Dopamine-Mediated Major Depressive Disorder in the Neural Circuit of Ventral Tegmental Area-Nucleus Accumbens-Medial Prefrontal Cortex: From Biological Evidence to Computational Models

Yuanxi Li; Bing Zhang; Xiaochuan Pan; Yihong Wang; Xuying Xu; Rubin Wang; Zhiqiang Liu

doi:10.3389/fncel.2022.923039

Dopamine-Mediated Major Depressive Disorder in the Neural Circuit of Ventral Tegmental Area-Nucleus Accumbens-Medial Prefrontal Cortex: From Biological Evidence to Computational Models

Front Cell Neurosci. 2022 Jul 22:16:923039. doi: 10.3389/fncel.2022.923039. eCollection 2022.

Authors

Yuanxi Li^{1

2}, Bing Zhang^{3

4}, Xiaochuan Pan¹, Yihong Wang¹, Xuying Xu¹, Rubin Wang¹, Zhiqiang Liu^{3

5}

Affiliations

¹ Institute for Cognitive Neurodynamics, School of Mathematics, East China University of Science and Technology, Shanghai, China.
² Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
³ Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Anesthesia and Brain Function Research Institute, Tongji University School of Medicine, Shanghai, China.

Abstract

Major depressive disorder (MDD) is a serious psychiatric disorder, with an increasing incidence in recent years. The abnormal dopaminergic pathways of the midbrain cortical and limbic system are the key pathological regions of MDD, particularly the ventral tegmental area- nucleus accumbens- medial prefrontal cortex (VTA-NAc-mPFC) neural circuit. MDD usually occurs with the dysfunction of dopaminergic neurons in VTA, which decreases the dopamine concentration and metabolic rate in NAc/mPFC brain regions. However, it has not been fully explained how abnormal dopamine concentration levels affect this neural circuit dynamically through the modulations of ion channels and synaptic activities. We used Hodgkin-Huxley and dynamical receptor binding model to establish this network, which can quantitatively explain neural activity patterns observed in MDD with different dopamine concentrations by changing the kinetics of some ion channels. The simulation replicated some important pathological patterns of MDD at the level of neurons and circuits with low dopamine concentration, such as the decreased action potential frequency in pyramidal neurons of mPFC with significantly reduced burst firing frequency. The calculation results also revealed that NaP and KS channels of mPFC pyramidal neurons played key roles in the functional regulation of this neural circuit. In addition, we analyzed the synaptic currents and local field potentials to explain the mechanism of MDD from the perspective of dysfunction of excitation-inhibition balance, especially the disinhibition effect in the network. The significance of this article is that we built the first computational model to illuminate the effect of dopamine concentrations for the NAc-mPFC-VTA circuit between MDD and normal groups, which can be used to quantitatively explain the results of existing physiological experiments, predict the results for unperformed experiments and screen possible drug targets.

Keywords: Hodgkin-Huxley (HH) model; NAc-mPFC-VTA circuit; dopamine; dynamical receptor binding model; major depressive disorder.