Noradrenergic mechanisms of vagus nerve stimulation mediated stroke rehabilitation

迷走神经刺激介导的中风康复的去甲肾上腺素能机制

• 批准号: 10624945
• 负责人: CATHERINE A THORN
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624945
• 关键词: Agonist; Attention deficit hyperactivity disorder; Automobile Driving; Behavioral; Cells; Chronic; Development; Effectiveness; Exhibits; FDA approved; Fiber; Forelimb; Guanfacine; Individual; Infusion procedures; Injury; Intervention; Ischemic Stroke; Lesion; Mediating; Motor; Motor Cortex; Neocortex; Neurobiology; Neuromodulator; Neuronal Plasticity; Neurons; Norepinephrine; Participant; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Physiological; Play; Pre-Clinical Model; Publishing; Quality of life; Rattus; Receptor Signaling; Recovery; Recovery of Function; Rehabilitation therapy; Research; Role; Signal Pathway; Signal Transduction; Stroke; Synapses; Synaptic plasticity; System; Techniques; Testing; Therapeutic Effect; Tracer; Training; Treatment Efficacy; United States; Upper Extremity; Validation; Viral; Work; antagonist; atomoxetine; chronic stroke; clinical translation; disability; effective therapy; exercise rehabilitation; experimental study; improved; inhibitor; locus ceruleus structure; method development; motor function recovery; motor impairment; motor rehabilitation; neocortical; nerve injury; nerve supply; neuroregulation; noradrenergic; novel; novel strategies; optogenetics; patient response; pharmacologic; post stroke; pre-clinical; receptor; reuptake; stroke model; stroke patient; stroke recovery; stroke rehabilitation; treatment response; treatment strategy; vagus nerve stimulation

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.

项目摘要/摘要 神经损伤引起的运动障碍（例如中风）会影响美国数百万的人。 这些伤害通常会导致慢性上肢残疾，这​​可能会大大降低生活质量。这是 广泛认为，运动皮层（M1）中的可塑性是中风后功能恢复的基础。因此， 增强神经塑性的方法的发展有望在患者中更大的功能恢复。我们有 制定了一种新的策略来促进电机网络中的突触可塑性并增强电动机的恢复 中风后的功能。该技术使用短暂的迷走神经刺激（VNS）来参与 康复运动过程中的神经调节电路。当与运动康复训练配对时，迷宫 神经刺激（VNS）影响M1可塑性，并显着提高前肢功能的恢复 中风的临床前模型。此外，根据最近成功的关键试验，VNS疗法已接受FDA 批准是慢性中风中上肢功能恢复的第一种神经调节疗法。 虽然VNS疗法代表了慢性中风患者的潜在转化干预措施 需要开发来优化该治疗策略的效率 - 以提高 治疗效应和对VNS治疗反应的参与者数量。成功的关键 开发更有效的方法是对产生的机制的清晰理解 神经塑性可实现中风恢复。据认为，VN可以通过增加活动 M1中的神经调节剂，形成了新皮质状态导电到可塑性。去甲肾上腺素（Norepinephrine，NE）， 特别是，已知在依赖VNS的神经塑性中起关键作用，但是这个重要 在中风恢复的背景下，神经调节系统对VNS的效率有所促进。 在当前的建议中，我们旨在批判性地研究VNS依赖性参与的功能相关性 甲肾上腺素能在驱动突触可塑性和中风后功能恢复方面的网络。在目标一世中，我们使用 询问VNS驱动的大规模注射NORADENAGIC神经元激活的光遗传学方法 基因座凝固是必要的，足以增强皮质脊髓连通性和前肢电动机 中风后的性能。在AIM II中，我们测试运动皮层内的局部甲肾上腺素能信号传导是否为 VNS介导的中风恢复的中心。在AIM III中，我们测试是否辅助药物 中央甲肾上腺素能信号的增强可以提高中风期间VN的有效性 康复。 通过随便检查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， 拟议的目的将阐明VNS增强康复的神经生物学基础并告知 中风患者更有效的治疗选择的开发和验证。