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Region-specific dysregulation of endocannabinoid system in learned helplessness model of depression

Supplemental Digital Content is available in the text. Researches have indicated that the endocannabinoid system (ECS) plays a crucial role in pathophysiology of depressive disorder. However, both hypo- and hyperfunction of the ECS were reported in depressive patients or animal models of depression. We proposed that the dual functional changes of the ECS in depression might be due to its region-specific dysregulation. Therefore, we investigated the mRNA expression of genes coding for the components of the ECS in the key depression-associated brain regions of the mouse learned helplessness model of depression. We found that in the mPFC, mRNA of transient receptor potential vanilloid type 1 (TRPV1) was significantly decreased in learned helplessness-resilient mice, whereas diacylglycerol lipases-α (DAGL-α) was decreased in both learned helplessness and learned helplessness-resilient mice. In the hippocampus, a significant increase of DAGL-α was observed in learned helplessness-resilient mice. In the amygdala, G-protein-coupled receptor 55 (GPR55) and DAGL-α were significantly decreased in both learned helplessness and learned helplessness-resilient mice. Meanwhile, fatty acid amide hydrolase (FAAH) was significantly decreased only in learned helplessness-resilient mice. In the LHb, the GPR55 was significantly decreased in both learned helplessness and learned helplessness-resilient mice, whereas the DAGL-β and FAAH were significantly downregulated only in learned helplessness-resilient mice. Therefore, our study reveals novel implications of the ECS in the development of depression-like or depression-resilient behaviors and discloses a region-specific manner of the ECS dysregulation by learned helplessness stress, suggesting that brain region-specific strategy might be necessary for the ECS to be intervened for the precise treatment of depression.