Vagal neurocircuitry and its influence on gastric motility

Abstract

A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

Conflict of interest statement

Competing interests statement<

The authors declare no competing interests.

Figures

Figure 1. Anatomical organization of the nucleus tractus solitarius and the dorsal motor nucleus of the vagus

Coronal sections of the brainstem at caudal (caudal to area postrema), intermediate (at the level of the area postrema) and rostral (rostral to area postrema) levels. Brainstem areas lateral and ventral to the dorsal vagal complex (DVC) have not been represented. The location of the rostrocaudal columns representing areas of origin of the vagal branches within the dorsal motor nucleus of the vagus (DMV, pink areas) are shown in the intermediate coronal section, and the projections of rostrocaudal groups of motor neurons are shown in the rostral coronal section. The nucleus tractus solitarius (NTS) subnuclei and their main gastrointestinal-related inputs are shown in their approximate rostrocaudal locations. AP, area postrema; cc, central canal; IV, fourth ventricle; TS, tractus solitarius; XII, nucleus of the hypoglossus.

Figure 2. The brainstem neurocircuit comprising vagovagal reflexes

Vagal afferent fibres relay sensory information from the upper gastrointestinal tract, entering the CNS via the TS and transmitting sensory information to neurons of the NTS using glutamate as their main neurotransmitter,. The NTS neurons integrate this visceral sensory information, which is then conveyed to higher centres, such as the PVN, as well to the adjacent neurons of the DMV. Although a large array of neurotransmitters are used by NTS neurons, the main neurotransmitters are GABA, Glu and NE. Of these neurotransmitters, GABA seems to play a major part in controlling DMV neuronal firing rate and, by consequence, regulates vagal efferent outflow and modulation of gastric tone and motility,. Preganglionic parasympathetic neurons of the DMV use ACh, which interacts with nicotinic receptors, to excite postganglionic myenteric neurons and/or interstitial cells of Cajal. Vagal motor activation can induce both excitatory and inhibitory effects via stimulation of postganglionic neurons, which either release ACh onto excitatory muscarinic receptors or release inhibitory NANC neurotransmitters such as nitric oxide or vasoactive intestinal polypeptide onto gastric smooth muscles. Notably, NANC neurotransmission has an effect on gastric tone and motility, but not secretion. Ach, acetylcholine; AP, area postrema; DMV, dorsal motor nucleus of the vagus; GABA, γ-aminobutyric acid; Glu, glutamate; NANC, non-adrenergic non-cholinergic; NE, noradrenaline; NTS, nucleus tractus solitaries; PVN, paraventricular nucleus of the hypothalamus; TS, tractus solitarius.

Figure 3. Neurocircuits activated by gastrointestinal peptides

The vagus nerve has a major role in the feedback control of gastric motility. After ingestion of nutrients, specialized enteroendocrine cells within the small intestine release gastrointestinal peptides, which, in most cases, induce a robust gastroinhibition (that is, feedback control). In the past few years, studies have shown that the mechanism of action of many of these peptides involves hormonal as well as paracrine effects. The hormonal activity of these peptides is facilitated by the close proximity of these specialized cells to the villi vasculature. Gastrointestinal hormones can therefore act at sites other than vagal afferent fibres, including the portions of the dorsal vagal complex (DVC) and the hypothalamus that lie outside the blood–brain barrier. DVC, dorsal vagal complex; EEs, enteroendocrine cells.

Figure 4. Oxytocin receptor trafficking in the dorsal vagal complex and changes in gastric motility

a | In control animals, oxytocin activates the oxytocin receptor on the surface of the subset of DMV neurons that control the NANC nitric oxide pathway. This interaction increases their firing rate and activates NANC postganglionic neurons, which ultimately decrease gastric tone and motility. The GABAergic terminals impinging on the subset of DMV neurons controlling pathways other than the NANC nitric oxide pathway are unaffected by oxytocin. b | Following the increase in cAMP levels, the oxytocin receptors present in the subset of GABAergic terminals impinging onto the previously unresponsive DMV neurons that control pathways other than the NANC nitric oxide pathway are translocated to the terminal surface. Oxytocin binding to these translocated receptors reduces the amplitude of the GABA current and increases the firing rate of the DMV neurons, leading to increased release of acetylcholine in enteric neurons and increased gastric tone and motility. The relative influence of the NANC nitric oxide pathway is probably diminished by the increased activation of the cholinergic pathway, thereby resulting in the overall increase in tone and motility observed upon oxytocin perfusion. Ach, acetylcholine; DMV, dorsal motor nucleus of the vagus; ENS, enteric nervous system; GABA, γ−aminobutyric acid; NANC, nonadrenergic noncholinergic