# Dysfunctional Orexin-Regulated Neural Circuits in Alzheimer's Disease

> **NIH NIH R03** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $156,000

## Abstract

Persons with Alzheimer's Disease (AD) experience spatial disorientation that emerges early in the disease
process. In both humans and rodent models of AD, dysfunction within the retrosplenial cortex (RSC), a crucial
locus for spatial navigation and memory, is observed prior to the onset of cognitive decline. Understanding the
mechanisms underlying RSC dysfunction is important to develop strategies aimed at improving spatial
navigation and memory in AD. We observe aberrant RSC network activity that includes reduced RSC rhythmic
synchrony during spatial navigation in a mouse model of AD, yet the cellular and molecular basis for these
defects are unknown. Here, using a newly developed mouse line, we identify a specific population of RSC
neurons that express the orexin 1 receptor (RSCOX1R) and are activated by the neuropeptide orexin. In WT
mice, direct stimulation of these RSCOX1R neurons enhances RSC synchrony, suggesting these neurons are an
important population in which to examine cellular mechanisms of AD-related RSC dysfunction, and to target for
therapeutic intervention. Orexin signaling affects numerous physiologic processes, including spatial memory,
and abnormalities in orexin signaling are implicated in AD pathology. Studies of specific orexin-regulated
memory circuits in AD is lacking, however. In this proposal, we examine whether RSCOX1R neurons are directly
altered in the 5xFAD model of AD (Aim 1). We also test the hypothesis that the activation of RSCOX1R neurons
or enhancement of orexin-signaling/regulation of RSC neurons can restore the AD-associated deficits in RSC
rhythmic activity (Aim 2). The completion of this work will pave the way for larger-scale follow up studies across
multiple models of AD, with the potential to identify novel RSC and orexin-based therapies aimed at
ameliorating a range of spatial memory and cognitive deficits in persons with AD.

## Key facts

- **NIH application ID:** 10372270
- **Project number:** 1R03AG070454-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Paulette B. Goforth
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2022-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372270

## Citation

> US National Institutes of Health, RePORTER application 10372270, Dysfunctional Orexin-Regulated Neural Circuits in Alzheimer's Disease (1R03AG070454-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10372270. Licensed CC0.

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