Insulin reduces excitation in gastric-related neurons of the dorsal motor nucleus of the vagus.
The dorsal motor nucleus of the vagus (DMV) in the caudal brain stem is composed mainly of preganglionic parasympathetic neurons that control the subdiaphragmatic viscera and thus participates in energy homeostasis regulation. Metabolic pathologies, including diabetes, can disrupt vagal circuitry and lead to gastric dysfunction. Insulin receptors (IRs) are expressed in the DMV, and insulin crosses the blood-brain barrier and is transported into the brain stem. Despite growing evidence that insulin action in the brain is critical for energy homeostasis, little is known about insulin's action in the DMV. We used whole cell patch-clamp recordings in brain stem slices to identify effects of insulin on membrane and synaptic input properties of DMV neurons, including a subset of gastric-related cells identified subsequent to injection of a retrograde label into the gastric wall. Insulin application significantly reduced the frequency of spontaneous and miniature excitatory, but not inhibitory postsynaptic currents, with no change in amplitude (P < 0.05). Insulin also directly hyperpolarized the membrane potential (-4.2 ± 1.3 mV; P < 0.05) and reduced action potential firing (P < 0.05). Insulin effects were eliminated in the presence of a ATP-dependent K+ (K(ATP)) channel antagonist tolbutamide (200 μM), or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (100 nM), suggesting that insulin inhibition of excitatory input to gastric-related DMV neurons was mediated by K(ATP) channels and depended on PI3K activity. Insulin regulation of synaptic input in the DMV may influence autonomic visceral regulation and thus systemic glucose metabolism.
Dept. of Physiology, Univ. of Kentucky College of Medicine, MS508 Chandler Medical Center, 800 Rose St., Lexington, KY 40536, USA.
Camille B
CB
Blake
Bret N
BN
Smith
D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D007328:Insulin / Q000378:metabolism*; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D056347:Neuroanatomical Tract-Tracing Techniques; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011972:Receptor, Insulin / Q000378:metabolism*; D013270:Stomach / Q000294:innervation*; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*
D007328:Insulin; D054086:KATP Channels; D018377:Neurotransmitter Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin