lactate sensing fibroblasts in stroke

Stroke is the most common cause of brain damage, due to the insufficient capacity of the brain to repair ischemia induced neural damage. It has been shown, however, that transient forebrain ischemia leads to neurogenesis, and exercise has been shown to both reduce the likelihood of stroke and the lesion area caused by stroke.The migration and proliferation of neural stem cells into the infarcted area is dependent on growth factors such as vascular-endothelial growth factor (VEGF). We have recently shown that physical activity/exercise promotes angiogenesis in the brain via lactate dependent activation of HCAR1 and subsequent release of VEGF from e.g. pial fibroblast-like cells in the brain. We hypothesize that (part of) the protective effect of exercise in stroke is mediated through HCAR1-dependent release of growth factors from fibroblasts to promote neurogenesis. We will perform exercise regimes and lactate injections prior to induction of stroke in wild type mice and in KO mice lacking the HCAR1. We will then perform behavioral studies of cognitive and motor functions to reveal if knock-out mice that lack HCAR1 develop larger functional loss in response to stroke. We will perfom immunohistochemical analysis to reveal whether the lesion area that develops in response to stroke differs between the genotypes, and to analyze alterations in markers for oxidative stress/inflammaton and neuroprotection. We will use the minimum amount of animals to achieve statistically valid results. We expect the results to contribute to our understanding of neuroprotection in stroke and to the development of new treatments against the neural damage associated with stroke.