Brief high-fat diet exposure temporally reshapes affective behavior and prefrontal cortex function.

High-fat diet consumption is linked to a higher risk of obesity, diabetes, cardiometabolic diseases, psychiatric disorders, and cognitive dysfunction. Energy homeostasis and mood fluctuate throughout the 24-hour day, and perturbations in these rhythms have consequences for brain, body, and behavior. Our recent work demonstrates that layer 2/3 pyramidal neurons in the prelimbic prefrontal cortex (plPFC), a key region in affective behavior and cognitive function, undergo daily rhythms in their physiological function. In this study, we investigate how a one-week acute high-fat diet (aHFD) alters affective behavior and plPFC function. Further, we used time-of-day as a tool to determine how initiation of a HFD impacts the physiological properties of layer 2/3 plPFC pyramidal neurons in male and female mice. To explore these phenomena, we implemented the open-field test (OFT) and DeepLabCut to gain dynamic whole-body spatiotemporal resolution in our behavioral analysis. Next, we employed patch-clamp electrophysiology to determine how aHFD alters the intrinsic membrane properties and action potential dynamics of these neurons. Here we show that aHFD produces time-of-day dependent changes in exploratory behavior and physiology of plPFC pyramidal neurons, including altered intrinsic properties, firing profiles, and voltage-dependent membrane conductance in both sexes. These results lay the groundwork to explore the physiological mechanisms by which aHFD impacts plPFC function, affective behavior, and cognition. Overall, this study highlights the importance of understanding how diet impacts neural function before the onset of obesity.