Abstract
Neurons in the brainstem dorsal vagal complex integrate neural and humoral signals to coordinate autonomic output to viscera that regulate a variety of physiological functions, but how this circuitry regulates metabolism is murky. We tested the hypothesis that premotor, GABAergic neurons in the nucleus tractus solitarius (NTS) form a hindbrain micro-circuit with preganglionic parasympathetic motorneurons of the dorsal motor nucleus of the vagus (DMV) that is capable of modulating systemic blood glucose concentration. In vitro, neuronal activation or inhibition using either excitatory or inhibitory designer receptor exclusively activated by designer drugs (DREADDs) constructs expressed in GABAergic NTS neurons increased or decreased, respectively, action potential firing of GABAergic NTS neurons and downstream synaptic inhibition of the DMV. In vivo, DREADD-mediated activation of GABAergic NTS neurons increased systemic blood glucose concentration, whereas DREADD-mediated silencing of these neurons was without effect. The DREADD-induced hyperglycemia was abolished by blocking peripheral muscarinic receptors, consistent with the hypothesis that altered parasympathetic drive mediated the response. This effect was paralleled by elevated serum glucagon and hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK1) expression, without affecting insulin levels or muscle metabolism. Activity in a hindbrain inhibitory microcircuit is sufficient to modulate systemic glucose concentration, independent of insulin secretion or utilization.
Highlights
The brain orchestrates peripheral responses to changes in blood glucose concentration[1,2,3]
We stimulated GABAergic nucleus tractus solitarius (NTS) neurons selectively by utilizing a chemogenetic approach, using a stereotaxically injected cre-recombinase-inducible adeno-associated viruses expressing the chemogenetic designer receptor exclusively activated by designer drugs (DREADDs) and the fluorescent marker, mCherry, into the dorsal vagal complex (DVC) of mice that express cre-recombinase in GABAergic neurons (i.e., vGAT-Cre mice, Slc32a1tm2(cre)lowl/J; the Jackson Laboratories; stock 016962; Fig. 1a)
We initially tested whether GABAergic NTS neurons expressing hM3Dq-mCherry (AAV8 DIO hM3Dq) increased their activity in response to the DREADD ligand, clozapine-N-oxide (CNO; 10 μM). mCherry-expressing NTS neurons were targeted for patch-clamp recordings in acutely prepared brainstem slices (Fig. 1c)
Summary
The brain orchestrates peripheral responses to changes in blood glucose concentration[1,2,3]. Www.nature.com/scientificreports afferent input[40,41] and are themselves glucose responsive[35,36], and GABAergic NTS neurons project prominently to the DMV42 contributing significantly to vagal motor neuron activity[43,44]. GABA neurons in the NTS are positioned to potently modulate vagal motor activity in response to neural and circulating metabolic signals, but their influence on systemic glucose regulation is unknown. The DVC, its GABAergic circuitry, appears ideally situated to regulate peripheral glucose metabolism The release of these hormones with opposite effects on systemic glucose levels makes it difficult to predict how vagal activity changes modulate blood glucose concentration. We hypothesized that experimentally increasing the activity of GABAergic neurons in the DVC would inhibit DMV motor neurons and increase blood glucose concentration, whereas experimentally decreasing the activity of GABAergic neurons in this region would have the opposite effects
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