Stress-induced modulation of vagal afferents

Abstract

Vagally-dependent gastric functions, including motility, tone, compliance, and emptying rate play an important role in the regulation of food intake and satiation. Vagal afferent fibers relay sensory information from the stomach, including meal-related information, centrally and initiate co-ordinated autonomic efferent responses that regulate upper gastrointestinal responses. The purpose of this mini-review is to highlight several recent studies which have uncovered the remarkable degree of neuroplasticity within gastric mechanosensitive vagal afferents as well as the recent study by Li et al., in this issue of Neurogastroenterology and Motlilty, who show that the mechanosensitivity of gastric vagal afferents is dysregulated in a murine model of chronic stress. The authors demonstrate that both gastric mucosal and tension afferents are hypersensitive following chronic stress, and responses to mucosal stroking and muscle stretch are enhanced significantly. Since gastric distension and volumetric signaling is important in satiety signaling and meal termination, this may provide a mechanistic basis for the gastric hypersensitivity associated with stress-associated clinical problems such as functional dyspepsia.

Gastric vagal afferents and the regulation of food ingestion

Studies in both humans and rodent models have shown that food intake and satiation is regulated, at least in part, by gastric motor functions, including motility, tone, compliance, and the rate of gastric emptying, all of which are important to the rate at which nutrients can be ingested and absorbed [1–3]. The important role of the vagus in early satiation is being increasingly recognized, resulting in more attention being paid to the critical role of vagally-mediated neurocircuits in the neural control of food intake and energy homeostasis [4, 5]. Sensory information from the gastrointestinal (GI) tract is relayed centrally via the afferent vagus nerve, the cell bodies of which lie in the paired nodose ganglion, the central terminals of which enter the brainstem via the tractus solitarius, and terminate on neurons of the nucleus of the tractus solitarius. Vagal afferents that transduce sensory information from the GI tract can be distinguished based upon their response to distention or pressure, their region of innervation and receptive fields (mucosal, muscle, or serosal/mesenteric) or their preferred stimulus modality (chemical, osmotic, mechanical) [6]. Vagal afferents innervating the stomach (gastric vagal afferents) can be typically classified as mucosal or muscular (tension) afferents.

Mucosal afferents, which innervate the mucosal layer but do not appear to make direct contact with the gastric lumen, are responsive to mucosal stroking and may play a role chemosensation [7] as well as the possible detection of food within the stomach, particularly the size of food particles. The activation of mucosal afferents initiates vagally-dependent reflexes to delay gastric emptying to ensure adequate grinding of food [8]. Tension afferents (both intraganglionic lamellar endings as well as intramuscular arrays) innervate the gastric smooth muscle [9] and detect gastric distension in response to food ingestion [10]. Such volumetric signaling appears important as an early satiety signal to initiate meal termination and limit food intake.

Several studies over the past decade have highlighted a significant degree of neuroplasticity within gastric vagal afferent signaling and, as such, vagal afferent dysfunction may play a causative role in many gastrointestinal pathophysiology. Mechanosensitive gastric vagal afferents are sensitized by gastric inflammation as well as thermal and chemical insult [11, 12], for example, which is thought to contribute to the development of dyspepsia. The mechanosensitivity of gastric tension afferents is decreased following diet-induced obesity [13–16], and even short periods (3–5 days) of exposure to a high fat diet compromise the ability of glucose to modulate serotonergic responses of vagal afferents and neurons [17, 18]. The reduced sensitivity to gastric distention, hence food ingestion, may therefore be reasonably expect to contribute to the increased meal size, hyperphagia, and weight gain associated with ingestion of a palatable diet. The mechanosensitivity of gastric vagal afferents also display a pronounced circadian rhythm, which may regulate meal patterning. In mice, for example, gastric vagal afferent mechanosensitivity decreases during the dark cycle which facilitates meal ingestion and increases meal size during the active, nocturnal, period [19]. Of interest, the circadian rhythm of gastric vagal afferents is lost in obese animals, which may partially explain the increased meal size particularly during the light phase when food intake is normally suppressed [20]. In this issue, Li et al., have provided the first evidence that the mechanosensitivity of gastric vagal afferents is also increased by chronic stress, which may contribute to the gastric hypersensitivity observed in functional dyspepsia [21].

Vagal afferent plasticity and stress

To assess alterations in gastric vagal afferent mechanosensitivity, Li et al., created a model of chronic stress where they exposed male C57Bl/6 mice to one or two randomly assigned stressors daily, for 8 weeks [21]. The unpredictable nature of the stress paradigms is thought to limit stress adaptation. At the conclusion of the period of stress loading, the stomach with attached vagal nerves were excised and the response of single gastric vagal afferent fibers to mucosal stroking (mucosal afferents) and circular stretch of the stomach (tension afferents) were assessed. The authors also assessed the effects of leptin gastric vagal afferent mechanosensitivity, given its well-described role in vagally-dependent satiation and the regulation of food intake, as well as the previously described plasticity in the response of mechanosensitive gastric vagal afferents to leptin [14, 22, 23].

Following chronic stress, the authors demonstrate that the responses of mucosal gastric vagal afferents to mucosal stroking, as well as tension gastric vagal afferents to circular stretch, was increased significantly. Indeed, the response of tension-sensitive gastric vagal afferents in particular were increased almost two-fold across the range of applied stretch; this may be a very physiologically relevant response since even relatively small increases in gastric volumes may then result in a significant increase in gastric vagal afferent activity which would be expected to initiate feedback mechanisms to signal satiation at lower gastric distention volumes; this may provide an explanation for the gastric hypersensitivity associated with functional dyspepsia and stress, which is often associated with early satiety and reduced meal size [3, 24, 25]

In contrast to the observed increase in gastric vagal afferent mechanosensitivity, however, the ability of leptin to excite mucosal gastric vagal afferents [22] was lost following chronic stress. As yet, it is unclear whether this is due to a loss of leptin responsiveness, or whether the stress-induced increase in mucosal gastric vagal afferent activity is simply preventing the observation of any additional increase. The ability of leptin to increase the mechanosensitivity of mucosal gastric vagal afferents has been proposed to play a role in its anorexigenic actions, since the increase in mechanosensitivity is proposed to initiate a vagally-dependent sensory feedback response to delay gastric emptying and terminate food ingestion. Conversely, the loss of leptin gastric vagal afferent responsiveness is associated with diet-induced obesity and hyperphagia [22, 26, 27]. The loss of leptin responsiveness in the current context of chronic stress may be a compensatory adaptation to the observed gastric hypersensitivity, since gastric leptin mRNA levels were also noted to be reduced, but such an apparent discrepancy will require further investigation.

Functional dyspepsia and vagal hypersensitivity

Functional dyspepsia, defined as chronic gastroduodenal symptoms in the absence of an identifiable organic cause is exacerbated by stress, and stressful events increase GI symptoms in susceptible individuals [28–30]. While attention has been focused on the role that dysregulated brain-gut connections play in the etiology of stress and functional gastrointestinal disorders [31–33], studies have also suggested that maladaptive gut-brain signaling may also impact disease pathophysiology. In particular, studies in humans have identified alterations in gastric sensitivity associated with functional dyspepsia [24, 34]. In the current issue, the study by Li et al., is one of the first to identify alterations in gastric vagal afferent mechanosensitivity in a murine model of chronic stress [21]. It is important to note, however, that the rodent model used in the described study recapitulates some, but not all, of the common clinical features of functional dyspepsia. Notably, the rodent model of mild chronic stress did not note any change in gastric emptying, which is contrast to the 20–50% of patients that report delayed gastric emptying, whereas increased anxiety, decreased body weight, and decreased meal number were features of the rodent model, however, which are observed commonly in the patient population [28, 30].

Of note, the study by Li et al., investigated the stress-induced alterations in mechanosensitivity of gastric vagal afferents only in male mice. Vagal afferent fibers and neurons express both nuclear and membrane-bound estrogen receptors [35–37], implying their functions may be modulated by gondal hormones in both a short- and long-term manner. Of interest, female rodents have been shown to have a significant greater number of myelinated vagal afferent fibers, and the excitability of these low threshold mechanosensitive neurons is increased by physiologically-relevant concentrations of estrogen [38]. Additionally, the the expression of neurokinin-1 receptors on vagal afferent neurons is upregulated by estrogen [39] suggesting that vagal sensory processing, including nociceptive signaling, may be modulated by the estrus cycle. Of note, functional dyspepsia is more prevalent in the female population, and females report increased severity of dyspeptic symptoms [28, 30]. The contribution of estrogen-dependent signaling to altered mechanosensation is, however, at present still speculative.

Summary and Conclusions

The remarkable degree of plasticity with gastric vagal afferent neurons and fibers suggests that dysregulation of vagally-dependent sensory processing may play a prominent role in several gastrointestinal pathologies. Clinical studies have demonstrated that gastric hypersensitivity is associated with functional dyspepsia, the symptoms of which are known to be exacerbated by stress and food ingestion. In the current issue, Li et al., demonstrate that, in a rodent model of chronic mild stress, the mechanosensitivity of gastric vagal afferents is increased significantly, which may provide a mechanistic basis for the gastric hypersensitivity observed in functional dyspepsia. Questions still remain as to the temporal pattern of dysregulated vagal afferents relative to the insult of chronic stress, particularly whether the gastric hypersensitivity occurs in response to long-term dysregulation in the brain-gut axis, whether disrupted gut-brain signaling contributes to the pathogenesis of this disease, and whether estrogen-dependent alterations in vagal signaling may amplify mechanosensitivity. The murine model described herein provides an experimental basis for investigations into role of vagal dysfunction in this chronic, and clinically relevant, disease.