Neural circuitry in the dorsal vagal complex

Abstract 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 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 to control of feeding and digestion, relatively little is known about local connections within 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 tightly regulated by both glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control of motor output to the stomach 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 dysfunction effects people with diabetes mellitus and is attributed to altered vagal control of the stomach. We 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. Project Description Page 6