underpinnings of VNS-enhanced rehabilitation and inform the development and validation of more effective treatment options for stroke patients.