Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions

Abstract

The meticulous regulation of the gastrointestinal (GI) tract is required for the coordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders and the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second-order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of GI functions.

Keywords: brainstem; gastrointestinal; glutamate.

Graphical abstract

Figure 1.

Schematic diagram summarizing glutamate transmission within central vagal brainstem neurocircuits regulating GI functions. Vagal afferent signals are relayed centrally via the afferent (sensory) vagus and enter the brainstem via the tractus solitarius, releasing glutamate (Glu) to activate neurons of the nucleus of the tractus solitarius (NTS; upper right). Glutamate released from vagal afferents activates postsynaptic NTS ionotropic glutamate receptors (AMPA and, at higher frequencies of stimulation, NMDA receptors) as well as metabotropic glutamate receptors (mGluR). Glutamate release from vagal afferent terminals is modulated by a variety of presynaptic receptors including 5-HT3, TRPV1, and mGluR. Synaptic glutamate levels are regulated by glutamate transporters (GAT) present on astrocytes and presynaptic afferent terminals. NTS neurons integrate vagal afferent inputs with those from brainstem, midbrain, and higher CNS centers involved in autonomic homeostasis and transmit the integrated signal to the adjacent dorsal motor nucleus of the vagus (DMV) using norepinephrine, GABA, and glutamate as neurotransmitters. Glutamate released from NTS neurons activates postsynaptic DMV ionotropic glutamate receptors (AMPA and, following acute high fat diet exposure, NMDA receptors) as well as postsynaptic mGluR. Glutamate release from NTS terminals is modulated by a variety of presynaptic receptors including mGluR, insulin, and GABA_A receptors, in addition to other metabotropic and ionotropic receptors not listed. Astrocytes play a significant role in regulating synaptic glutamate levels via GAT, as well as via release of gliotransmitters following insult or injury such as inflammation and obesity. Ach, acetylcholine; NANC, non-adrenergic, non-cholinergic; P2X, ATP-gated P2X receptor.