Diabetes mellitus is a major health concern, affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including include heart disease, stroke, hypertension, blindness, nervous system damage, and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control, including control of blood glucose homeostasis. Experiments utilize murine models of type 1 and type 2 diabetes. Preautonomic neurons of the dorsal vagal complex, which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV), are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes, leading to autonomic dysregulation, including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that GABA neurons in the NTS in particular are responsive to elevated glucose. Paradoxically, GABAA receptor-mediated responses in the DMV are persistently enhanced in a model of type 1 diabetes, in a manner consistent with maintenance of prolonged hyperglycemia. Some, but not all of these responses are preserved in a type 2 diabetes model, suggesting a form of GABA receptor plasticity that mediates the decreased vagal output seen in diabetes. In addition, modulation of GABA receptors in the dorsal vagal complex has a significant effect on blood glucose levels, and this effect is hypothesized to be enhanced in diabetic mice versus controls. This proposal aims to determine the causes and underlying features of the recently-discovered, diabetes-induced plasticity of the GABAergic system in the vagal complex. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to altered GABAergic inhibition changes associated with diabetes development in the streptozotocin-treated mouse, a model of type 1 diabetes, and the TallyHo mouse, a model of type 2 diabetes.
Aim 1 will determine insulin- and glucose- dependence of enhanced tonic GABA currents in diabetic mice, aim 2 will identify cellular mechanisms contributing to diabetes-associated GABA receptor plasticity in the DMV, and aim 3 will determine the effects of GABA receptor modulation in the dorsal vagal complex on systemic glucose homeostasis. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint, based on modulating specific inhibitory neural functions in the brainstem to address diabetes-related autonomic dysregulation in patients.

Public Health Relevance

Preganglionic parasympathetic neurons in the vagal complex innervate the abdominal organs and critically regulate whole blood glucose metabolism. These neurons are sensitive to elevated glucose and undergo long-lasting changes in synaptic excitability in animal models of diabetes. The proposed experiments will examine mechanisms underlying diabetes-associated inhibition changes in the vagal complex that represent reactive responses to chronic hyperglycemia and/or hyperinsulinemia, which may contribute to disease pathology and symptoms. The eventual goal of informing future studies aimed at treating pathologies underlying diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Hyde, James F
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University of Kentucky
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United States
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Derera, Isabel D; Delisle, Brian P; Smith, Bret N (2017) Functional Neuroplasticity in the Nucleus Tractus Solitarius and Increased Risk of Sudden Death in Mice with Acquired Temporal Lobe Epilepsy. eNeuro 4:
Boychuk, Carie R; Smith, Bret N (2016) Glutamatergic drive facilitates synaptic inhibition of dorsal vagal motor neurons after experimentally induced diabetes in mice. J Neurophysiol 116:1498-506
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Boychuk, C R; Halmos, K Cs; Smith, B N (2015) Diabetes induces GABA receptor plasticity in murine vagal motor neurons. J Neurophysiol 114:698-706
Smith, Bret N (2015) The Wanderer Falters: Central Vagal Dysregulation Triggers SUDEP. Epilepsy Curr 15:269-70
Halmos, K C; Gyarmati, P; Xu, H et al. (2015) Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes. Neuroscience 306:115-22
Xu, H; Smith, B N (2015) Presynaptic ionotropic glutamate receptors modulate GABA release in the mouse dorsal motor nucleus of the vagus. Neuroscience 308:95-105
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

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