Insulin reduces excitation in gastric-related neurons of the dorsal motor nucleus of the vagus

Abstract

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.

cAMP-dependent insulin modulation of synaptic inhibition in neurons of the dorsal motor nucleus of the vagus is altered in diabetic mice

“…We recently reported that insulin inhibited the membrane potential directly and suppressed glutamatergic excitatory neurotransmission in DMV neurons in a concentration-related fashion but had no effect on GABA release in the DMV under normal conditions (8). Here, all recordings were made with Cs-based internal recording solutions to block K ϩ conductances and, therefore, prevent direct effects of insulin on the neuronal membrane of the recorded cell, which were previously shown to be K ϩ -dependent.…”

“…Insulin action in the brain influences many factors involved in energy homeostasis, including hepatic glucose production (22,42,46,50), food intake (10), and satiety (5). At least some of these actions occur in the DVC, where insulin directly modulates vagal motor neuron activity (8). The brain, in particular, the DVC, is both affected by and contributes to blood glucose dysregulation associated with diabetes.…”

“…We previously found that insulin hyperpolarizes vagal motor neurons and decreases synaptic excitation, but not inhibition, in the DMV of control mice (8). On the basis of evidence that other peptides can alter inhibition in the DVC in the presence of elevated cAMP (11)(12)(13), we tested the effects of insulin application on synaptic inhibition in the presence of elevated cAMP levels using whole cell patch-clamp recordings from DMV neurons in brain stem slices.…”

Caffeine Intake Improves Fructose-Induced Hypertension and Insulin Resistance by Enhancing Central Insulin Signaling

“…4 The effect of insulin on the baroreceptor reflex in nucleus tractus solitarii (NTS) is probably mediated by a change in sympathetic nervous activity. 4,5 Furthermore, sympathectomy can prevent the development of fructose-induced hypertension in rats. 6 Recent studies suggest that fructose consumption increases superoxide generation and attenuates baroreflex response.…”

Nicotine enhances inhibition of mouse vagal motor neurons by modulating excitability of premotor GABAergic neurons in the nucleus tractus solitarii

“…Useful labeling of DMV and NTS neurons occurs after 60 -72 h, a time well before onset of cellular or functional degradation (Card et al 1993;Glatzer et al 2003;Smith et al 2000). This method allows preganglionic DMV motor neurons and synaptically connected, premotor NTS neurons that are specifically related to gastric motor output to be identified and targeted for electrophysiological recording in the in vitro brain stem slice preparation (Blake and Smith 2012;Davis et al 2003;Derbenev et al 2004;Gao et al 2009;Gao and Smith 2010;Glatzer et al 2003Glatzer et al , 2007Glatzer and Smith 2005;Smith et al 2000;Williams et al 2007). Neurons expressing EGFP or mRFP1 were visualized in living tissue under epifluorescence by using fluorescein isothiocyanate (FITC) or tetramethylrhodamine isothiocyanate (TRITC) filter sets.…”