Project Summary Cognitive impairment is a common functional sequela of stroke, although the neural substrate underlying which is yet to be identified. White matter hyperintensity (WMH), a progressive form of degeneration and a marker of small vessel disease, is a major risk factor for post stroke cognitive impairment. Emerging studies support an inverse relationship between WMH burden and the volume of the hippocampus, which is a key brain structure for memory function and may undergo secondary degeneration. Preliminary data show that the hippocampus is remote from cortical stroke and not affected acutely after stroke. However, our electrophysiology data suggest that network communication between the cortex and hippocampus became disrupted during chronic stroke, which is consistent with connectome-based analysis showing damaged cortical regions are well connected with neural networks involved in spatial learning. We hypothesize that WM lesions predispose to post stroke cognitive impairment due to exacerbated connectivity loss and remote degeneration in the learning and memory region. Our immediate goal is to understand how stroke affects hippocampal function from the perspective of brain connectivity. As a proof-of-principle translational study, we will carry it out in the spontaneously hypertensive rats at an age when spontaneous WM lesion is detected. To determine the role of connectivity loss in post stroke cognitive impairment in the setting of WM lesion, we will first map the lesion location and extent in both WM and GM, and quantify hippocampal subfield volume. We will then determine the changes in structural connectivity with the neuroVIISAS-based connectome platform built with tract tracing and DTI streamline data to reveal how global and local networks are affected. Lesioned regions with direct or indirect connections with the hippocampus will be identified. The dynamic effect of stroke and WM lesion on learning/memory function will be determined by modeling the coactivation pattern between a pair of lesioned region and functional region involved in spatial learning with FitzHugh-Nagumo neuron simulation using the weighted and directed connectome. Electrophysiology correlates of hippocampal activity and network communication will be assessed to complement data in neurobehavior and connectivity. We anticipate that the knowledge of lesion extent, location, and the effect on network connectivity in the setting of hypertension will provide insight into the role of WM lesion in post stroke cognitive decline. It may also enable the identification of relay brain regions undergoing functional changes and possibly the progression of connectivity loss.