# Impact of Amyloid Beta on Hippocampal Neurophysiology and Calcium Activity across the Sleep-Wake Cycle

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $416,261

## Abstract

Understanding the relationship between A and memory dysfunction in Alzheimer’s disease
remains an essential objective. Although animal models of Alzheimer’s that over-express the
amyloid precursor protein show perturbed calcium in individual neurons, memory is
fundamentally a neural systems property of the intact hippocampus, and how A impacts the
integrity of neural systems calcium activity in the functioning hippocampus is unknown. During
exploratory behavior, neurons represent space as place fields, coordinating their action
potentials with the hippocampal theta oscillation, a rhythm dependent on acetylcholinergic (ACh)
inputs from the medial septum; but during quiet wakefulness and slow wave sleep, ACh levels
fall and theta is replaced with a physiological state in which neurons fire instead with sharp-
wave ripple events. Given that ACh’s contribution to hippocampal function extends to
Alzheimer’s, with ACh esterase inhibitors providing the mainstay of therapy and associated with
significant improvements in memory, we hypothesize that the cholinergic system impacts the
neurophysiological effects of A deposition, such that A’s effects on dynamic calcium activity in
the functioning hippocampus will depend on hippocampal state and cholinergic tone across the
sleep-wake cycle. In addition, since fluctuations in cytoplasmic calcium may derive both from
neuronal depolarization and from calcium-induced calcium release, calcium activity may be an
imperfect surrogate for electrophysiological activity. To address these issues, we will study (1)
the relationship between neuronal calcium activity and hippocampal electrophysiology in freely
behaving normal animals, (2) how this relationship is impacted by Ain two Alzheimer’s disease
mouse models, and (3) how ACh impacts A's effects on calcium activity and action potentials.
To investigate these aims, we will combine chronic electrophysiological techniques with newly
available miniature microscope imaging technologies (Inscopix head mounted mini-microscope)
and robust, genetically encoded calcium fluorophores (GCAMP6f). We will acquire local field
potentials together with single unit recordings and calcium imaging of hippocampal neurons as
A over-expressing mice and littermate controls perform a behavioral task and across their
sleep-wake cycles. We will attempt to rescue A-associated abnormalities with a -secretase1
inhibitor now in clinical trials, and we will employ pharmacology to evaluate the impact of ACh
on A’s effects on hippocampal physiology. Together, these efforts will establish the effects of
Aon neuronal action potential activity and calcium activity across the sleep-wake cycle,
providing key insights into Alzheimer’s disease and identifying new targets for its treatment.

## Key facts

- **NIH application ID:** 10142328
- **Project number:** 5R01AG054551-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephen N. Gomperts
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,261
- **Award type:** 5
- **Project period:** 2017-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142328

## Citation

> US National Institutes of Health, RePORTER application 10142328, Impact of Amyloid Beta on Hippocampal Neurophysiology and Calcium Activity across the Sleep-Wake Cycle (5R01AG054551-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10142328. Licensed CC0.

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