# Uncharted Territory: Mapping and Manipulating Cholinergic Basal Forebrain Activity in a Mouse Model of Alzheimer's Disease

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2022 · $47,110

## Abstract

PROJECT SUMMARY
Alzheimer’s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the
United States. The most effective interventions for AD are pharmaceuticals that include acetylcholinesterase
inhibitors, which prevent the degradation of acetylcholine. While these treatments are capable of temporarily
improving the symptoms of disease, they do not halt or reverse AD progression. Several histopathological
hallmarks have been associated with AD, including formation of extracellular Aβ plaques, neurofibrillary tangles,
and accelerated degeneration of basal forebrain neurons (the primary source of acetylcholine in the brain). This
marked degeneration of the basal forebrain has been observed in human AD MRI studies and typically indicates
the advent of early disease. In fact, the degeneration of acetylcholine projecting, or cholinergic neurons in this
region that is believed to be an important underlying cause of the cognitive deficits that emerge as disease
progresses. However, human studies are limited, as we are not able to examine brain degeneration with cell
type specificity using currently available imaging modalities. This highlights an important gap in our
understanding of AD: it is unknown whether basal forebrain cholinergic neuron (BFCN) degeneration occurs in
an organized manner, nor how the extent of this degeneration correlates to cognitive deficits. Therefore, further
investigation of BFCNs in the context of AD is needed. This leads to our central hypothesis: that BFCN
signaling is adversely altered in a consistent temporal and spatial pattern, and that stimulating BFCN
activity will mitigate cognitive symptoms. The overarching goal of this project is to better characterize BFCN
signaling in the pathological context of AD. This will be examined through two primary aims, both of which utilize
the 5xFAD model of AD, a transgenic mouse model known for rapid manifestation of the AD phenotype and has
been shown to exhibit BFCN degeneration. Experiments proposed in Aim 1 will investigate longitudinal
alterations in BFCN circuitry by leveraging myriad targeted cellular manipulations to perform in vivo fMRI of
BFCN functional connectivity in awake mice, and to generate a timeline of molecular profiles for BFCNs using
TRAP-seq. Aim 2 will explore how artificially stimulating and silencing BFCNs influences cognitive function in
the context of AD. Together, these data will further our understanding of BFCN degeneration in AD and better
define the roles of BFCNs in cognition.

## Key facts

- **NIH application ID:** 10537906
- **Project number:** 1F30AG076265-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Benjamin Belfort
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $47,110
- **Award type:** 1
- **Project period:** 2023-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537906

## Citation

> US National Institutes of Health, RePORTER application 10537906, Uncharted Territory: Mapping and Manipulating Cholinergic Basal Forebrain Activity in a Mouse Model of Alzheimer's Disease (1F30AG076265-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10537906. Licensed CC0.

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