Fasting and hypoglycemia elicit powerful gastrointestinal contractions. Whereas the relationship between utilizable nutrient and gastric motility is well recognized, the explanation of this phenomenon has remained incomplete. A relatively recent controversial report suggested that astrocytes in the dorsal hindbrain may be the principal detectors of glucoprivic stimuli. Our own studies also show that a subset of astrocytes in the solitary nucleus (NST) is activated by low glucose. It is very likely that information about glucopenia may directly impact gastric control because the hindbrain is also the location of the vago-vagal reflex circuitry regulating gastric motility. Our in vivo single unit neurophysiological recordings in intact rats show fourth ventricular application of 2-deoxyglucose (2-DG) inhibits NST neurons and activates dorsal motor nucleus (DMN) neurons involved in the gastric accommodation reflex. Additionally, as shown in earlier studies, either systemic insulin or central 2-DG causes an increase in gastric motility. These effects on motility were blocked by fourth ventricle pretreatment with the astrocyte inactivator fluorocitrate. Fluorocitrate administered alone has no effect on gastric-NST or -DMN neuron responsiveness, or on gastric motility. These results suggest that glucoprivation-induced increases in gastric motility are dependent on intact hindbrain astrocytes.

Glucoprivation is a strong signal for the initiation of gastrointestinal contractions. While this relationship between utilizable nutrient levels and gastric motility has been recognized for more than 100 years, the explanation of this phenomenon has remained incomplete. Using widely differing approaches, recent work has suggested that the hindbrain is responsible for this chemoreflex effect. Surprisingly, astrocytes may be the main glucodetector elements under hypoglycemic conditions. Our own work using in vitro live cell calcium imaging shows that astrocytes in the NST increase cytoplasmic calcium in a concentration dependent manner in reaction to reductions in glucose. This effect is reversed on restoration of normal glucose concentrations. In vivo single unit neurophysiological recordings show that brainstem neurons driving gastric motility are activated by glucoprivic stimuli. Studies in intact animals verify that both dorsal medullary and systemic glucoprivation significantly increases gastric motility. Astrocyte inactivation with fluorocitrate blocks the pro-motility effects of glucoprivation. Thus, it appears that intact astrocyte signaling may be essential to glucoregulatory control over gastric motility.

Non-technical summary Cholecystokinin (CCK) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein; it also functions to suppress feeding. CCK is also recognized as a neurotransmitter within the central nervous system (CNS). As such, there are receptors for CCK both in the periphery as well as within the CNS. Thus, it is not certain where the principal site of action is for CCK to affect gastric reflexes and feeding behaviour. We show that picomole amounts of systemic CCK are sufficient to modulate gastric reflexes and that these effects are probably mediated via peripheral vagal afferents in the proximal gut. Knowledge of how and where this peptide hormone acts increases our understanding of the regulation of feeding behaviour.Abstract Cholecystokinin (CCK) is a potent regulator of visceral functions as a consequence of its actions on vago-vagal reflex circuit elements. This paper addresses three current controversies regarding the role of CCK to control gastric function via vago-vagal reflexes. Specifically: (a) whether CNS vs. peripheral (vagal afferent) receptors are dominant, (b) whether the long (58) vs. short (8) isoform is more potent and (c) whether nutritional status impacts the gain or even the direction of vago-vagal reflexes. Our in vivo recordings of physiologically identified gastric vagal motor neurones (gastric-DMN) involved in the gastric accommodation reflex (GAR) show unequivocally that: (a) receptors in the coeliac-portal circulation are more sensitive in amplifying gastric vagal reflexes; (b) in the periphery, CCK8 is more potent than CCK58; and (c) the nutritional status has a marginal effect on gastric reflex control. While the GAR reflex is more sensitive in the fasted rat, CCK amplifies this sensitivity. Thus, our results are in stark contrast to recent reports which have suggested that vago-vagal reflexes are inverted by the metabolic status of the animal and that this inversion could be mediated by CCK within the CNS.

Previous studies from our laboratory illustrated the potential for stromal cell-derived factor one [CXCL12; also referred to as SDF-1] to act on its receptor [CXCR4] within the dorsal vagal complex [DVC] of the hindbrain to suppress gastric motility (Hermann et al., 2008). While CXCR4 receptors are essential for normal brain development, they also play a critical role in the proliferation of the HIV virus and initiation of metastatic cell growth in the brain. Anorexia, nausea, and failed autonomic regulation of gastrointestinal function are significant causes of morbidity and are contributory factors in the mortality associated with these disease states. The implication of our previous study was that CXCL12 caused gastric stasis by acting on gastric reflex circuit elements in the DVC. This hindbrain complex includes vagal afferent terminations in the solitary nucleus, neurons in the solitary nucleus (NST) and visceral efferent motorneurons in the dorsal motor nucleus (DMN) that are responsible for the regulation of digestive functions from the oral cavity to the transverse colon. In the current study, in vivo single-unit neurophysiological recordings from physiologically-identified NST and DMN components of the gastric accommodation reflex show that while injection of femtomole doses of CXCL12 onto NST or DMN neurons has no effect on their basal activity, CXCL12 amplifies the effect of gastric vagal mechanosensory input to activate the NST and, in turn, inhibit DMN motor activity.