Dissecting the effects of distinct VTA projections on peripheral immunity

The Ventral Tegmental Area (VTA) is a crucial component of the brain's reward system and is known to regulate motivated behaviour. Recent studies have shown that activation of VTA dopaminergic (DA) neurons can stimulate anti-bacterial and anti-tumour immunity, suggesting a potential link between mental states and an organism's immune response to disease. However, the specific mechanisms underlying these peripheral effects are still unclear. Given that VTA-DA neurons project to multiple brain regions, and each pathway promote different behaviour we considered that also the immune effects of each projection may be distinct. In this study, we employed neuronal tracing and retro-DREAD manipulations to investigate the relative contributions of VTA projections to the Nucleus Accumbens (NAc), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) in immune regulation. Our results reveal that each projection has distinct effects on the peripheral immune response to infection. Notably, the VTA-mPFC projections have an opposing effect on the anti-bacterial immune response compared to the projections from the VTA to the BLA. Surprisingly, the VTA projections to the NAc had a limited effect on the peripheral immune response, even though it is the most robust projection site that is innervated by the VTA neurons. We also examined the downstream anatomical connections of each projection, which shed light on the potential mechanisms generating the specific effects on the immunity. These findings provide a basis for understanding the role of VTA neuronal pathways in immune regulation and may have implications for developing diagnostic and therapeutic strategies for immune pathologies.