# Defining the functional organization of cerebellar output circuits that control feeding behavior

> **NIH NIH R01** · SCINTILLON INSTITUTE FOR PHOTOBIOLOGY · 2022 · $428,564

## Abstract

Project Summary
How does the neuropathology in mouse models of Alzheimer’s disease (AD) influence the function of neural
circuitry? Preliminary data demonstrates distinctions in neuropathology severity in different brain regions of AD
mouse models. Three of these brain regions, the hypothalamus, hippocampus, and cerebellum, have well
characterized neural circuits that function in food intake. We have observed that the hippocampus and
hypothalamus contain a high density of Ab plaques and microglia markers in AD mouse models. While these
markers worsen with age, we observe virtually no Ab plaques or microglia in the cerebellum. Thus, because our
prior work has identified the structure, function and neural activity dynamics of feeding circuits in these three
regions, we have a rich experimental framework to assess the impact of these markers of neurodegeneration in
three distinct brain regions. We propose to examine the neural activity dynamics and function of circuits in these
regions during feeding behavior in different ages of AD mice in order to better understand a) how AD pathology
influences neural circuits and b) to identify the aspects of neural circuit function that are protected in the
cerebellum. This proposal will test these hypotheses through two aims. Aim 1 examines the neural activity
dynamics of hypothalamic, hippocampal and cerebellar feeding circuits in AD mice. Using deep-brain imaging of
genetically encoded calcium indicators, we aim to assess whether the absence of neuropathology in the
cerebellum of our AD mouse models preserves the neural activity pattern of cerebellar neurons and not
hypothalamic/hippocampal neurons during AD progression. We will determine the activity dynamics of
hypothalamic, hippocampal and cerebellar feeding circuits in response to feeding or gastric infusion of nutrients
in humanized APP-knockin (APP-KI) mice at 3, 6 and 9 months. Aim 2 assesses the ability of hippocampal,
hypothalamic and cerebellar circuit function in feeding control of AD mice. We will use optogenetic and
chemogenetic approaches to activate and inhibit feeding circuits in APP-KI mice. The ability of these circuits to
influence food intake and metabolic parameters in AD mice will be taken at 3, 6, and 9 months and will be
compared with non-AD controls. Through the examination of the activity and function of feeding circuits in the
context of AD pathogenesis, these aims build off our originally funded R01 to explore how well-defined behavioral
outputs and neural function are changed by the neuropathology that underlies AD. These experiments may lead
to further support for our hypothesis that the cerebellum represents a neuroprotected region in AD and aging.

## Key facts

- **NIH application ID:** 10499849
- **Project number:** 3R01DK124801-02S1
- **Recipient organization:** SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
- **Principal Investigator:** John Nicholas Betley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $428,564
- **Award type:** 3
- **Project period:** 2021-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499849

## Citation

> US National Institutes of Health, RePORTER application 10499849, Defining the functional organization of cerebellar output circuits that control feeding behavior (3R01DK124801-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10499849. Licensed CC0.

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