Neuroimmune Circuitry of Midbrain Dopamine Neurons

Congratulations to Drs. Adithya K Gopinath, and Michael Okun on the publication of “Neuroimmune Circuitry of Midbrain Dopamine Neurons,” which appears in the Journal of Pharmacology and Experimental Therapeutics June 2024.


Objective: Dopamine neuronal regulation of peripheral immunity has gained increased attention in neurodegenerative and neuropsychiatric diseases. Our prior studies and the literature suggest that activation or inhibition of midbrain dopamine neurons modulates the immune responses, mediated by catecholaminergic inputs to peripheral immune organs.

Knowledge Gap: The pathway(s) from midbrain to periphery by which dopaminergic neurons signal to peripheral immune organs is less understood.

Hypothesis: Based on the literature and our prior studies, we predicted that the dorsal vagal complex (DVC) mediates a ventral midbrain-to-periphery circuit for immune modulation.

Design and Methods: We employed multiple complementary approaches to map the neural circuitry between midbrain and DVC. DATcre animals received intracranial injections of Cre-dependent anterograde AAV expressing eGFP or mRuby-tagged Synaptophysin into the ventral midbrain. Brains were collected one month after injection and examined for eGFP or mRuby fluorescence in the DVC. Next, to determine whether DVC neurons can respond to dopaminergic inputs, we examined expression of DRD1 and DRD2 in the DVC, using DRD1cre and DRD2cre mice crossed to Ai9-TdTomato mice, resulting in red fluorescent cell bodies that express these receptors. Striatum and PFC projections were examined as positive control regions throughout.

Results: Our findings so far suggest that DAT+ midbrain dopamine neurons send projections to the DVC, as indicated by eGFP+ processes, and make synapses in the DVC, as indicated by mRuby-Synaptophysin puncta in the DVC. These processes originate in Cre-expressing midbrain neurons. In addition, we found DRD1+ neurons in the nucleus of the solitary tract (NTS) and DRD2+ neurons in the area postrema (AP), which are nuclei within the DVC. These findings indicate that not only do midbrain dopamine neurons send projections to and synapse onto the DVC, but also that the DVC expresses dopamine receptors necessary to respond to midbrain dopaminergic inputs.

Ongoing Studies: We will assess how optogenetic activation of midbrain dopamine terminals in the DVC modulates DVC neuron activity. In addition, using anterograde AAVs, we will map midbrain-to-DVC projections and the subsequent projections to peripheral immune organs such as liver, bone marrow, spleen, and thymus to identify immune compartments that may be modulated by dopamine neuronal activity.

Conclusions: These studies represent a transformative step investigating the mechanistic relationships between midbrain dopamine neuronal activity and peripheral immune responses, with broad implications for neurological and neuropsychiatric conditions where dopamine signaling has gone awry.