Glutamate-mediated antidepressant effects of Jieyu I formula via modulation of PFCCaMKII-LHbCaMKII/GABA circuitry in lipopolysaccharide-induced depression model.

ETHNOPHARMACOLOGICAL RELEVANCE: Jieyu I Formula (JY-I) is an improved version of the classic formula "Sini San" documented in the books Shanghan Lun, which is known for regulating the liver and treating depression. However, the disturbance of neuronal signal transmission in the neural circuit of the brain is closely related to the occurrence of depression, yet its neural mechanism is still unclear.

AIM OF THE STUDY: This study aimed to observe the antidepressant effect of JY-I on depressed mice induced by lipopolysaccharide and its underlying central nervous system mechanisms, focusing on the prefrontal cortex (PFC) to lateral habenular nucleus (LHb) neural circuit in the depressed mice model.

MATERIALS AND

METHODS

JY-I comprised herbs include Bupleurum chinense, Fructus Aurantii, Paeonia lactiflora, Lotus Seed Heart, Schisandra chinensis, and Hypericum perforatum, which are prepared in a ratio of 2:2:2:2:1:1. The mouse model of depression was induced by lipopolysaccharide. The antidepressant efficacy of JY-I was observed by behavioral tests. Observation of the PFC/LHb neuron activity in mice using in-vivo electrophysiological combined with optogenetic technology. Subsequently, the activity of the LHb neuron was observed using immunofluorescence staining analysis and Western blot. Inject Rabies virus into the LHb brain region and observe the projection of the PFC from upstream brain regions received by the LHb. Using chemogenetic techniques to activate/inhibit the PFC-LHb neural circuit and investigate the effect of JY-I on depression-like behaviors.

RESULTS

Depression-like behaviors in mice can be induced by intraperitoneal administration of lipopolysaccharide, the behavior changes were reversed with the administration of the JY-I. The combination of optogenetics and electrophysiological recording result indicates that JY-I activates glutamate (Glu) neurons in the PFC, thus maintaining an optimal excitatory/inhibitory (E/I) balance and ameliorating depression-like behaviors. Notably, the PFC, a crucial brain area for emotion regulation, exerts its antidepressant effect on downstream LHb region through the activation of Glu neurons.

CONCLUSIONS

JY-I can significantly improve lipopolysaccharide-induced depression-like behaviors. JY-I exerts antidepressant effects by activating the PFC Glu neurons projecting to the LHb, revealing a promising therapeutic target for depression.