Perinatal high fat diet increases inhibition of dorsal motor nucleus of the vagus neurons regulating gastric functions

• Published in: Neurogastroenterology and motility Vol. 30; no. 1
• Main Authors: McMenamin, C. A., Travagli, R. A., Browning, K. N.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2018
• Subjects: Animals; Bicuculline - administration & dosage; Brain slice preparation; Brain stem; Brain Stem - physiology; Diet, High-Fat; DMV; Embryos; GABA Agonists - administration & dosage; GABA Antagonists; GABA receptors; Gastric motility; Gastrointestinal Motility; Gliotoxin; High fat diet; Isoxazoles - administration & dosage; Male; Microinjection; Motility; Motor nuclei; Neural Inhibition; Neurons; Neurons - drug effects; Neurons - physiology; Perinatal exposure; perinatal high fat diet; Pyridazines - administration & dosage; Rats, Sprague-Dawley; Receptor density; Rodents; Synaptic strength; Vagus nerve; Vagus Nerve - drug effects; Vagus Nerve - physiology; γ-Aminobutyric acid A receptors; gastric motility; DMV; GABA receptors; perinatal high fat diet
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.13150

Background Previous studies suggest an increased inhibition of dorsal motor nucleus of the vagus (DMV) neurons following exposure to a perinatal high fat diet (PNHFD); the underlying neural mechanisms, however, remain unknown. This study assessed the effects of PNHFD on inhibitory synaptic inputs to DMV neurons and the vagally dependent control of gastric tone and motility. Methods Whole‐cell patch clamp recordings were made from DMV neurons in thin brainstem slices from Sprague‐Dawley rats fed either a control diet or HFD (14 or 60% kcal from fat, respectively) from embryonic day 13 onwards; gastric tone and motility were recorded in in vivo anesthetized rats. Key Results The non‐selective GABAA antagonist, BIC (10 μmol L–1), induced comparable inward currents in PNHFD and control DMV neurons, but a larger current in PNHFD neurons at higher concentrations (50 μmol L–1). Differences were not apparent in neuronal responses to the phasic GABAA antagonist, gabazine (GBZ), the extrasynaptic GABAA agonist, THIP, the GABA transport blocker, nipecotic acid, or the gliotoxin, fluoroacetate, suggesting that PNHFD altered inhibitory transmission but not GABAA receptor density or function, GABA uptake or glial modulation of synaptic strength. Similarly, the increase in gastric motility and tone following brainstem microinjection of low doses of BIC (1‐10 pmoles) and GBZ (0.01‐0.1 pmoles) were unchanged in PNHFD rats while higher doses of BIC (25 pmoles) induced a significantly larger increase in gastric tone compared to control. Conclusions and Inferences These studies suggest that exposure to PNHFD increases the tonic inhibition of DMV neurons, possibly contributing to dysregulated vagal control of gastric functions. Perinatal high fat diet exposure (PNHFD) increases tonic inhibitory inputs to gastric‐projecting DMV neurons, increasing DMV neuronal inhibition and vagal efferent inhibition of gastric tone and motility. While the mechanisms responsible for this increased synaptic inhibition remain unknown, they do not appear to involve an increased number of function of GABA receptors, GABA uptake, or neuroglial modulation of synaptic strength. Alterations in brainstem neurocircuit development may dysregulate vagal control of gastric motor functions which, in turn, may be at least partially responsible for the increased propensity of PNHFD‐exposed offspring to develop obesity and related comorbidities in later life. View the podcast on this paper at the following sites: iTunes: https://itunes.apple.com/gb/podcast/neurogastroenterology-motility-january-2018/id1321324295 Youtube: https://youtu.be/nnOpG-ijYD8