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Scientists reveal new circuit mechanisms underlying depression


A team headed by Prof.LI Xiaoming, executive vice dean of School of Medicine, made a major breakthrough in the study of depression. The study, published in the January 15th issue of Nature Medicine, found new molecular and circuit mechanisms mediating the pathogenesis of depression.

For the past five years the team has focused on a brain area called the amygdala. Postmortem brain analyses and imaging studies of depressed patients have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, how BLA-related neural circuits are involved in the pathogenesis of depression remains largely unexplored.

Researchers identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons in the nucleus accumbens (NAc), and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2NAc circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor. Knockdown of cannabinoid receptors in the CCKBLA-D2NAc circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2NAc circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects.

"There is still a long way to go in using medical cannabis for the treatment of depression, " said Prof. LI. "Our research suggests that cannabinoid receptors can be used as a biomarker for the diagnosis of depression. We have synthesized a clinical PET tracer for cannabinoid receptors in our lab, and relevant clinical studies are being carried out."

"The authors provide strong evidence for the important role of CB1-R expressed on BLA CCK+ glutamatergic neurons modulation in the response to severe stress," commented reviewers of Nature Medicine. "The work is likely to have a major impact on the conceptualization of major depressive disorder, stress neurobiology, and synaptic organization/function of BLA circuits." 

The study was funded by the National Natural Science Foundation of China and is one of the key projects of NSFC's "Major Research Plan for Emotion and Memory Neural Circuits Base".

Source: School of Medicine