Hyperpolarization-Activated Channel 1 Modulates Resilience and Susceptibility to Social Avoidance Induced by Witnessing Social Defeat Stress

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 posttraumatic stress disorder (PTSD). The role of hyperpolarization-activated 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 subjected to either chronic physical stress or witnessing social defeat stress. Behavioral assessments included measures of social avoidance, stress reactivity, fear memory, and spatial working memory. Neuronal excitability, h current (I_h), and synaptic transmission in dorsal hippocampal CA1 neurons were measured using whole-cell patch-clamp recordings. Conditional overexpression or deletion of Hcn1 was used to further examine its role. Mice who witnessed social defeat underwent 12 days of PE treatment. Results: Mice that witnessed social defeat exhibited behavioral impairments similar to 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 I_h, 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.