# Delaying cognitive decline in mouse models of Alzheimer's disease via near-infrared light optogenetics

> **NIH NIH R21** · UNIVERSITY OF WYOMING · 2022 · $180,625

## Abstract

ABSTRACT
During sleep, the thalamus generates a characteristic brief pattern of 8-15 Hz electroencephalographic
(EEG) waves that predominantly occur during light stages of non-rapid eye-movement sleep (NREMS).
Reduced spindle may cause impaired learning and Mild Cognitive Impairment (MCI) in AD and is a
biomarker for early AD-related changes in brain dynamics. Conversely, promoting sleep oscillations by
transcranial stimulation enhances memory consolidation in MCI. By developing a set of novel,
noninvasive, bacteriophytochrome-based optogenetic tools to control cAMP synthesis (adenylate
cyclase, AC) and breakdown (phosphodiesterase, PDE), we will make spindles accessible for
noninvasive manipulations that spare other sleep rhythms. These enzymes are activated by light in the
so-called near-infrared optical window (NIRW). The NIRW light-activated modules are suitable for the
rapid yet long-lasting and noninvasive manipulation of cAMP in thalamic neurons in intact animals,
because NIRW light penetrates through mammalian skulls and brain tissues better than the light of any
other spectral region. We will examine a provocative novel hypothesis that cellular pathology and
cognitive decline caused by Alzheimer’s disease (AD) related mutations can be restored via enhancing
thalamocortical spindles waves during sleep in vivo. We will first develop novel noninvasive optogenetic
tools to manipulate AC and spindle oscillations (Aim 1). Then, we will examine whether NIRW-AC and
NIRW-PDE bi-directionally modulate the progression of AD–related neuropathology and cognitive
decline via their actions re: spindle wave regulations (Aim 2). Upon completion of this project, we will
have developed genetically encoded NIRW-light activated tools, allowing noninvasive manipulation in
deep brain regions of live animals. Results are expected to provide a sound basis for investigation in
disease models that involve spindle wave and cAMP aberrations, such as AD, and suggest novel non-
invasive intervention strategies to counteract brain dementias caused by AD.

## Key facts

- **NIH application ID:** 10392484
- **Project number:** 5R21AG072803-02
- **Recipient organization:** UNIVERSITY OF WYOMING
- **Principal Investigator:** Mark Gomelsky
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $180,625
- **Award type:** 5
- **Project period:** 2021-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10392484

## Citation

> US National Institutes of Health, RePORTER application 10392484, Delaying cognitive decline in mouse models of Alzheimer's disease via near-infrared light optogenetics (5R21AG072803-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10392484. Licensed CC0.

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