A hindbrain inhibitory microcircuit mediates vagally-coordinated glucose regulation

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 d esigner r eceptor e xclusively a ctivated by d esigner d rugs (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.

Astrocytes in the nucleus of the solitary tract: Contributions to neural circuits controlling physiology

“…These neurons clearly form a key component of CRR-driving circuitry since their optogenetic activation increases glucagon secretion [98] . In support of this, chemogenetic activation of GABAergic NTS neurons increases hepatic glucose production in mice [99] .…”

“…Furthermore, when lower glucose is available for conversion to lactate in astrocytes (and subsequent shuttling to neurons) this may result in reduced neuronal ATP generation. In glucose-inhibited NTS neurons this causes AMPK-dependent enhanced excitability and increased glucagon and hepatic glucose production [ 98 , 99 ]. This is supported by evidence indicating that Ca 2+ responses to extracellular low glucose or glucopivation are attenuated in glucose-inhibited NTS neurons and NTS TH neurons in brain slices from mice [93] .…”

Interplay Between Systemic Metabolic Cues and Autonomic Output: Connecting Cardiometabolic Function and Parasympathetic Circuits

“…The NTS and its neighboring circumventricular organ, area postrema (AP), are also implicated as central metabolic sensors, including neurons that respond to insulin ( Ruggeri et al, 2001 ; Blake and Smith, 2012 ), glucose ( Balfour et al, 2006 ; Lamy et al, 2014 ; Boychuk et al, 2015a ; Roberts et al, 2017 ), ghrelin ( Cui et al, 2011 ), and leptin ( Barrera et al, 2011 ). Importantly, the ability of these brain regions to directly sense metabolic state can influence peripheral physiology ( Ritter et al, 2000 ; Ferreira et al, 2001 ; Lamy et al, 2014 ; Boychuk et al, 2019 ). For example, in terms of cardiometabolic behavior, insulin microinjections into the NTS decreased the activity of baroreceptor-sensitive NTS neurons ( McKernan and Calaresu, 1996 ; Ruggeri et al, 2001 ), and despite only limited effects on resting heart rate ( McKernan and Calaresu, 1996 ; Krowicki et al, 1998 ), insulin in the NTS significantly reduced the baroreflex response ( McKernan and Calaresu, 1996 ; Ruggeri et al, 2001 ).…”

Effects of metabolic state on the regulation of melanocortin circuits

“…Fourth, how are counter-regulatory responses induced during and after exercise relayed to arcuate neurons? Counter-regulatory activities depend upon both neuronal circuits, which function as a “reflex” as well as humoral signals [ 26 , 56 , 74 , 92 , 125 , 141 , 142 , 145 , 193 , 214 ]. As hormone-mediated regulatory activity is slower than direct neuronal activity, the changes observed at the beginning of exercise (within seconds to minutes) likely involve circuit-mediated changes in activity (possibly recruitment of various reflexes) while the long-term (lasting for hours to days) changes in neuronal activity is likely dependent upon humoral signals.…”