Role of hippocampal HCN Channels in social avoidance

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.