Abstract
A role for glial cells in brain circuits controlling feeding has begun to be identified with hypothalamic astrocyte signaling implicated in regulating energy homeostasis. The nucleus of the solitary tract (NTS), within the brainstem dorsal vagal complex (DVC), integrates vagal afferent information from the viscera and plays a role in regulating food intake. We hypothesized that astrocytes in this nucleus respond to, and influence, food intake. Mice fed high‐fat chow for 12 hr during the dark phase showed NTS astrocyte activation, reflected in an increase in the number (65%) and morphological complexity of glial‐fibrillary acidic protein (GFAP)‐immunoreactive cells adjacent to the area postrema (AP), compared to control chow fed mice. To measure the impact of astrocyte activation on food intake, we delivered designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes (encompassing NTS, AP, and dorsal motor nucleus of the vagus) using an adeno‐associated viral (AAV) vector (AAV‐GFAP‐hM3Dq_mCherry). Chemogenetic activation with clozapine‐N‐oxide (0.3 mg/kg) produced in greater morphological complexity in astrocytes and reduced dark‐phase feeding by 84% at 4 hr postinjection compared with vehicle treatment. hM3Dq‐activation of DVC astrocytes also reduced refeeding after an overnight fast (71% lower, 4 hr postinjection) when compared to AAV‐GFAP‐mCherry expressing control mice. DREADD‐mediated astrocyte activation did not impact locomotion. hM3Dq activation of DVC astrocytes induced c‐FOS in neighboring neuronal feeding circuits (including in the parabrachial nucleus). This indicates that NTS astrocytes respond to acute nutritional excess, are involved in the integration of peripheral satiety signals, and can reduce food intake when activated.
Highlights
Food intake is controlled by the coordinated action of numerous brain regions but a complete understanding remains elusive (Andermann &Lowell, 2017)
We have shown for the first time that astrocytes in the nucleus of the solitary tract (NTS) react dynamically to excess intake of an energy dense food by upregulating glial-fibrillary acidic protein (GFAP) expression and showing morphological plasticity
These glia are responsive to short-term energy imbalance, both fasting and acute high-fat feeding (Buckman et al, 2015; Fuente-Martín et al, 2012), and direct manipulation of their activity using designer receptors exclusively activated by designer drugs (DREADDs) alters food intake (Chen et al, 2016; Yang et al, 2015). Both studies using activating DREADDs in arcuate nucleus (ARC) astrocytes show a modest increase in food intake during the light phase, when mice are not typically eating (Chen et al, 2016; Yang et al, 2015)
Summary
Food intake is controlled by the coordinated action of numerous brain regions but a complete understanding remains elusive Given the similarities between the NTS and the ARC, namely that both nuclei contain neurons that exert powerful effects on feeding behavior and are adjacent to circumventricular organs, we hypothesized that NTS astrocytes may be involved in mediating satiety. In support of this hypothesis NTS astrocytes sense synaptic input from the vagus nerve, which drives intracellular Ca2+ increases in ex vivo brain slices (McDougal, Hermann, & Rogers, 2011). There has not been a causal demonstration of the impact of NTS astrocyte activation on physiological feeding behavior. We targeted the expression of excitatory designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes to allow specific chemogenetic activation of these cells and determined the impact on feeding behavior in mice
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