The goal of this proposal is to determine the role of two specific GABAergic interneurons, somatostatin (Sst) and neuropeptide Y (Npy) expressing neurons, in the regulation of Brainstem neural circuitry controlling gastric function. Our studies, focusing on the major brain nuclei of this circuit that form the dorsal vagal complex (DVC) in the hindbrain, namely the medial nucleus tractus solitarius (mNTS) and dorsal motor nucleus of the vagus (DMV), indicate that local GABA signaling in these nuclei is critical for modulation of vagal output to the stomach. However, the identity of the GABA neurons to which this inhibitory signaling can be attributed is lacking. Recent advances in transgenic mouse models, virus injection and optogenetic techniques have made it possible to isolate and selectively stimulate specific cell types. Using these technologies, we have begun to acquire nascent data on the identity and role of the neurons involved in GABA signaling in the DVC. Furthermore, these techniques have been instrumental in obtaining information on the likely mechanisms by which a regulator of energy homeostasis, namely an endogenous agonist of the melanocortin receptor system (McR), produces its differential effects on gastric function (e.g., tone and motility) in the NTS (inhibitory) and in the DMV (excitatory). The focus of the present proposal is on the genetically and virally defined Sst and Npy neurons in the DVC. We will investigate the functional role of these neurons in DVC circuitry by determining their electrophysiological and morphological characteristics in relation to other neurons that comprise the neural circuitry controlling gastric function via trans-synaptic labeling. Our previously published data and preliminary findings show that optogenetic stimulation of Sst/Npy neurons in the NTS or DMV strongly influence the activity of neurons along the Brain-Gut axis. Based on these results, we will pursue our overall hypothesis that Sst and Npy neurons in the DVC serve as key complementary components that regulate the vago-vagal gastric circuitry. Finally, we will assess the role of Sst and Npy neurons in an in vivo model of gastric function. In this model, we will test the hypothesis that stimulation of Sst and Npy GABA neurons in the mNTS and DMV will selectively affect gastric tone and motility. The knowledge gained from our proposed studies will contribute greatly to understanding vago-vagal circuitry controlling gastric function, with the potential of providing an important template for studying homeostasis in other autonomic reflex systems.
The gastric vago-vagal brain circuitry plays a critical role in the regulation of stomach activity. Dysfunction of this circuitry has been implicated in a multitude of disorders including Parkinson's, obesity, diabetic gastroparesis, gastric reflux, hyperinsulinemia, hyperglycemia, and achalasia. This research will begin to elucidate how the output of vago-vagal circuitry is controlled with a view towards identifying the identity of the distinct neurons regulating the circuity, and establishing a strong foundation for studying circuitries that control other autonomic functions.
