# Role of hippocampal HCN Channels in social avoidance

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2024 · $393,981

## Abstract

Contact PD/PI: Kim, Chung Sub
Abstract
Social stress in humans increases the risk of mental health problems. Individuals who experience physical and/or
emotional bullying display anxiety, depression, and social avoidance. Despite the gender differences and
individual variance in stress-related mental disorders, most preclinical research on the effects of social stress
has been conducted on male subjects. Chronic social defeat stress (CSDS) is a rodent model of psychosocial
stress that causes fear-based social avoidance and anhedonia. We have developed direct physical (i.e., inter-
male and inter-female aggression) and witnessing mouse models of social avoidance. Using male and female
mouse models of social avoidance, we find that hyperpolarization-activated cyclic nucleotide-gated nonselective
cation (HCN) channels are increased in the dorsal hippocampus of susceptible male and female mice. Moreover,
the levels of HCN protein expression and hyperpolarization-activated current (Ih) are higher in susceptible female
mice than in susceptible male mice. Notably, behavioral responses to social defeat are different between male
and female mice. Consistent with these preclinical findings, HCN1 mRNA expression in isolated CA1 areas is
elevated in human patients with major depressive disorder. We hypothesize that hippocampal HCN channels
mediate sex-dependent behavioral coping and individual differences in social avoidance. To test this hypothesis,
we propose three specific aims. In Aim 1, we will test the hypothesis that the changes in neuronal activity
mediated by the HCN channels in the hippocampal CA1 neurons affect behavioral susceptibility and resilience
to social defeat. In Aim 2, we will test the hypothesis that the HCN channels in the hippocampal CA1 neurons
affects sex differences in behavioral coping with social defeat and individual differences in social avoidance. In
Aim 3, we will test the hypothesis that estradiol promotes sex-dependent behavioral susceptibility and passive
coping with social defeat through HCN channels. Together, the results are expected to provide insights into the
novel molecular and cellular mechanisms underlying dendritic HCN channels that regulate stress coping and
individual differences in social defeat and offer novel therapeutic targets for stress-related mental disorders.

## Key facts

- **NIH application ID:** 10990378
- **Project number:** 1R01MH134958-01A1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Chung Sub Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,981
- **Award type:** 1
- **Project period:** 2024-07-10 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10990378

## Citation

> US National Institutes of Health, RePORTER application 10990378, Role of hippocampal HCN Channels in social avoidance (1R01MH134958-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10990378. Licensed CC0.

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