Project Summary This proposal is a competitive renewal application which goal was to elucidate the mechanisms by which ischemic preconditioning (IPC) affords protection against cerebral ischemia (4th cycle). Five major observations emerged from our studies: 1) IPC, PKCε and resveratrol upregulate BDNF levels, which plays a key role in neuroprotection; 2) IPC and PKCε activation promote significant electrophysiological alterations that lead to ischemic tolerance; 3) resveratrol preconditioning (RPC) requires SIRT1 activity for neuroprotection, and promotes significant gene reprograming; 4) PKCε and RSV upregulates the synaptic plasticity master regulator Arc; and 5) RPC exhibits a prolonged window of ischemic tolerance (2 weeks) prior to middle cerebral artery occlusion (MCAo), suggesting that this type of preconditioning exerts prolonged epigenetic modifications. From these findings, we have gathered new preliminary data that further supports that RPC preserves synaptic plasticity and mitigates cognitive impairments following MCAo. Since, stroke is one of the main causes of Vascular Cognitive Impairment (VCI), which is one of the most common Alzheimer’s disease related dementias (ADRDs), our main goal in this application is to investigate RPC mediate modifications in synaptic and cognitive functions. Three specific aims are proposed: 1) To determine the effect of RPC on cognitive outcomes in young and aged female and male rats; 2) To determine the mechanisms by which RPC ameliorates hippocampal synaptic deficits following MCAo; and 3) Identification of cell specific transcriptional profiles associated with RPC mediated hippocampal synaptic plasticity and septum nuclei preservation. These 3 aims will shed light on novel pathways that mitigate stroke-induced cognitive deficits and may provide novel therapies to protect specifically stroke patients from cognitive decline and may even be used for other ADRD patients, specifically those that are affected by VCI.