Motivational Neural Circuitry and Epigenetic Regulation in a VR-Based Decision-Making Task

초록

Motivation is essential for goal-directed behavior and adaptive decision-making, yet its underlying neural and epigenetic mechanisms remain incompletely understood. To investigate these processes, we employed a virtual reality (VR)-based T-maze task in head-fixed mice, combined with two-photon calcium imaging to capture real-time neural dynamics. Mice were stratified into high- and low-motivation groups based on behavioral performance. The high-motivation group showed significantly elevated neural activity in the anterior cingulate cortex (ACC) during correct trials, a pattern not observed in the low-motivation group. Post-task immunohistochemistry revealed increased c-Fos expression in both the ACC and ventral tegmental area (VTA), indicating task-related activation of these regions. To further dissect the circuit-level underpinnings, we performed two-photon dopamine imaging, achieving single-cell resolution of dopamine signals in the ACC during task performance. Epigenetic profiling revealed a motivation-dependent increase in histone dopaminylation (H3K4me3Q5Dop) within the ACC of high-motivation mice. CUT&RUN assays identified genomic loci enriched with this modification. These findings suggest that motivated behavior engages specific dopaminergic circuits and is associated with distinct epigenetic signatures, offering new insights into the molecular substrates of cognitive engagement.