Brainstem Astrocytes Regulate Estrus-Dependent Oscillations in Food Intake

Previous studies have shown that dorsal vagal complex (DVC) astrocytes play important roles in homeostatic regulation of food intake and caloric balance, specifically upregulation of NMDA receptor-mediated glutamatergic signaling to brainstem dorsal motor nucleus of the vagus (DMV) motoneurons restores caloric balance following exposure to caloric dense diets. DMV neurons are critical to the regulation of gastric functions, including motility, tone, and emptying; hence food intake and energy homeostasis. Prior studies have also shown that caloric intake in female rats fluctuates across the estrus cycle, with food intake being lowest during periods of high estrogen levels. The aim of the current study was to investigate whether these estrus-cycle dependent oscillations in food intake also involve DVC astrocyte adaptation. Immunohistochemical measurement of astrocytes across the estrus cycle uncovered an increase in glial-fibrillary acidic protein immunoreactivity (GFAP-IR) as well as an increase in astrocyte morphological complexity associated with high estrogen levels. Chemogenetic inhibition of DVC astrocytes eliminated food intake oscillations, whereas chemogenetic activation resulted in a consistent decrease in food intake, regardless of estrus status. Electrophysiological recordings from DMV neurons revealed that the estrus-dependent decrease in food intake was associated with activation of DMV NMDA receptors, and pharmacological inhibition of either estrogen receptors or brainstem astrocytes prevented this mechanism. In contrast, application of estradiol uncovered astrocyte- and NMDA-receptor dependent signaling to DMV neurons in low estrogen states. The findings of the present study demonstrate that DVC astrocytes and/or NMDA signaling play a fundamental role in estrogen-dependent fluctuations in food intake and energy homeostasis.