# PROJECT 2-Network properties of entorhinal/dentate gyrus and CA3 region in behaviorally-characterized aged rats

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2021 · $627,336

## Abstract

Our research program under this funding mechanism has provided evidence for specific effects of aging
on medial temporal lobe (MTL) circuits that contribute to individual differences in cognitive outcomes in
aging. Because advancing age represents the strongest risk factor for Alzheimer’s Disease (AD), individual
differences in aging itself may confer risk or resilience for that disease, indicating potential relevance beyond
the limited condition of age-related cognitive impairment. Project 2 investigates circuit-specific mechanisms
within the broad memory system network that underlie individual differences in both impaired and preserved
cognitive outcomes, and considers sex as a potential factor for differential vulnerability to decline. As first
described in our research with outbred Long-Evans male rats characterized for age-related impaired memory
(AI), a condition of neural overactivity in the MTL translated in clinical observational studies of elderly
individuals, with further augmentation in aMCI patients at greater risk for late onset AD. Within the aged rat
study population, our background research demonstrated that neural overactivity contributes to memory
impairment by using experimental intervention with therapeutics, a finding that has also translated
therapeutically in clinical studies. Alongside those achievements, accumulating evidence suggests that
adaptive recruitment of inhibitory function beneficially supports resilience to memory decline in aged
unimpaired rats (AU). Research in Project 2 will now examine the functional significance of inhibitory
recruitment as a potentially adaptive mechanism in the preservation of cognitive function in aging. In that
context, Project 2 will investigate a mechanism for homeostatic regulation, to examine loss of function in AI and
potential gain of function in AU. Project 2 will study the condition of this mechanism across the
EC/hippocampal system with anatomical methods for circuit-specific alterations. The CA2 hippocampal
subfield has become an additional subregion of high interest in our model; loss of function contributes to
excess activity possibly contributing to the AI condition while greater recruitment may occur in AU rats, giving a
bi-directional role for homeostatic control in both late life outcomes. Project 2 will also lead in the use of
experimental tools with potential therapeutic relevance, as it has in the past with the Sv2a agent levetiracetam.
Studies under Aim 4 in Project 2 will test agents that act as allosteric modulators of GABAA α5 receptors.
These receptors have highly restricted localization in the mammalian brain and may offer greater precision for
targeting the neurobiological conditions underlying impairment in AI and providing a test for the functional
significance of AU biomarkers, which have indicated augmented inhibition to maintain excitatory/inhibitory
balance in brain aging. Thus, in the research plans in the current application, Project 2 maintains a str...

## Key facts

- **NIH application ID:** 10171061
- **Project number:** 2P01AG009973-26A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Michela Gallagher
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $627,336
- **Award type:** 2
- **Project period:** 1997-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171061

## Citation

> US National Institutes of Health, RePORTER application 10171061, PROJECT 2-Network properties of entorhinal/dentate gyrus and CA3 region in behaviorally-characterized aged rats (2P01AG009973-26A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10171061. Licensed CC0.

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