# Role of Cholecystokinin in the Dentate Gyrus

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $461,401

## Abstract

Project Summary
The existence of active adult neurogenesis in mammals, including humans, suggests striking structural plasticity
and regenerative capacity within the mature nervous system. Adult-born granule cells (GCs) derived from radial
neural stem cells (rNSCs) within the dentate gyrus (DG) have been shown to play a critical role in specific forms
of memory. Impaired memory, commonly associated with Alzheimer’s disease (AD), correlates with impaired
rNSC behavior and hippocampal neurogenesis in AD mouse models and human patients, likely due to lack of
permissive niche environment to support neurogenesis. Therefore, identifying critical niche components capable
of maintaining NSCs and promoting sustainable neurogenesis will enable development of novel strategies to
enhance functional repair from endogenous NSCs.
 Increasing evidence from human studies have provided tremendous support for the alterations of
cholecystokinin (CCK) system in AD patients. Despite these promising findings, the functional role of CCK in
heathy and AD brains remains unknown. Our goal is to explore the unprecedented role of endogenous CCK in
regulating neurogenic niche and neurogenesis in normal and AD mice. This proposal is built upon a series of
our recent findings. Specifically, we found that stimulating DG CCK interneurons to increase CCK level in the
DG provides a permissive niche environment to support rNSC proliferation and production of proliferating
progeny through the trophic effects of CCK on dentate astrocytes in promoting their glutamatergic
gliotransmission. In contrast, reducing dentate CCK disrupts neurogenic niche by inducing reactive astrocytes
and neuroinflammation, which correlates with decreased activation of rNSCs and production of proliferating
progeny, suggesting an anti-inflammatory role of CCK in DG. Interestingly, 5xFAD mice exhibit dystrophic CCK
neurites and reduced dentate proCCK expression, which correlates with reactive astrocytes, impaired
neurogenesis, and memory deficits. These data suggest that AD pathology may interact with dentate CCK
interneurons to impact various functional aspects associated with DG. These interesting findings sparked the
following directions we would like to pursue. Aim 1 is to test the hypothesis that dentate astrocytes mediate CCK-
dependent regulation of NSCs and neurogenesis through glutamatergic gliotranmission from astrocytes; Aim 2
is to test the hypothesis that reduced dentate CCK impairs NSC proliferation and neurogenesis through reactive
astrocytes mediated interferon-γ signaling onto NSCs; Aim 3 is to test the hypothesis that increasing dentate
CCK restores impaired neurogenic niche, neurogenesis, and memory in 5xFAD mice.

## Key facts

- **NIH application ID:** 10185194
- **Project number:** 1R01NS121300-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Juan Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $461,401
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185194

## Citation

> US National Institutes of Health, RePORTER application 10185194, Role of Cholecystokinin in the Dentate Gyrus (1R01NS121300-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10185194. Licensed CC0.

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