Electrophysiological and neurotransmitter characterization of neurons involved in the hypothalamus-bulb-liver/pancreas axis that participate in glycemic control.

Abstract

Glucose plays a crucial role as an energy substrate for most cells. Therefore, it is vital to maintain precise control of its plasma concentration to prevent variations in its availability that could result in serious health complications. The liver plays an essential role in this control, as it is responsible for the production, storage, and release of glucose, adjusting to the body's needs. Additionally, pancreatic hormones, such as glucagon and insulin, exert antagonistic effects on glycemic regulation, depending on the individual's nutritional state. Insulin plays an important role in reducing glucose levels in the body by stimulating glucose uptake in skeletal muscle, suppressing hepatic glucose production, and regulating its secretion. This mechanism also occurs through the central action of insulin on neurons in hypothalamic and bulbar nuclei that control hepatic and pancreatic functions via the autonomic nervous system. Regarding neurotransmitters, there is evidence of a relationship between the neuropeptide oxytocin (OT) and glycemic control. Studies have shown that insulin infusion in the brain increases plasma OT concentration, suggesting an interaction between the oxytocinergic neurons of the PVN and the central action of insulin. Supporting these findings, recent studies published by our laboratory demonstrated that applying OT increased the excitability of DMV neurons projecting to the liver (DMV-liver). A strong presence of oxytocinergic terminals near DMV-liver neurons was also observed. Thus, we hypothesize that OT may be the neurotransmitter involved in the central action of insulin, activating parasympathetic (vagal) pathways between PVN-DMV-liver/pancreas. Therefore, the central objective of this work will be to identify the connections, neurochemical phenotype, and electrical properties of neurons involved in the hypothalamus-bulb-liver/pancreas axis in glycemic control. To achieve this, we will use neuroanatomical techniques with transneuronal tracing of the liver/pancreas-brain axis, animal transgenics, in situ hybridization analyses using RNAscope, and electrophysiological recordings from DMV-liver/pancreas neurons.