Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking

Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or neuronal ensembles in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify anti-craving relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of originally, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or excitatory overdrive. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting inhibitory underdrive. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory overdrive and inhibitory underdrive likely underlies EEs anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.