Noradrenergic mechanisms of vagus nerve stimulation mediated stroke rehabilitation

项目总结/摘要 在美国，由神经损伤如中风引起的运动障碍影响着数百万人。 这些损伤通常导致慢性上肢残疾，这会大大降低生活质量。是 广泛认为运动皮层（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大的功能恢复。我们有 开发了一种新的策略，以促进运动网络中的突触可塑性，并增强运动神经元的恢复。 中风后的功能该技术使用短暂的迷走神经刺激（VNS）脉冲， 神经调节回路在康复锻炼。当与运动康复训练配对时，迷走神经 神经刺激（VNS）诱导M1可塑性，并显着改善前肢功能的恢复， 中风的临床前模型。此外，基于最近成功的关键试验，VNS治疗已获得FDA批准， 批准作为首个神经调节疗法用于慢性卒中患者上肢功能恢复。 虽然VNS治疗代表了慢性卒中患者的潜在变革性干预，但其他 需要开发以优化这种治疗策略的功效-以改善 治疗效果和对VNS治疗有反应的参与者的数量。成功的关键 制定更有效的方法是对引起 有助于中风恢复的神经可塑性。VNS被认为是通过增加 M1中的神经调质，创造一种有助于可塑性的新皮质状态。去甲肾上腺素（去甲肾上腺素，NE）， 特别是，已知在VNS依赖性神经可塑性中起关键作用，但这是否重要 神经调节系统在中风恢复的背景下对VNS疗效的关键贡献仍然未知。 在目前的建议中，我们的目标是严格审查依赖于VNS的参与的功能相关性， 脑卒中后去甲肾上腺素能神经网络对突触可塑性和功能恢复的影响在Aim I中，我们使用 光遗传学的方法来询问VNS驱动的广泛投射的去甲肾上腺素能神经元的激活是否在 蓝斑是必要的，足以增强皮质脊髓连接和前肢运动 中风后的表现在目标II中，我们测试了运动皮层内的局部去甲肾上腺素能信号是否被激活。 VNS介导的中风恢复的中心。在目标III中，我们测试是否具有预防性药理学作用， 增强中枢去甲肾上腺素能信号可以提高VNS在卒中中的有效性 康复活动. 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， 所提出的目标将阐明VNS增强康复的神经生物学基础， 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.