Abstract
Post-stroke optogenetic stimulation has been shown to enhance neurovascular coupling and functional recovery. Neuronal nitric oxide synthase (nNOS) has been implicated as a key regulator of the neurovascular response in acute stroke; however, its role in subacute recovery remains unclear. We investigated the expression of nNOS in stroke mice undergoing optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN). We also examined the effects of nNOS inhibition on functional recovery using a pharmacological inhibitor targeting nNOS. Optogenetically stimulated stroke mice demonstrated significant improvement on the horizontal rotating beam task at post-stroke days 10 and 14. nNOS mRNA and protein expression was significantly and selectively decreased in the contralesional primary motor cortex (cM1) of cLCN-stimulated mice. The nNOS expression in cM1 was negatively correlated with improved recovery. nNOS inhibitor (ARL 17477)-treated stroke mice exhibited a significant functional improvement in speed at post-stroke day 10, when compared to stroke mice receiving vehicle (saline) only. Our results show that optogenetic stimulation of cLCN and systemic nNOS inhibition both produce functional benefits after stroke, and suggest that nNOS may play a maladaptive role in post-stroke recovery.
Highlights
Ischemic stroke represents one of the largest contributors to morbidity in the USA [1]
We have shown that optogenetic stimulation of contralesional lateral cerebellar nucleus (cLCN) in a mouse stroke model selectively decreases Neuronal nitric oxide synthase (nNOS) expression and the observed reduction is correlated with improved recovery
We further investigated the role of nNOS in post-stroke recovery using a pharmacological nNOS inhibitor. nNOS inhibitor-treated stroke mice exhibited a significant functional improvement when compared to stroke mice receiving vehicle only (Fig. 6)
Summary
Ischemic stroke represents one of the largest contributors to morbidity in the USA [1]. Brain stimulation delivered via electrical current or magnetic stimulation represents one emerging therapeutic avenue [5] These techniques non- activate all cell types, making it difficult to elucidate the underlying cell types and mechanisms driving recovery. We recently demonstrated that stimulation of the contralesional lateral cerebellar nucleus (cLCN)—a target chosen for its significant excitatory cortical connections—yielded robust functional recovery, as well as increasing plasticity marker GAP43 in the ipsilesional primary somatosensory cortex (iS1) [7]. These findings suggest that targeted brain stimulation
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