Noradrenergic mechanisms of vagus nerve stimulation mediated stroke rehabilitation

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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.