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Biol. Psychiatry, Apr 08 2025, S0006-3223(25)01113-8 | https://doi.org/10.1016/j.biopsych.2025.03.025
Hyperpolarization-activated channel 1 modulates resilience and susceptibility to social avoidance induced by witnessing social defeat stress
Jiwon Kim, Sandali Michael, Kritika Pokharel, Chung Sub Kim
Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
Corresponding Author to Chung Sub Kim, Ph.D
Department of Neuroscience & Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
Corresponding Author to Chung Sub Kim, Ph.D
Abstract
Background
Physical social defeat stress models are widely used to study chronic stress. In contrast, witnessing social defeat, observing aggression without direct involvement, is less studied but has growing relevance to disorders such as post-traumatic stress disorder (PTSD). The role of hyperpolarization-activated cation channel 1 (HCN1) in stress responses to witnessing social defeat is unclear, and the effects of prolonged exposure (PE) therapy, commonly used in PTSD treatment, have not been tested in this context.
Methods
Male mice were either subjected to chronic physical or witnessing social defeat stress. Behavioral assessments included measures of social avoidance, stress reactivity, fear memory, and spatial working memory. Neuronal excitability, h current (Ih), and synaptic transmission in dorsal hippocampal CA1 neurons were measured using whole-cell patch-clamp recordings. Conditional overexpression or deletion of HCN1 was employed to further examine its role. Witnessing-defeated mice underwent 12 days of PE treatment.
Results
Mice that witnessed social defeat exhibited behavioral impairments like physically defeated mice, showing changes in social behavior, fear memory, spatial working memory, and stress responses. These impairments were linked to increased HCN1 expression, elevated Ih, and reduced neuronal excitability. Overexpression of HCN1 induced susceptibility-like behaviors, while HCN1 deletion promoted resilience-like behaviors. Impaired AMPA receptor transmission at distal dendrites in witness-susceptible mice was replicated by HCN1 overexpression and reversed by ZD7288, an HCN channel blocker. PE-resistant mice displayed reduced excitability, while PE-responsive mice exhibited normal-like excitability.
Conclusions
HCN1 channels play a key role in regulating stress responses and contribute to resilience or susceptibility following social defeat.
Physical social defeat stress models are widely used to study chronic stress. In contrast, witnessing social defeat, observing aggression without direct involvement, is less studied but has growing relevance to disorders such as post-traumatic stress disorder (PTSD). The role of hyperpolarization-activated cation channel 1 (HCN1) in stress responses to witnessing social defeat is unclear, and the effects of prolonged exposure (PE) therapy, commonly used in PTSD treatment, have not been tested in this context.
Methods
Male mice were either subjected to chronic physical or witnessing social defeat stress. Behavioral assessments included measures of social avoidance, stress reactivity, fear memory, and spatial working memory. Neuronal excitability, h current (Ih), and synaptic transmission in dorsal hippocampal CA1 neurons were measured using whole-cell patch-clamp recordings. Conditional overexpression or deletion of HCN1 was employed to further examine its role. Witnessing-defeated mice underwent 12 days of PE treatment.
Results
Mice that witnessed social defeat exhibited behavioral impairments like physically defeated mice, showing changes in social behavior, fear memory, spatial working memory, and stress responses. These impairments were linked to increased HCN1 expression, elevated Ih, and reduced neuronal excitability. Overexpression of HCN1 induced susceptibility-like behaviors, while HCN1 deletion promoted resilience-like behaviors. Impaired AMPA receptor transmission at distal dendrites in witness-susceptible mice was replicated by HCN1 overexpression and reversed by ZD7288, an HCN channel blocker. PE-resistant mice displayed reduced excitability, while PE-responsive mice exhibited normal-like excitability.
Conclusions
HCN1 channels play a key role in regulating stress responses and contribute to resilience or susceptibility following social defeat.
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-04-20)
- 국외 연구진
- 생명과학 > 신경생물학
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