Brain-body Circuit by Which Midbrain Dopamine Neuronal Activity Modulates Splenic Immunity

Midbrain dopamine neurons are integral to central nervous system function, yet their influence on peripheral immunity remains underexplored. This study identifies a neural circuit connecting midbrain dopamine neurons to the spleen through the dorsal vagal complex (DVC) and celiac ganglion. Using DAT:Cre mice and Cre-dependent viral tracers, we demonstrated that midbrain dopamine neurons project to the DVC, where they form synapses and modulate neuronal activity. Electrophysiological recordings revealed that DVC neurons express D1-like and D2-like dopamine receptors, responding to dopamine with altered excitability. Chemogenetic activation of midbrain dopamine neurons induced dopamine release in the DVC and increased cFos expression in both the DVC and celiac ganglion, indicating enhanced neuronal activity along this circuit. Anterograde multi-transsynaptic tracing confirmed connectivity from the midbrain to the spleen via the celiac ganglion. Activation of this circuit resulted in reduced spleen weight as well as a significant decrease in naive CD4+ T-cell populations without affecting total T-cell numbers. These findings unveil a functional midbrain-DVC-celiac ganglion-spleen pathway, through which midbrain dopamine neurons modulate splenic immunity. This novel insight into the neural regulation of the immune system has important implications for diseases involving altered dopamine neurotransmission, highlighting potential targets for immunotherapeutic interventions. ### Competing Interest Statement The authors have declared no competing interest.