Title : Medial prefrontal cortex, dopamine and glutamate modulation in regulating reward-seeking and frustration responses
Abstract:
Adaptive behavior depends not only on learning from rewards, but also on the brain’s capacity to respond when expected rewards fail to occur. Reward omission is a powerful trigger of negative emotional states such as frustration and anxiety and is increasingly recognized as a key mechanism underlying maladaptive behaviors in neuropsychiatric and neurological disorders. The medial prefrontal cortex (mPFC) plays a central role in integrating reward expectations with emotional regulation, yet the specific contributions of its dopaminergic and glutamatergic signaling remain poorly understood. In this study, we investigated how dopamine D2 and NMDA receptor signaling within the mPFC regulates reward-seeking behavior and emotional responses under conditions of reward omission. Using a cued sucrose-seeking task, we show that intact D2 and NMDA receptor activity in the mPFC is critical for sustaining reward-seeking behavior when expected rewards are omitted, revealing a key mechanism supporting behavioral persistence in the face of negative prediction errors. In contrast, only D2 receptor blockade disrupted cue-driven reward-seeking behavior, indicating a selective role for dopaminergic signaling in cue–reward associations. Notably, selective NMDA receptor blockade and functional silencing of the mPFC reduced anxiety-like behavior following reward omission, dissociating motivational persistence from emotional reactivity. These findings highlight a nuanced and bidirectional role of the mPFC, in which dopaminergic and glutamatergic pathways differentially regulate motivation and affective responses when expectations are violated. Together, our results provide new mechanistic insight into how the prefrontal cortex orchestrates behavioral and emotional adaptation to unmet expectations. These findings have direct relevance for conditions characterized by impaired reward processing and maladaptive persistence, including depression, anxiety disorders, addiction, and neurodegenerative diseases affecting frontal circuits.
