Cannabinoid Type 1 Receptors Regulate The Amygdala-accumbens Circuit And Are Involved In Depressive-like Behavior

Major depressive disorder(MDD)is one of the most common and debilitating neurobiological illnesses affecting about 17%of the world's population.MDD is characterized by diverse debilitating symptoms that include despair and social avoidance.However,the underlying biological mechanisms of MDD remain unclear.Basal lateral amygdala(BLA)has been extensively studied in regard to fear and anxiety.Despite evidence from human imaging studies implicating changes in volume,metabolism and valence response of the BLA in depressed patients.A major downstream target of the BLA is the nucleus accumbens(NAc).Activation of total excitatory BLA inputs into the NAc drives positive reinforcement,stimulating a specific part of the NAc-projecting BLA neurons can result in avoidance behavior.These results imply that within the BLA-NAc circuitry,there are at least two neural sub-circuits encoding opposite emotional valences.Cannabinoid type-1 receptors(CB1R)have been implicated in the regulation of mood and depression.Genetic deficiency in or antagonism of CB1R can cause an increase in depressive-like behavior.One well-known case is the anti-obesity drug rimonabant,a CB1R antagonist that increases the risk of severe depression among some users.In contrast,Synthetic cannabinoids with agonist activity of the central CB1R alleviate depressive-like symptoms in animal models.However,the neural circuit mechanism mediating maladaptive CB1R function in depression and the antidepressant effects of cannabinoids are unclear.Here,in mice,we found that the CCK neuropeptidergic neurons in the BLA were predominantly glutamatergic,long-projecting and excitatory,selectively targeting D2 MSNs in the NAcc.Optogenetic manipulation of the CCKBLA-D2NAcc circuit drives negative behavior and disrupts positive reinforcement.To examine whether CCKBLA-D2NAcc circuit exhibits aberrant physiological adaptations in depression,we employed a 10-day chronic social defeat stress(CSDS)-induced depression model and found that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice.Of note,3-day inhibiting BLA CCK neuronal outputs to the NAcc in susceptible mice ameliorated depressive-like behavior and artificially driving activity in this circuit was sufficient to induce the depressive-like phenotype in a subthreshold social defeat stress(SSDS)paradigm.Interestingly,we found that CB1R is selectively expressed in the CCKBLA-D2NAc circuit and is reduced in the CCKBLA-D2NAcc circuit of susceptible mice following social stress.To investigate whether changes in CB1R are crucial to synaptic functions and stress susceptibility,we selectively knocked down CB1R in mice by using the Cre-dependent short-hairpin(sh)CB1R virus and found that knockdown of CB1R in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility.Notably,administration of synthetic cannabinoids in the NAc of susceptible mice to activate the residual CB1R was sufficient to produce antidepressant-like effects.Overall,our studies reveal the circuit and molecular mechanisms of depression.In summary,our study resolves the controversies regarding the valence coding of the BLA-NAc circuit,highlighting CCK as a molecular marker to define the valence of different BLA-NAc subcircuits.Importantly,our data establish CB1R in the CCKBLA-D2NAc circuit as a powerful determinant of depression.Moreover,marijuana has been known for its mood-elevating and euphoric effects for centuries,our study provides a novel circuitry-based mechanism for how marijuana exerts these anti-depression effects:by selectively activating the CB1R in the aversive CCKBLA-D2NAc circuitry to suppress its activity.Thus,our results may provide a fundamentally new framework for understanding the molecular and circuit mechanism of depression and shed important light on developing new antidepression treatments.