Motivational neural circuitry and epigenetic regulation in a VR-based decision-making task

초록

Motivation is essential for adaptive, goal-directed behavior, yet the mechanisms by which it is represented across neural circuits and molecular pathways remain incompletely understood. To investigate these processes, we employed a virtual reality–based T-maze in head-fixed mice, combined with two-photon calcium imaging to capture real-time neural dynamics. High motivational animals exhibited superior task performance, completing more trials with greater accuracy, accompanied by enhanced neuronal activity in the anterior cingulate cortex (ACC). Circuit mapping revealed selective engagement of the ACC–ventral tegmental area (VTA) pathway, indicating that motivated behavior recruits defined mesocortical dopaminergic circuits. Complementary real-time dopamine imaging further demonstrated trial-specific increases in dopaminergic signaling within the ACC, tightly correlated with task performance and motivational state. At the molecular level, motivated behavior was associated with a selective elevation of histone dopaminylation (H3K4me3Q5Dop) in the ACC, while other histone modifications remained largely unchanged. Genome-wide profiling of dopaminylated chromatin revealed enrichment of this mark at promoters of synapse-related genes, highlighting a potential link between neuromodulatory signaling and transcriptional regulation. Notably, the vesicular glutamate transporter Vglut1 exhibited motivation-dependent up-regulation, consistent with its promoter peak of dopaminylation. Together, these findings establish a multi-level framework in which dopaminergic input shapes neural activity, engages epigenetic regulation of synaptic gene programs, and connects motivational states to long-lasting molecular and synaptic adaptations.