Cannabinoid-dependent depotentiation remodels habenula synaptic homeostasis during chronic stress and prevents depression-like behaviors in stressed mice

Stress allostasis is the active process of adapting to stressors, thus becoming essential for maintaining emotional homeostasis, whose dysfunction may lead to depression onset (allostatic overload). However, it remains unclear how synapses remodel in key emotion-related brain circuits during stress allostasis and how they dynamically evolve and lead to stress allostatic overload (e.g. depression) during chronic stress. Given the pivotal role of lateral hypothalamus (LH) to lateral habenula (LHb) synapses in stress information processing, here, we suggested that LH-LHb synaptic plasticity might serve as a neural substrate of stress allostasis. Male C57BL/6J mice were used for all experiments. In vitro whole-cell electrophysiology was applied for measurements of synaptic transmission onto the LHb in mice received restraint stress (RS) and social defeat stress (SDS). Western blot, immunohistochemistry staining and in vivo fiber photometry were used to detect endocannabinoid synthesis and release. Behavioral testing, such as open field test (OFT), forced swim test (FST) and sucrose preference test (SPT), were used for depression-like behavior testing. LHb neurons exhibit synaptic depotentiation which naturally and recurrently occurs following synaptic potentiation induced by daily exposure to stress. Chronic stress facilitates synaptic potentiation and dampens depotentiation specifically at LH-LHb synapses via selective inhibition of endocannabinoid (eCB) synthesis, thereby leading to an irreversible potentiated state in LHb (allostasis overload). Interventions with cannabinoid replenishment or optogenetic stimulation prevent depression-like behaviors via enhancing synaptic depotentiation at LH-LHb afferent. Our study reveals that eCB-dependent depotentiation at LH-LHb synapses serves as a circuit-specific mechanism contributing to stress allostasis and provides a foundation for future investigations to depression-like behaviors.