# Reducing vascular cognitive impairment within and across generations by epigenetic conditioning

> **NIH NIH R21** · LSU HEALTH SCIENCES CENTER · 2021 · $404,250

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 10212499
- **Project number:** 1R21NS118223-01A1
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** JEFFREY M GIDDAY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,250
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212499

## Citation

> US National Institutes of Health, RePORTER application 10212499, Reducing vascular cognitive impairment within and across generations by epigenetic conditioning (1R21NS118223-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212499. Licensed CC0.

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