# The role of hippocampal neurogenesis in alcohol withdrawal seizure and cognition

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $402,500

## Abstract

Abstract
Alzheimer's disease (AD) is an irreversible neurodegenerative disorder. Among potential AD etiology, alcohol
abuse and withdrawal has been suggested as a high-risk factor for AD and early-onset dementia; however, the
precise mechanism by which alcohol impacts on AD pathophysiology has yet understood. Aggregation of
amyloid b (Ab) peptide in the extracellular space of specific brain structures such as the hippocampus plays a
causal role in the pathogenesis of AD. Although AD is increasingly viewed as a heterogeneous and multifaceted
disorder, hippocampal hyperactivity and high levels of Ab secretion in the hippocampus are common signatures
during early stages of AD. Recent studies from both human AD patients and familial AD (FAD) mouse models
have suggested that a vicious cycle of Ab-mediated hyperactivation of the hippocampus underlies AD
development and AD-related dementia (ADRD) in the preclinical stages. In response to the NOSI, we seek to
understand the role of alcohol in hippocampal hyperactivity and Ab secretion. Specifically, we will test the
hypothesis that 1) alcohol withdrawal (AW) induces hippocampal hyperactivity, 2) hyperactive hippocampus then
increases the release and deposition of Ab, and 3) secreted Ab, in turn, contributes to hyperexcitability of
hippocampus. We recently discovered that AW after chronic alcohol consumption induces non-convulsive
seizures and that elevated activity of adult-born dentate gyrus cells (abDGCs) leads to hippocampal hyperactivity
and seizures during a sustained period of abstinence. These observations have provided the foundation for the
hypothesis that AW is a key element that initiates and aggravates a vicious cycle of Ab-mediated hyperactivation
of the hippocampus via hippocampal abDGCs. In this proposal, we will test following hypotheses: 1) that
hyperactivity of the hippocampus induced by AW promotes soluble Ab secretion (Aim 1) and 2) that specific
inhibition of hippocampal newborn DGCs may normalize hippocampal hyperactivity and Ab secretion (Aim 2).
Results from these experiments are expected to provide entirely new cellular and circuitry mechanisms by which
AW following chronic alcohol exposure promotes hyperactivity of the hippocampus, the onset and progression
of AD, and memory impairments. We expect to provide a foundation for developing strategies to prevent and
treat AW-mediated AD pathology by modulating targeted hippocampal neural circuits.
Relevance to the NOSI: The PI’s current RO1 grant seeks to understand how alcohol induces hippocampal
hyperactivity and seizure development via abDGCs and does not focus on AD. Therefore, our request for
administrative supplements to determine the role of AW-induced hippocampal hyperactivity in a vicious cycle of
Ab-mediated hippocampal hyperactivity and AD development is within the scope of the parent research.

## Key facts

- **NIH application ID:** 10496502
- **Project number:** 3R01AA027766-03S1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Hoonkyo Suh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 3
- **Project period:** 2020-04-10 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496502

## Citation

> US National Institutes of Health, RePORTER application 10496502, The role of hippocampal neurogenesis in alcohol withdrawal seizure and cognition (3R01AA027766-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10496502. Licensed CC0.

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