# Enhancing adult-born neurons to restore brain functions in Alzheimer's disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $714,945

## Abstract

Project Summary
 Patients with Alzheimer’s disease (AD) exhibit progressive memory loss, depression, and anxiety,
accompanied by impaired adult hippocampal neurogenesis (AHN). Although young adult-born neurons (ABNs)
have been shown to play an important role in memory and emotion processing under physiological conditions,
their function and therapeutic potential in degenerated AD brains remain largely undefined. A long-standing
question has been centering on whether AHN could be enhanced in otherwise impaired AD brains to restore
cognitive and affective functions. Our recent study showed that stimulating hypothalamic supramammillary
nucleus (SuM) exerts robust neurogenic effects in healthy wild-type (WT) mice. Specifically, chronic patterned
optogenetic stimulation of SuM leads to increased production of behaviorally-relevant ABNs with enhanced
developmental properties. Importantly, acute chemogenetic activation of these SuM-enhanced ABNs improves
memory performance and reduces anxiety-like behavior. We further tested this strategy in 5xFAD mice. Strikingly,
patterned SuM stimulation restores the number and developmental properties of ABNs and acute chemogenetic
activation of a small population of these SuM-enhanced ABNs (~500 ABNs/DG, <0.05% total granule cells/DG)
is sufficient to restore memory and reduce anxiety/depression-like behaviors in AD mice. These findings highlight
the therapeutic potential of enhanced ABNs (number, quality, and activity) in functional restoration in AD. Building
upon these findings, we propose the following aims to decipher the mechanisms underlying these beneficial
effects mediated by activation of SuM-enhanced ABNs using two complementary AD mouse models. Aim 1 will
determine the functional properties of SuM-enhanced ABNs and the molecular regulators underlying SuM-
mediated enhancement of neurogenesis in AD mice. Aim 2 will determine activity-dependent contribution of
SuM-enhanced ABNs to local hippocampal circuit and brain-wide network dynamics in AD mice. Aim 3 will
determine the effects of SuM-enhanced ABN activation on microglia properties, AD pathology, and hippocampal
function in AD mice.

## Key facts

- **NIH application ID:** 10906982
- **Project number:** 5R01AG084207-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Juan Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $714,945
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906982

## Citation

> US National Institutes of Health, RePORTER application 10906982, Enhancing adult-born neurons to restore brain functions in Alzheimer's disease (5R01AG084207-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10906982. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*