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 #
5R01DK056132-10
Application #
8307977
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
2012-07-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$314,429
Indirect Cost
$101,257
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
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
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
Zsombok, Andrea; Bhaskaran, Muthu D; Gao, Hong et al. (2011) Functional plasticity of central TRPV1 receptors in brainstem dorsal vagal complex circuits of streptozotocin-treated hyperglycemic mice. J Neurosci 31:14024-31
Gao, Hong; Smith, Bret N (2010) Tonic GABAA receptor-mediated inhibition in the rat dorsal motor nucleus of the vagus. J Neurophysiol 103:904-14
Derbenev, Andrei V; Duale, Hanad; Rabchevsky, Alexander G et al. (2010) Electrophysiological characteristics of identified kidney-related neurons in adult rat spinal cord slices. Neurosci Lett 474:168-72
Duale, Hanad; Lyttle, Travis S; Smith, Bret N et al. (2010) Noxious colorectal distention in spinalized rats reduces pseudorabies virus labeling of sympathetic neurons. J Neurotrauma 27:1369-78
Gao, Hong; Glatzer, Nicholas R; Williams, Kevin W et al. (2009) Morphological and electrophysiological features of motor neurons and putative interneurons in the dorsal vagal complex of rats and mice. Brain Res 1291:40-52
Chen, Jing; Paudel, Kalpana S; Derbenev, Andrei V et al. (2009) Simultaneous Quantification of Anandamide and Other Endocannabinoids in Dorsal Vagal Complex of Rat Brainstem by LC-MS. Chromatographia 69:1-7
Zsombok, Andrea; Smith, Bret N (2009) Plasticity of central autonomic neural circuits in diabetes. Biochim Biophys Acta 1792:423-31

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