Abstract Body: Mental stressors such as family separation and social isolation (SI) cause emotional and social stress which are the risk factors for both atrial fibrillation (AF) and abnormal behaviors. However, the underlying mechanisms of these stress-evoked abnormalities remain unclear. Our group recently revealed a critical role of stress-activated kinase JNK2 in AF and anxiety under stressed conditions.

Based on our pilot findings, we investigate the role of cardiac JNK2 in driving both AF risk and abnormal behaviors via a heart-brain talk.

We employed two unique mouse models: cardiac-specific JNK2dn (overexpressing inactive dominant-negative JNK2 to inhibit endogenous cardiac JNK2) and neuron-specific MKK7D-NuCre (with tamoxifen-induced MKK7D to activate neuronal JNK2). Retired breeder (RB) or group housed (5 mice/cage) naïve wildtype (WT) and JNK2dn mice were single housed (social isolation, SI) for up to 4 and 12 weeks (wks). Anxiety (digging, cornering) and aggressive (fighting, mounting) behaviors were assessed using resident-intruder and open field tests before and after 4wk or 12wk SI. AF inducibility (episodes/attempt/animal) was assessed using our optimized pacing protocol.

At baseline, WT-RB had longer durations of aggression (28±2 vs. 17±3s; n=8,7; p<0.05) and anxiety behaviors (105±7 vs. 17±4s; n=8,7; p<0.001) than age-matched non-SI naïve controls. After 4 and 12wks of SI, WT-RB mice showed a two-fold and eight-fold increase in aggression and anxiety, respectively, compared to non-SI naïve WT (n=8,7). Strikingly, WT-RB with 4 and 12wk-SI showed a progressively increased pacing-induced AF incidence vs. naïve controls (0.305±0.081 vs. 0 episodes, n=4,5; p<0.05). However, cardiac-specific JNK2 inhibition in 12wk-SI JNK2dn-RB mice (n=5) eliminated not only AF but also aggressive and anxious behaviors as seen in WT-RB SI mice, suggesting a critical and unique role for cardiac JNK2 in driving both AF and abnormal behaviors. In contrast, neuron-specific JNK2 activation in MKK7D-NuCre showed no AF but higher levels of aggression and anxiety than that of tamoxifen-treated WT littermates (n=7,5), suggesting activated neuronal JNK2 drives abnormal behavior but not AF. Overall, we revealed for the first time that emotional stress (SI) leads to activated JNK2 in the heart, which drives both AF genesis and promotes anxiety and aggression via a heart-to-brain talk. JNK2 inhibition could be a promising therapeutic strategy for stress-induced AF and abnormal behaviors.