Homeostatic and Hedonic Signals Differentially Regulate cFos Activation in PVN MC4R, PVN pro-TRH, PBN vGlut2, and PBN CRF Neuronal Populations

Abstract

Background: The high worldwide prevalence of obesity, with palatable food hyperphagia as its main etiological factor, justifies studying neural circuit alterations under conditions such as chronic stress and exposure to high-energy diets, which elevate palatable food preference and body weight. Short-term intake of palatable food, acting as a satiety stimulus, activates melanocortin-4 receptor-expressing neurons in the paraventricular hypothalamic nucleus (PVNMC4R) and those from the caudo-lateral region of the parabrachial nucleus (PBN). It remains unclear whether stress targets this circuit, reducing satiety, or whether 2-week palatable diet exposure alters anorexigenic cells’ responsiveness to stress, such as MC4R, pro-thyrotropin-releasing hormone (pro-TRH), vesicular glutamate transporter 2 (vGlut2), and corticotropin-releasing factor (CRF)-expressing neurons. Methods: Male adult Wistar rats subjected to isolation stress or group-housed and fed with chow or palatable food for 2 weeks were fasted and then re-fed for 2 h with chow or chocolate milk. Using immunohistochemical analyses, we determined the circuit responsiveness to stimuli, identifying the cFos-indicated activation of anterior and medial PVN-MC4R, PVN-pro-TRH, PBN-vGlut2, and PBN-CRF-expressing cells. We also analyzed VTA tyrosine hydroxylase and accumbal type-2 dopamine receptor expression, where PBN neurons’ activity impacts and modulates the food-rewarding properties of DAergic circuit responses. Results: PVNMC4R+cFos cells responded differently depending on food type, diet duration, combination, and nature of stimuli (homeostatic/hedonic); their responsiveness pattern was similar to PBNvGlut2+cFos and different from anterior PVNpro-TRH+cFos cells. Conclusions: The results suggest that 2-week palatable diet exposure changes satiety-circuit cells’ responsiveness, showing enhanced activity when stress and palatable food are combined, which seemed associated with their higher food intake.