Neurocognitive impairment secondary to vascular contributions to cognitive impairment and dementia (VCID) exacts devastating tolls on our aging population, and to date, efficacious therapies remain elusive. Epigenetics- based therapeutics hold promise in this regard, as growing evidence continues to document the epigenetic induction of beneficial, disease-resilient phenotypes in response to distinct patterns of ?positive stress? (`eustress'). Such profound findings indicate that reprogramming the activation and repression of a broad array of innate genes can actually protect the brain from injury in the absence of any exogenous, pharmacologic treatment. Indeed, recent findings from our lab using a well-established model of VCID indicate that repetitively conditioning mice with brief periods of nonharmful systemic hypoxia (RHC) prevents memory loss in vivo, and preserves hippocampal synaptic plasticity ex vivo, caused by three months of chronic cerebral hypoperfusion secondary to bilateral carotid artery stenosis. Moreover, we have discovered that adult, first-generation progeny of mice that were treated with RHC prior to mating also exhibit these same VCID-resilient phenotypes ? in the absence of any direct treatment. Thus, the present proposal is founded on the overall hypothesis that adaptive epigenetics-based treatments can prevent VCID-associated cognitive loss, both within and across generations. Studies in Aim 1 are designed to determine if the aforementioned intergenerational protection against cognitive impairment that results from parental RHC requires treatment of both parents, or only the father or mother. The outcome of these studies will inform future studies of germ cell epigenetic change that ultimately underlies this transfer of induced, beneficial phenotypes. Studies in Aim 2 are designed to start unraveling the epigenetic regulatory mechanisms responsible for the protection against VCID-associated cognitive impairment in mice directly treated with RHC, focusing specifically on histone deacetylase 3 (HDAC3) and the role it plays in the transcriptional regulation of genes that contribute to RHC-mediated dementia resilience. Results of these studies will begin to build a molecular framework for how histone-based epigenetic modifications of gene expression can prevent memory loss in VCID. Overall, our investigations will provide mechanistic insights into the efficacious and ongoing clinical trials of remote conditioning for VCID, a translational counterpart of our RHC therapy that involves inducing repetitive cycles of skeletal muscle hypoxia with blood pressure cuff devices. And they will plant the seeds for advancing epidemiological and epigenetic research programs to explore the exciting possibility that an induced resilience to VCID may be heritable in humans as well.
The ability of a stressful but nonharmful stimulus to induce robust adaptive epigenetic changes that can transiently protect tissues and cells from injury has been recognized for several decades, and is the theoretical basis now supporting many ?conditioning? clinical trials for acute myocardial and cerebral ischemia. Our recent studies in a mouse model of vascular contributions to cognitive impairment and dementia (VCID) demonstrate that repetitive conditioning establishes a dementia-resilient phenotype in treated animals, and also in their untreated first-generation adult progeny. Studies in the current proposal are designed to determine if this neurovascular protective phenotype is transferred across generations by germ cells of the father, or mother, or both, and to begin to elucidate the epigenetic mechanisms responsible for protecting against memory loss, with a focus on histone deacetylase inhibitors.
