# Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $666,023

## Abstract

Project Summary/Abstract
The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk
factor for Alzheimer’s Disease (AD) and dementia. In addition to aging, sedentary behavior ranks first in the
US and third in the world as a risk factor for causing cognitive decline and exacerbating AD. Greater and
accelerated rates of cognitive impairment in women with AD underscore the need for identifying the
mechanisms by which exercise prevents cognitive decline in normal aging and AD in both sexes. As observed
by our labs and others, hippocampus-dependent learning is facilitated by exercise in situations that are usually
subthreshold for encoding and memory consolidation and requires the induction of brain-derived neurotrophic
factor (BDNF). Our data suggest that specific exercise patterns can engage a ‘molecular memory’ for that
experience that persists through periods of sedentary behavior and enables a short exercise session, to again,
induce hippocampal BDNF and facilitate memory. We have proposed that epigenetic mechanisms mediate
this “molecular memory” of exercise, as the epigenome represents a signal transduction platform that is
capable of encoding past experience, current metabolic states (because nearly every epigenetic modification
is a metabolite) and establishing stable changes in cell function that lead to long-term changes in behavior.
Preliminary data in this proposal lead us to propose the novel hypothesis that specific patterns of exercise
establish a molecular feedback loop that integrates rate-limiting aspects of acetyl-CoA metabolism and
histone acetylation/methylation mechanisms to modulate gene expression required for long-term memory
formation and synaptic plasticity. Our goal in this proposal is to define, in aging wild type and 5xFAD female
and male mice, the exercise parameters that establish a molecular memory, to investigate the effect of
exercise on acetyl-CoA metabolic pathways and histone modifications and to determine whether
manipulations to this molecular feedback loop overcome deficiencies in synaptic plasticity and memory
formation in aging and 5xFAD female and male mice. We propose three Aims. Aim 1 - Determine how specific
exercise patterns affect synaptic plasticity and memory formation in aging wild type mice and 5xFAD mice.
Aim 2 - determine the effect of exercise on acetyl-CoA metabolic pathways, histone modification, and gene
expression in aging wild type mice and 5xFAD mice. Aim 3 - determine the effect of ameliorating hippocampal
acetyl-CoA deficiencies in aging and 5xFAD mice on gene expression, synaptic plasticity and memory
formation. Overall, successful completion of the research in this proposal will improve our understanding of
how the epigenome integrates information from metabolism (acetyl-CoA dynamics) and experience
(exercise), how this interplay becomes impaired with aging and in the context of AD, and how pharmacological
modulation of acetyl-CoA dyna...

## Key facts

- **NIH application ID:** 10420533
- **Project number:** 1R01AG076835-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Carl Wayne Cotman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $666,023
- **Award type:** 1
- **Project period:** 2022-06-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420533

## Citation

> US National Institutes of Health, RePORTER application 10420533, Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain (1R01AG076835-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10420533. Licensed CC0.

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