Computational Modeling of the LHb-VTA Pathway in Major Depression Disorder

Major depression disorder (MDD) is a prevalent but severe psychiatric disorder, yet it is unclear how MDD is induced. Recently, accumulated evidence of in vivo animal experiments suggested that the lateral habenula (LHb) might play an important role in regulating the brain's dopamine (DA)ergic mechanism. Some abnormal changes and activities in the LHb region may lead to the excessive inhibition of the downstream DAergic neurons and thus induce MDD symptoms. However, how these abnormalities in the LHb cause the excessive inhibition of the DAergic neurons is still not clearly demonstrated. In this paper, we built a computational model for the pathway between the LHb and the ventral tegmental area (VTA) to simulate the different neurophysiological processes with the LHb regulation in healthy and MDD individuals. From the simulation results of the LHb-VTA pathway model we found that both the firing pattern conversion of the LHb neuron from regular tonic to burst, and the overexpression of Kir channel proteins on the LHb astrocyte membrane could more strongly inhibit the VTA DAergic neuron, which corresponds to the experimental results of previous in vivo animal studies. Our model and simulation results may shed light on future studies to further understand the pathology of MDD.