# Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $601,071

## Abstract

The serotonin (5HT) system has been widely implicated in the pathophysiology of stress-induced mood
disorders, such as anxiety and major depression. Selective serotonin reuptake inhibitors (SSRIs) are the most
widely used antidepressants for treating these disorders. Strongly linked to both mood disorders and the
efficacy of SSRI treatment is the regulation of adult hippocampal neurogenesis, a process of generating new
neurons from neural precursor cells (NPCs) in the adult dentate gyrus (DG). Importantly, stress, mood
disorders, and SSRI treatment have all been shown to alter the 5HT system and influence adult hippocampal
neurogenesis, suggesting that 5HT signaling is critical for regulating this process. Currently, we have limited
understanding of serotonergic regulation of adult hippocampal neurogenesis, largely due to the broad action of
5HT on the neurogenic niche and lack of information on the expression patterns of 5HT receptors in adult-born
cells. Identification of cell-type specific expression of 5HT receptors is challenging because 5HT is capable of
binding to 14 distinct 5HT receptor subtypes. To fill these gaps in our understanding, we performed preliminary
studies and demonstrated that functional 5HT1A receptors (5HT1ARs) are expressed early in adult NPCs,
including type 1 neural stem cells and type 2a early neural progenitors. Strikingly, the functional 5HT1ARs in
NPCs are only found in female (but not male) mice. Supporting sex-dependent expression of 5HT1ARs in
NPCs, we found that selective deletion of 5HT1ARs in adult NPCs leads to a significant reduction of newborn
cells derived from NPCs only in females (not males). These results suggest that expression of 5HT1ARs in
NPCs are required for proper lineage progression of NPCs in a sex-dependent manner. These interesting
findings sparked several immediate directions we propose to pursue: In Aim 1, we will examine cell-autonomous and sex-dependent contributions of 5HT1ARs to early neurogenic responses induced by external
and serotonergic circuit stimuli; In Aim 2, we will investigate the causal role of membrane potential in regulating
development of normal and 5HT1AR-deficient adult NPCs; In Aim 3, we will examine the role of 5HT1AR-deleted newborn neurons in hippocampal network activity and hippocampus-dependent behavior.

## Key facts

- **NIH application ID:** 9945127
- **Project number:** 1R01MH122692-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Juan Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $601,071
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9945127

## Citation

> US National Institutes of Health, RePORTER application 9945127, Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function (1R01MH122692-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9945127. Licensed CC0.

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