Brainstem Astrocytes Regulate Food Intake under Physiological and Pathophysiological Conditions Via NMDA Receptor Activation

Previous studies have shown that activation of brainstem astrocytes is sufficient and necessary to restore caloric balance within 3-5 days of exposure to acute high fat diet. Astrocyte activation upregulates NMDA-receptor mediated glutamatergic signaling to brainstem dorsal motor nucleus of the vagus (DMV) motoneurons regulating gastric functions such as motility, tone and emptying, ultimately regulating food intake and energy homeostasis. The purpose of this study was to test the hypothesis that brainstem astrocyte activity is a final common pathway regulating food intake under a variety of physiological and pathophysiological conditions. Food intake varies across the estrus cycle in an estrogen-dependent manner. Food intake was measured daily in female Sprague-Dawley rats (200-300g) across 3 estrus cycles, assessed via vaginal lavage. Rats were euthanized and brainstems removed when rats were in estrus or diestrus, and astrocyte activity assessed via GFAP-immunoreactivity. Male Sprague Dawley rats (150-200g) were subjected to anorexigenic stimulation (GLP-1 0.3mg/kg i.p, or CCK 3mg/kg i.p) or pathophysiological anorexia (2hr psychological restraint stress, or 90min physical water avoidance stress). Food intake measurements were assessed (2 and 4hr at onset of dark cycle, expressed as %baseline; N=3 for each) prior to brainstem fixation and assessment of GFAP-immunoreactivity (N=3 for each). Whole cell patch clamp recordings were made from DMV neurons in thin brainstem slices to assess whether the NMDA receptor antagonist, AP5 (25mM) decreased miniature excitatory postsynaptic currents (mEPSC) in DMV neurons (N=3-5 neurons for each). In female rats (N=6), food intake decreased during estrus (P=0.0235) and was associated with an increase in GFAP-IR within the DMV (mean fluorescence intensity = 39.1±5.76 vs 27.0±2.91 pixels/mm 2 ; P= 0.0265). In male rats, the decrease in food intake associated with anorexigenic signaling or anorexia was accompanied by am increase in GFAP-IR and ability of AP5 to decrease mEPSC frequency (see Table). [Table: see text] These results suggest that physiological (estrus, anorexigenic neurohormones) and pathophysiological (psychological or physical stress) decreases in food intake are associated with activation of DMV astrocytes and upregulation of NMDA-mediated glutamatergic signaling. Our studies imply that brainstem astrocytes play a fundamental role in homeostatic control of caloric balance and food intake, and act as a common final pathway by vagal efferent outflow is regulated. Uncovering the mechanistic basis by which astrocytes regulate caloric intake may provide avenues by which future therapeutic interventions for energy balance disorders (obesity or malnutrition) can be developed. NIH DK124098 and DOD W81XWH2110915 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.