Neuronal communication in the dorsal vagal complex (DVC) is critical for integrating visceral afferent and other inputs, and translating that integrated signal into a coordinated parasympathetic motor output via the vagus nerve. In particular, GABAergic inhibition is a dominant regulator of neuronal function in the area. Despite the recognized importance of this circuitry in controlling feeding and digestion, relatively little is known about local cellular interactions in the DVC. The general hypothesis of this proposal is that activity of neurons in the dorsal motor nucleus of the vagus (DMV) that control gastric function is prominently controlled by inhibitory GABAergic inputs arising from neurons in the nucleus tractus solitarius (NTS). The activity of NTS GABA neurons is regulated by both glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control of preganglionic vagal motor output is accomplished by both phasic and tonic postsynaptic GABAA receptor-mediated inhibition and that specific cellular interactions in the DVC are organized in a manner that consistent with the concept, well developed in other sensory-motor systems, that local inhibitory circuitry coordinates responses between functional areas of the solitary complex. Gastrointestinal and other autonomic dysfunction affects people with diabetes mellitus and hyperglycemia significantly alters central vagal motor function. We further propose that GABAA receptor-mediated currents in gastric-related DMV neurons are functionally altered in a model of type 1 diabetes mellitus. We will use a multidisciplinary approach to examine GABA-mediated synaptic transmission between neurons in the DVC, focusing particularly on inhibitory synaptic control of identified GABAergic neurons in the NTS, as well as on neurons in the DMV in the context of gastrointestinal control. Electrophysiological experiments will be done in vitro using brain slice preparations from mature male mice in which DMV and NTS neurons can be identified by their anatomical connection with the stomach, their GABA content, or both. With whole-cell patch-clamp recordings, we will use photoactivation of caged glutamate to stimulate selectively the soma-dendritic regions of local neurons in order to analyze GABA-mediated connections within the solitary complex.
We aim to determine: 1) the contribution of tonic GABAergic currents to neuronal activity in the DMV;2) how identified gastric-related GABAergic neurons in the NTS are regulated by GABA input;and 3) effects of hyperglycemia on GABA currents in a model of type 1 diabetes. We will correlate electrophysiological results with pharmacological and molecular biological analyses to construct a cellular model of local GABAergic control of DMV neuron activity.

Public Health Relevance

Inhibitory connections between neurons that regulate the gastrointestinal system are critical to feeding and digestion, but how they control output to the stomach is largely unknown. We have uncovered evidence of a heretofore unstudied and powerful means of regulating how the brain controls the gut, and that this mechanism is altered in a model of type 1 diabetes mellitus. The experiments here will examine the synaptic mechanisms controlling gut-related neuron activity and will point to new ways of modifying activity of the gastrointestinal system in response to specific triggers associated with feeding and under pathological conditions of metabolic dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056132-11
Application #
8490350
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Hyde, James F
Project Start
2001-06-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$303,424
Indirect Cost
$97,713
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
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
Bach, Eva C; Halmos, Katalin Cs; Smith, Bret N (2015) Enhanced NMDA receptor-mediated modulation of excitatory neurotransmission in the dorsal vagal complex of streptozotocin-treated, chronically hyperglycemic mice. PLoS One 10:e0121022
Boychuk, Carie R; Gyarmati, Peter; Xu, Hong et al. (2015) Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii. J Neurophysiol 114:999-1007
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, Hong; Boychuk, Jeffery A; Boychuk, Carie R et al. (2015) Nicotine enhances inhibition of mouse vagal motor neurons by modulating excitability of premotor GABAergic neurons in the nucleus tractus solitarii. J Neurophysiol 113:1165-74
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
Boychuk, Carie R; Zsombok, Andrea; Tasker, Jeffrey G et al. (2013) Rapid Glucocorticoid-Induced Activation of TRP and CB1 Receptors Causes Biphasic Modulation of Glutamate Release in Gastric-Related Hypothalamic Preautonomic Neurons. Front Neurosci 7:3
Derbenev, Andrei V; Smith, Bret N (2013) Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity. PLoS One 8:e70505

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