The dorsal vagal complex (DVC) is essential to integrating visceral sensory afferents and various other inputs in order to produce appropriate parasympathetic motor outputs via the vagus nerve, which is vital for energy homeostasis. Certain pathologies, such as diabetes, can cause disruption of this circuit. Diabetes mellitus is a metabolic disorder that results in dysfunctional glucose regulation by insulin deficiency (type-1) or resistance (type-2). Hyperglycemia, a condition of diabetes, significantly alters central vagal function and diabetics often experience gastric dysfunction, gastroparesis and other visceral symptomatology. Insulin crosses the blood brain barrier and is transported into the brainstem over twice as rapidly as into whole brain, and neuronal insulin receptors are expressed in the DVC. Neuronal insulin and insulin receptors are required for normal control of glucose homeostasis and the regulation of peripheral energy homeostasis and glucose metabolism. Despite the importance of the DVC and the evidence that insulin action in the brain is critical for homeostasis, very little is known about insulin's action in the brain, specifically the DVC. This proposal will test the effects of insulin on cellular communication within the DVC. The general hypothesis is that insulin is inhibiting neurons in the dorsal motor nucleus (DMV). I predict that this occurs directly and indirectly by acting on glutamatergic neurons of in the nucleus of the solitary tract (NTS) that project to the DMV. Electrophysiological studies will be conducted in brainstem slice preparations from adult mice. Gastric-related neurons of DMV and NTS will be identified by their anatomical connection with the proximal stomach. With whole-cell patch clamp recordings, the effects of insulin will be examined on: 1) input to DMV neurons and 2) glutamatergic neurons of the NTS, identified with RT-PCR, that project to the DMV by "uncaging" glutamate in these neurons and examining paired-pulse responses in the DMV to electric stimulation of the NTS. These results will be coordinated with pharmacological and molecular biological analyses to generate models of insulin action in the vagal complex in mice.
This proposal will test the effects of insulin on the dorsal vagal complex, which controls gastric function. Because this region is located in the brainstem, which is adjacent to an incomplete portion of the blood brain barrier, hormones found in the bloodstream, such as insulin, can readily access this part of the brain. Diabetic patients often experience gastric dysfunction;thus the actions of insulin in this brain region are important to our understanding of the physiology of this disease. The results of this study will provide a clearer understanding of how insulin regulates autonomic function, which could lead to new insights in designing treatments for diabetes.
|Blake, Camille B; Smith, Bret N (2014) cAMP-dependent insulin modulation of synaptic inhibition in neurons of the dorsal motor nucleus of the vagus is altered in diabetic mice. Am J Physiol Regul Integr Comp Physiol 307:R711-20|