Food seeking suppression by environmental enrichment accompanies cell type- and circuit-specific prelimbic cortical modulation

Abstract Cues such as fast-food advertisements associated with food can provoke food cravings which may lead to unhealthy overeating. To effectively control such cravings, we need to better understand the factors that reduce food cue reactivity and reveal corresponding ‘anti-craving’ brain mechanisms. We previously reported that access to environmental enrichment (EE) that provides cognitive and physical stimulation in mice reduced cue-evoked sucrose seeking and prelimbic cortex (PL) neuronal reactivity. To date, the phenotype of PL neurons that undergo EE-induced adaptations has not been fully elucidated. Therefore, we used brain slice electrophysiology to investigate how EE modulated intrinsic excitability in the general population of PL interneurons and pyramidal cells. Additionally, we used retrograde tracing and the neuronal activity marker ‘Fos’ to investigate how EE modulated cue-evoked recruitment of pyramidal cells projecting to the paraventricular nucleus of the thalamus (PVT) and nucleus accumbens core (NAc). Before the cue-evoked sucrose seeking test, EE enhanced the general, baseline excitability of inhibitory interneurons, but not pyramidal cells, thereby promoting inhibitory ‘overdrive’. During cue-evoked sucrose seeking, EE suppressed recruitment of PVT-, but not NAc-projecting, neurons thereby selectively promoting corticothalamic, but not corticoaccumbens, excitatory ‘underdrive’. Collectively, we further illuminate EE’s ‘anti-food seeking’ actions whereby EE promotes both cell type-specific (inhibitory interneuron ‘overdrive’) and circuit-specific (excitatory corticothalamic ‘underdrive’) neuroadaptations in the PL. Competing Interest Statement The authors have declared no competing interest. Footnotes Conflict of interest: The authors declare no competing financial interests. Support: This research was supported by the UK Medical Research Council (MR/T03260X/1). Dr. Kate Peters is funded by the Leverhulme Trust (ECF-2022-437). Dr. Nobuyoshi Suto is partially supported by U01DA055017 from the National Institute on Drug Abuse/National Institute of Health, USA. Data availability statement: The datasets generated during and/or analyzed supporting the study’s conclusions are available from the corresponding author on reasonable request.