Defining the contribution of dorsal vagal complex astrocytes to the regulation of food intake

Abstract

Food intake is controlled by the coordinated action of numerous brain regions but a complete understanding of the process remains elusive. The nucleus of the solitary tract (NTS), located in the brainstem dorsal vagal complex (DVC) is the first site for integration of visceral synaptic and hormonal cues that act to inhibit food intake. NTS neurons receive synaptic input from sensory neurons of the vagus nerve that relay signals of gastrointestinal stretch and nutrient content. In response to these signals of ingestion, NTS neurons signal to higher brain centres in the hypothalamus and midbrain to inhibit hunger and promote meal termination. A role for astrocytes in brain circuits controlling food intake has begun to be identified. Hypothalamic astrocyte signalling has been implicated in regulating energy homeostasis. Despite a wealth of evidence showing astrocytes in the NTS/DVC are involved in synaptic integration of vagal signals and control of autonomic physiology, the potential role of these cells in feeding control has not been investigated. We hypothesised that NTS astrocytes, and those in the wider DVC, would be responsive to increases in food intake and, in turn, their activation would act in concert with NTS neurons to drive a corresponding suppression of food intake. To investigate this prospect we used dietary manipulation, immunohistochemistry, selective chemogenetic manipulation of DVC astrocytes, behavioural assays and electrophysiology in mice. The key findings of these studies show that in response to acute nutrient excess and gastric distention NTS astrocytes increase their expression of the cytoskeletal glial fibrillary acidic protein and adopt a more ramified morphology, indicative of activation. We also show that selective activation of Gq-proteincoupled receptor signalling in DVC astrocytes suppresses nocturnal food intake and refeeding after a fast. These studies provide evidence that astrocytes may be integrators and effectors of satiety signals and appropriate feeding responses in the DVC.