Medial prefrontal Cortex, dopamine and glutamate modulation in regulating Reward-Seeking and frustration responses

Behavior is often reinforced by rewarding experiences, which promote actions that yield positive outcomes contributing to adaptive decision-making. However, the absence of an anticipated reward can provoke negative emotional responses, such as frustration and anxiety, potentially leading to maladaptive behaviors. Understanding how the brain responds to reward and its omission is a growing focus in neuroscience, especially regarding how neurotransmitter systems in key circuits manage unmet expectations. The medial prefrontal cortex (mPFC), a central integrative hub, regulates downstream regions to process both rewarding and aversive outcomes. Although dopamine is known to guide reward prediction and adaptive behavior, the specific roles of dopaminergic and glutamatergic pathways in the mPFC remain unclear.

In this study, we investigated the influence of mPFC and the differential roles of dopaminergic D2 and NMDA receptors within the mPFC on reward-seeking behaviors using a cued sucrose-seeking task.

Our results show that D2 dopamine receptor and NMDA receptor activity in the mPFC are essential for maintaining reward-seeking behaviors when expected rewards are omitted, highlighting dopamine and glutamate's role in sustaining reward-persistent behavior. Conversely, only D2 blockade into mPFC affected cue-reward seeking behavior. Solely NMDA blockage in the mPFC and mPFC silencing reduced anxiety, suggesting a nuanced role for mPFC and glutamatergic signaling in managing the emotional response to unmet expectations.

These findings provide new insights into how distinct neurotransmitter systems in the mPFC and mPFC itself contribute to the behavioral and emotional adjustments following reward and reward omission.