Activation of brainstem astrocytes is both necessary and sufficient to restore caloric balance within an acute period (3-5 days) of exposure to a high-fat diet (HFD), via upregulation of an NMDA receptor-mediated glutamatergic signaling cascade to brainstem dorsal motor nucleus of the vagus (DMV) motoneurons. DMV neurons are crucial for regulating gastric functions, including motility, tone, and emptying, hence food intake and energy homeostasis. Additionally, prior studies indicate that caloric intake in female rats fluctuates across the estrus cycle, with the lowest food intake occurring during periods of high estrogen levels. The current study aimed to investigate whether estrus-cycle dependent oscillations in food intake in female rats also involves brainstem astrocyte activation. Estrus stage was assessed via vaginal lavage, and food intake was measured daily in Sprague-Dawley rats (200-300g) over three estrus cycles, before immunohistochemical assessment of astrocyte GFAP-immunoreactivity in rats with high (proestrus, estrus; HE) and low (diestrus, metestrus; LE) estrogen levels (N=4 per group). Whole cell patch clamp recordings were made from DMV neurons in thin brainstem slices, and the NMDA receptor antagonist, AP5, used to determine whether NMDA-dependent miniature excitatory postsynaptic currents (mEPSC) were present (N=5-8 neurons per group;). Immunohistochemical analysis of astrocytes showed an increase in GFAP-IR (mean fluorescence intensity = 39.1 ± 5.8 vs. 27.0 ± 2.9 pixels/mm2; P = 0.0265), accompanied by an increase in morphological complexity of astrocytes during HE periods. Chemogenetic inhibition of brainstem astrocytes via DCZ administration abolished the HE-dependent decrease in food intake (HE control 73.8 ± 4.8 vs. HE DCZ 83.0 ± 6.2 kcal/g, P = 0.036, n= 5 rats), whereas chemogenetic activation consistently reduced food intake (LE basal 101.7 ± 6.2 vs. LE DCZ 76.2 ± 4.6 kcal/g, P = 0.0059, n= 5 rats). Electrophysiological studies showed that NMDA-dependent mEPSCs were present (i.e. AP5 decreased mEPSC frequency) in 7/8 HE DMV neurons but this was abolished by prior application of an estrogen receptor antagonist (ICI 182,700; 92.6% ± 5.3% vs. 65.8% ± 6.0% of baseline, p = 0.0178) or pharmacological (fluoroacetate; 81.3% ± 5.0% vs. 65.8% ± 6.03% of baseline, p = 0.072) or chemogenetic (93.51 ± 7.99 vs. 65.8% ± 6.03% of baseline, p = 0.0173) inhibition of astrocytes. Conversely, AP5 had no effect in 8/8 LE DMV neurons, suggesting NMDA receptors were not activated (85.32% ± 2.58% of baseline). In contrast, NMDA receptor dependent currents were present in 4/5 LE DMV neurons following application of estradiol (70.66% ± 9.34% vs. 85.32% ± 2.58% of baseline, p = 0.0216) or chemogenetic astrocyte activation (54.61% ± 3.09% vs. 85.32% ± 2.58% of baseline, p = < 0.0001). The findings of this study show that brainstem astrocytes and/or NMDA signaling play a key role in estrogen-dependent fluctuations in food intake and energy balance, suggesting a potential mechanism by which caloric regulation may be disrupted during menstrual cycle irregularities or conditions of hormonal imbalance. This abstract was presented at the American Physiology Summit 2026 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.
Ozkaya et al. (Fri,) studied this question.