BIDIRECTIONAL NUCLEUS ACCUMBENS-MIDBRAIN CIRCUITS AND THEIR INVOLVEMENT IN ADAPTIVE REWARD PROCESSING

The bidirectional circuit linking medium spiny neurons (MSNs) in nucleus accumbens (NAc) and dopamine (DA) neurons in ventral tegmental area (VTA) is a central regulator of the brain's reward system. DA release in the NAc is associated with both reward motivation and consummation. The NAc consists primarily of inhibitory GABAergic MSNs, which can be subclassified by DA receptor expression, projection targets, or subregional location. NAc lateral shell MSNs of the “direct pathway” that express the excitatory DA receptor D1 and project to the VTA (NAc lat shell-VTA D1-MSNs) disinhibit VTA DA neurons by inhibiting local VTA GABAergic interneurons, thereby increasing DA activity. Although these NAc lat shell-VTA D1-MSNs generally encode reward, their precise contributions to specific aspects of reward processing remain unclear. Experiments in male C57BL/6 mice, using intersectional AAV vector strategies, indicate that a substantial proportion of midbrain-projecting NAc D1-MSNs also target the neighboring medial substantia nigra pars reticulata (medSNr) implicating it as a potential relay station between NAc and VTA. Using pathway specific DREADDs expression, our ongoing experiments aim to determine the effects of selectively stimulating NAc lateral shell D1-MSNs that project to the medSNr on: (1) conditioned place preference/aversion, along with underlying changes in activity across midbrain neuron populations assessed via c-Fos immunostaining. (2) DA release onto NAc lat shell D1-MSNs projecting to medSNr, as well as Ca²⁺ activity in VTA-NAc DA neurons recorded with dual-signal dual-fiber photometry, during operant reward motivation and consummation. Overall findings will advance understanding of the VTA-NAc signaling underlying adaptive reward processing.