Measuring and manipulating stress-responsive neuronal activity to improve post-stroke outcomes

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Stroke is a severe ischemic neurovascular injury, with high rates of incidence in the developed world, high mortality, and long-term disability for survivors. It is critical for the development of improved interventions that novel therapies take into account post-ischemic stroke (IS) temporality to target appropriate time windows for intervention. Hypothalamic-pituitary-adrenal (HPA) axis activation, which effectuates the neuroendocrine stress response, is elevated in the hyperacute phase post-IS, increasing corticotropin releasing hormone (CRH) and corticosteroid (CORT) signaling. Elevated stress and HPA activity pre-IS is associated with worse outcomes, and hypercortisolism in the subacute and chronic phases is both typical and deleterious. The hippocampus provides crucial negative feedback regulation of the HPA axis, and secondary post-IS damage to the hippocampus is common. Secondary damage to the hippocampus post-IS may depend on corticoiddependent signaling; this could set up a feed-forward loop whereby post-stroke potentiation of stress signaling propagates itself, promoting further excitotoxicity and neurodegeneration. A growing body of evidence suggests that targeting CRH signaling could reduce post-IS morbidity and mortality; this includes advanced anti-CRH antibody treatment and CRF1R antagonism. CNS control of HPA axis activation is likely a major contributor to CRH and corticoid elevation post-IS. The ventral hippocampus regulates CRH production and HPA activation through excitatory projections to the bed nucleus of the stria terminalis (BNST), which in turn sends inhibitory projections to CRH+ neurons in the paraventricular nucleus (PVN) of the hypothalamus. This circuit represents a viable target for temporally-modulated interventions after stroke. In this proposal we will investigate how BNST and PVN neuronal activity changes acutely poststroke, and how modulating the activity of key neuronal populations in these nuclei will be effective in improving functional outcomes and reducing neuronal damage in the hippocampus and throughout the brain after ischemia.