Electrophysiological properties and neurochemical identification of neurons involved in the hypothalamus-medulla-liver/pancreas axis that participates 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 control, as it is responsible for the production, storage, and release of glucose, adjusting to the body's needs. Furthermore, there is the participation of pancreatic hormones, such as glucagon and insulin, which exert antagonistic effects on the regulation of glycemia, depending on the individual's dietary status. Insulin plays an important role in reducing glucose levels in the body, stimulating glucose uptake by skeletal muscle, suppressing hepatic glucose production, and regulating its own secretion. This mechanism also occurs through the central action of insulin on neurons in the hypothalamic and bulbar nuclei that control liver and pancreatic functions through the autonomic nervous system. In terms of neurotransmitters, there is evidence of a relationship between the neuropeptide oxytocin (OT) and glycemic control. Studies reveal that insulin infusion into the brain increases the plasma concentration of OT, providing an interaction between PVN oxytocinergic neurons and the central action of insulin. Corroborating these findings, studies recently published by our laboratory showed that the application of OT increased the excitability of DMV neurons with projections to the liver (DMV-liver). An intense presence of oxytocinergic terminals close to DMV-liver neurons was also observed. Therefore, we hypothesize that an OT may be the neurotransmitter involved in the central action of insulin by activating the parasympathetic (vagal) pathways between PVN-DMV-liver/pancreas. Thus, the central aim of the work will be to identify the connections, neurochemical phenotype, and electrical properties of neurons that participate in the hypothalamus-medulla-liver/pancreas axis in the control of glycemia. For this, we use neuroanatomy techniques with transneuronal tracking of the liver/pancreas-brain axis, animal transgenesis, in situ hybridization analysis by RNAscope, and electrophysiological recordings of DVM-liver/pancreas neurons. (AU)