Impairment of episodic memory in an animal model of depression induced by chronic unpredictable stress

초록

Background Chronic stress occurs in everyday life and often results in depressive symptoms. Furthermore, clinical and preclinical studies indicated that cognitive dysfunction is related to major depressive disorder (MDD) (Raymond W Lam et al, 2014). Chronic unpredictable stress (CUS) is one of the animal behavior models for depression, which mimics daily-life stress in humans. Previous studies showed that CUS affect cognitive function as well as mood regulation (CO Bondi et al, 2008). However, it remains unclear that CUS may induce non-declarative or declarative memory dysfunction. Methods To investigate cognitive impairment in various memory forms in the animal depression model, we first exposed mice to 2-3 various stressors per day for 28 days (CUS). After CUS, we performed the forced swim test (FST) and sucrose preference test (SPT) to confirm induction of depressive-like phenotypes. Additionally, we performed three chamber sociability (or novelty) and elevated plus maze (EPM) tests to examine social dysfunction and anxiety-like behavior, respectively. Finally, we performed the WWW tasks (What Where When tasks) to investigate the CUS effect on episodic memory. Results. CUS successfully not only induced depressive, anxiety-like behaviors in FST, SPT, EPM tests but also decreased social preference and novelty. In particular, we separated the CUS group into stress-susceptible and stress-resilient based on SPT data. The CUS-susceptible group showed significantly increased depressive, anxiety-like behaviors in FST, SPT, EPM, but CUS-resilient group did not. Also, the CUS-susceptible group displayed decreased social preference compared to CUS-resilient and CUS-control groups. Additionally, we performed the optogenetics in the medial prefrontal cortex (mPFC) which is well known to a hub brain region for depressive-like behavior. We found phasic stimulation of mPFC is sufficient recovered depressive-like behavior. Finally, we investigated whether CUS induce dysfunction of episodic memory using the WWW tasks, and found that the CUS group showed a significant decrease in all of the WWW tasks. Conclusion These findings suggest that CUS, which causes depressive- and anxiety like-behaviors, can induce social and episodic memory dysfunction. Especially, the CUS-susceptible group showed dysfunction in emotional and social behaviors than the CUS-resilient group. We have plans to investigate the impairment of episodic memory in the CUS-susceptible vs. CUS-resilient groups and the relevant neural circuits to the dysfunction of cognitive function in the CUS model.