ABSTRACT Stroke is the leading cause of long-term disability among adults in the United States, with half of all stroke survivors experiencing moderate to severe impairment in motor, sensory, or cognitive function that require specialty care. Despite advances in the acute (< 24 hour) care of stroke, such as thrombolysis and recanalization, stroke patients still experience progression of brain injury that negatively affects patient outcomes. Cerebroprotection, the mitigation of damage to the entire neurovascular unit of the brain, is an extremely high priority in stroke care research. Torpor, a state of hypothermia and hypometabolism, has long been hypothesized to represent a cerebroprotective state. We have identified a previously under-studied, conserved population of GABAergic neurons expressing the kappa opioid receptor (KOR) in the medial preoptic area (POA) termed POAKOR+. In preliminary studies, we found that chemogenetic activation of POAKOR+ neurons induced a hypothermic and hypometabolic state that we refer to as synthetic torpor. Preliminary data suggest that induction of synthetic torpor immediately after experimental stroke reduces infarct size and decreases mortality in mice at 72 hours post-stroke. The data also suggest that induction of synthetic torpor alters metabolism of nucleotides, lipids, and the citric acid cycle, while altering metabolites such as ceramides and succinate that are associated with the progression of brain injury after stroke. While promising, these preliminary data highlight several key knowledge gaps that will be addressed in the proposed research study. First, we will investigate whether the cerebroprotective effects observed 72 hours after stroke also improve long-term behavioral outcomes (Aim 1). Second, our preliminary data suggests that the hypothermic depth and duration of synthetic torpor predicts stroke size, thus, we will investigate whether the cerebroprotective effects of synthetic torpor following stroke are dependent or independent of hypothermia (Aim 2). Third, while the metabolic pathways that are altered during synthetic torpor overlap with those altered by stroke, it is unknown if these metabolic changes occur independently of hypothermia and if the altered pathways and metabolites are related to cerebroprotection. We will investigate these metabolic changes, identify the pathways and metabolites that are uniquely altered in response to synthetic torpor, and characterize the temporal-spatial dynamics of cerebroprotection (Aim 3). Identified metabolites and metabolic pathways may represent targets for future cerebroprotective interventions. Succesful completion of the proposed research study will characterize the mechanistic underpinnings underlying synthetic torpor-mediated cerebroprotection and address the knowledge gap on whether induction of a torpor-like state through modulation of specific neural circuits represents a novel cerebroprotective strategy for the treatment of ischemic stroke...