# A 5-HTergic DRN vCA1 circuit and Alzheimer's disease

> **NIH NIH K99** · BAYLOR COLLEGE OF MEDICINE · 2024 · $111,911

## Abstract

PROJECT SUMMARY
Despite the tremendous efforts in Alzheimer’s disease (AD) research, we have not made much progress in
understanding the pathophysiology of AD or inhibiting/correcting AD-related behavioral symptoms. The recent
FDA-approved aducanumab demonstrated significant efficacy in reducing amyloid β (Aβ). Still, it showed a
limited effect in improving AD-related memory impairments. The specific neural circuits that mediate these
cognitive processes but are altered progressively in the AD brains may serve as a treatment target after the
removal of Aβ plaques. In my previous studies, I demonstrated that dorsal Raphe nucleus (DRN) serotonin (5-
HT) neurons provide monosynaptic inputs to the hippocampal ventral CA1 (vCA1). Further, genetic ablation of
5-HT synthesis selectively in these vCA1-projecting DRN neurons impaired spatial memory in young mice. In
addition, genetic deletion of the 5-HT 2C receptor (5-HT2CR) in the vCA1 led to spatial memory deficits in young
mice. I also observed that lorcaserin, a selective agonist of 5-HT2CR, can ameliorate spatial memory deficits in
a 6-month-old knock-in AD mouse model (APPNL-G-F), associated with restoration of synaptic plasticity in vCA1
neurons. Together, I developed a hypothesis that a 5-HTergic DRN to vCA1 circuit regulates spatial memory via
5-HT2CR, a therapeutic target for memory symptoms in Alzheimer’s disease. The K99 phase will focus on the
upstream node of this circuit, the vCA1-projecting 5-HT neurons. Fiber photometry experiments will be used to
monitor the real-time activity of these vCA1-projecting 5-HT neurons, as well as 5-HT release in the vCA1,
corresponding to memory acquisition and retrieval behaviors. The intersectional retrograde chemogenetic
approach will be used to further test whether inhibition of the vCA1-projecting 5-HT neurons would inhibit memory
function and whether activating these neurons would rescue memory impairments in APPNL-G-F mice and aged
mice. During the R00 phase, I will utilize the techniques and the problem-solving experience I acquire from the
K99 phase to test the functional significance of the downstream 5-HT2CR-expressing vCA1 neurons. I will use
fiber photometry to monitor the activity of 5-HT2CR-expressing vCA1 neurons during the memory test and will
use the chemogenetic approach to assess the functional relevance of these neurons in memory function. In
addition, I will also test the combination treatment of Aβ-lowering (aducanumab) and 5-HT2CR agonism
(lorcaserin) in APPNL-G-F mice and aged mice. The proposed studies will advance our knowledge of the circuitry
mechanisms underlying memory function and evaluate the possibility of 5-HT2CR agonism as a novel therapeutic
target for AD in combination with Aβ-reducing medications. In addition, the K99 phase will provide an ideal
training opportunity to equip me with essential techniques, knowledge, and problem-solving skills. These will
prepare me for the R00 phase of research and an independent resear...

## Key facts

- **NIH application ID:** 10888411
- **Project number:** 5K99AG078903-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hesong Liu
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $111,911
- **Award type:** 5
- **Project period:** 2023-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888411

## Citation

> US National Institutes of Health, RePORTER application 10888411, A 5-HTergic DRN vCA1 circuit and Alzheimer's disease (5K99AG078903-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10888411. Licensed CC0.

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