Short- and Long-Term High-Fat Diet Exposure Differentially Alters Phasic and Tonic GABAergic Signaling onto Lateral Orbitofrontal Pyramidal Neurons

The chronic consumption of caloric dense high-fat foods is a major contributor to increased body weight, obesity, and other chronic health conditions. The orbitofrontal cortex (OFC) is critical in guiding decisions about food intake and is altered with diet-induced obesity. Obese rodents have altered morphologic and synaptic electrophysiological properties in the lateral orbitofrontal cortex (lOFC). Yet the time course by which exposure to a high-fat diet (HFD) induces these changes is poorly understood. Here, male mice are exposed to either short-term (7 d) or long-term (90 d) HFD. Long-term HFD exposure increases body weight, and glucose signaling compared with short-term HFD or a standard control diet (SCD). Both short and long-term HFD exposure increased the excitability of lOFC pyramidal neurons. However, phasic and tonic GABAergic signaling was differentially altered depending on HFD exposure length, such that tonic GABAergic signaling was decreased with early exposure to the HFD and phasic signaling was changed with long-term diet exposure. Furthermore, alterations in the short-term diet exposure were transient, as removal of the diet restored electrophysiological characteristics similar to mice fed SCD, whereas long-term HFD electrophysiological changes were persistent and remained after HFD removal. Finally, we demonstrate that changes in reward devaluation occur early with diet exposure. Together, these results suggest that the duration of HFD exposure differentially alters lOFC function and provides mechanistic insights into the susceptibility of the OFC to impairments in outcome devaluation. SIGNIFICANCE STATEMENT This study provides mechanistic insight on the impact of short-term and long-term high-fat diet (HFD) exposure on GABAergic function in the lateral orbitofrontal cortex (lOFC), a region known to guide decision-making. We find short-term HFD exposure induces transient changes in firing and tonic GABA action on lOFC pyramidal neurons, whereas long-term HFD induces obesity and has lasting changes on firing, tonic GABA and inhibitory synaptic transmission onto lOFC neurons. Given that GABAergic signaling in the lOFC can influence decision-making around food, these results have important implications in present society as palatable energy dense foods are abundantly available.

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