The Circadian Rhythms Of ATP Release In The Medial Prefrontal Cortex And A Preliminary Study Of Its Correlation With Depressive-like Behaviors

According to the World Health Organization,by 2020,major depressive disorder(MDD)will become the second most common disease next to cardia-cerebrovascular disease and afflict approximately 17%of the population worldwide.However,the mechanisms behind depression are still unknown,and most antidepressants pose clinical challenges.Our previous studies indicate that ATP released by astrocytes in the medial prefrontal cortex(mPFC)produces rapid antidepressant effects,highlighting the importance of the gliotransmitter in emotional diseases.And our research further uncovers the change of circadian rhythms of ATP is correlated with depressive-like behaviors.To address this issue,firstly,with the use of in vivo microdialysis,we found rhythmic release of ATP in the mPFC of C57BL/6J mice.The circadian rhythm of ATP release peaked twice a day in the mPFC,with a peak-to-peak interval of around 14.67±0.73 hours(h).The peaks of ATP rhythm appeared abruptly during the alternation of day and night.Then,to see if light exposure plays any role in the circadian rhythm of ATP release,we conducted microdialysis under total darkness and found that the circadian rhythm of ATP release in the mPFC was largely unaltered,suggesting that light exposure had little effect on the rhythm of ATP release.We went on to explore whether the circadian release of ATP was altered in mice with depression-like behaviors.C57 mice were subjected to chronic social defeat stress(CSDS)and divided into susceptible and unsusceptible groups.Microdialysis were performed on susceptible,unsusceptible and control mice.We found that the circadian rhythms of ATP release were similar between unsusceptible and control mice,with a peak-to-peak interval of around 13.33±1.36h and 12.00±0.67h respectively.In susceptible mice,however,circadian rhythms of ATP release were largely undetectable,suggesting a correlation between circadian release of ATP in the mPFC and depressive-like behavior.Similar results were also observed in IP3R2 knockout mice,which displayed depressive-like behavior in the forced swimming test and sucrose preference test and a lack of rhythm of ATP release in the mPFC,further demonstrating a correlation between circadian release of ATP and depressive-like behavior.To sum up,we discovered the circadian rhythm of ATP release in the mPFC was independent of light exposure but closely correlated with depressive-like behavior.