Modulation of comorbid depression of neuropathic pain by dopamine input from VTA to the ventral hippocampus

Background: Chronic pain syndrome is a devastating disorder with poor clinical treatment. The circuitry and molecular mechanisms for depression comorbid with chronic pain are thus far unclear. We characterized the projection from the ventral tegmental area (VTA) to the ventral hippocampus (vHPC) and assessed the functional significance of the pathway in chronic pain-induced depressive comorbidity. Methods: A neuropathic cuff model was adopted and discriminated against the susceptible and resilient groups with or without depression-like behaviors, respectively. The anatomical feature and function of the VTA-vHPC pathway were assessed by tracer and virus-based tracing, immunofluorescent staining, fluorescence in situ hybridization (FISH), designer receptors exclusively activated by designer drugs (DREADDs), optogenetics, and ex vivo electrophysiology. Results: A group of medially-located dopaminergic (DAergic) neurons displayed few overlappings with the medial prefrontal cortex- or nucleus accumbens-projecting neurons, constituting the major projection from the VTA to the vHPC. The activity of vHPC-projecting DAergic neurons was downregulated in the susceptible group but not in the resilient group, as manifested by the decreased expression of tyrosine hydroxylase (TH), TH/FOS double-labeling, and excitability in retrogradely labeled VTA neurons. Chemogenetic activation of the pathway significantly improved depression rather than pain phenotype, but caspase 3-based ablation induced depression. Optogenetic activation of the VTA^DA-vHPC pathway produced similar anti-depressant effects in cuff animals in an equally D1 or D2 receptor-dependent manner. FISH and Western blotting disclosed a low-segregated expression of the D1 receptor in the pyramidal neurons and a highly-segregated expression of the D2 receptor in GABAergic neurons in vHPC, which underwent no change or upregulation following cuffing. Conclusion: Our results demonstrate a medially dominant VTA^DA projection to the vHPC. Reinforcement of this pathway can reverse the depression without affecting pain, thus providing insights into a connectivity-based strategy in the treatment of comorbid depression.