First published: 30 August 2020
Edited by: Kim Barrett & Melanie Gareau
- Stress triggers and exacerbates the symptoms of functional gastrointestinal disorders, such as delayed gastric emptying and impaired gastric motility.
- Understanding the mechanisms by which the neural circuits, impaired by stress, are restored may help to identify potential targets for more effective therapeutic interventions.
- Oxytocin administration or release ameliorates the stress‐induced delayed gastric emptying and motility. However, is it unclear whether the effects are mediated via the hypothalamic‐pituitary‐adrenocortical axis or the oxytocinergic projections from the paraventricular nucleus of the hypothalamus to brainstem neurones of the dorsal vagal complex.
- We used Cre‐inducible designer receptors exclusively activated by designer drugs to demonstrate the fundamental role of the oxytocinergic hypothalamic–vagal projections in the gastric adaptation to stress.
Stress triggers and exacerbates the symptoms of functional gastrointestinal (GI) disorders, such as delayed gastric emptying and impaired gastric motility. The prototypical anti‐stress hormone, oxytocin (OXT), plays a major role in the modulation of gastric emptying and motility following stress. It is not clear, however, whether the amelioration of dysregulated GI functions by OXT is mediated via an effect on the hypothalamic‐pituitary‐adrenocortical axis or the oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to neurones of the dorsal vagal complex (DVC). In the present study we tested the hypothesis that the activity of hypothalamic–vagal oxytocinergic neurocircuits plays a major role in the gastric adaptation to stress. Cre‐inducible designer receptors exclusively activated by designer drugs (DREADDs) were injected into the DVC of rats and retrogradely transported to allow selective expression in OXT neurones in the PVN. Following acute stress and either chronic heterotypic (CHe) or chronic homotypic (CHo) stress, gastric emptying was assessed via the [13C]‐octanoic acid breath test, and gastric tone and motility were assessed via strain gauges sewn on the surface of the stomach. Activation of the hypothalamic–vagal oxytocinergic neurocircuitry, by DREADD agonist clozapine‐N‐oxide (CNO), prevented the delayed gastric emptying observed following acute or CHe stress, and 4th ventricular administration of CNO increased gastric tone and motility. Conversely, CNO‐mediated inhibition of the hypothalamic–vagal oxytocinergic neurocircuitry prevented the CHo‐induced adaptation in gastric emptying, and an increase in gastric tone and motility. Taken together, the data support the hypothesis that hypothalamic–vagal oxytocinergic neurocircuits play a major role in the modulation of gastric emptying and motility following stress.
Stress induces dysregulation of the brain–gut axis and contributes to the pathophysiology of functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome (Stengel & Tache, 2009; Fukudo, 2013; Drossman, 2016; Labanski et al. 2020). A lack of resilience, habituation, or adaptation to stress results in an alteration in gastrointestinal (GI) motor functions, including delayed gastric emptying and accelerated colonic transit (Stengel & Tache, 2009; Khoo et al. 2010; Zheng et al. 2010; Babygirija et al. 2011; Jiang et al. 2019a). The functions of the upper GI tract, including gastric tone and motility, are modulated by the activity of pacemaker neurones of the dorsal motor nucleus of the vagus (DMV) whose activity is regulated by a robust tonic GABAergic input from the adjacent nucleus tractus solitarius (NTS), itself the recipient of GI sensory input (Travagli and Anselmi, 2016), as well as inputs from higher centres, including oxytocin (OXT) projections that originate exclusively from the paraventricular nucleus of the hypothalamus (PVN) (Browning & Travagli, 2014). These oxytocinergic neurocircuits appear at birth and increase markedly with age (Rinaman, 1998). In adult rats, OXT axons occur throughout the rostrocaudal extent of the DVC and appose closely to gastric‐projecting DMV neurones (Llewellyn‐Smith et al. 2012).
An extraordinary degree of adaptive plasticity is required to ensure that vagally regulated GI functions respond appropriately to a variety of intrinsic and extrinsic factors, including stress. In recent years, work from our laboratory has highlighted the significant degree of neuroplasticity in brainstem vagal GABAergic neurocircuits, particularly in response to stress‐related hormones, such as OXT, corticotropin‐releasing factor (CRF), thyrotropin‐releasing hormone and noradrenaline (or norepinephrine, NE) (Browning & Travagli, 2014; Travagli & Anselmi, 2016; Jiang et al. 2018a).
Activation of central oxytocinergic pathways has anxiolytic and anti‐stress effects, and is involved in the adaptive response to chronic repetitive stress (Jurek & Neumann, 2018; Winter & Jurek, 2019). OXT release reduces the expression and release of CRF, attenuates the activity and responsiveness of the hypothalamic‐pituitary‐adrenocortical (HPA) axis, and modulates autonomic and sensory systems associated with the stress response (Windle et al. 1997; Jurek & Neumann, 2018; Winter & Jurek, 2019). Indeed, inputs, including the oxytocinergic ones, onto gastric‐projecting vagal neurocircuitry undergo a high level of neuroplasticity in response to stressful stimuli (Browning & Travagli, 2014; Travagli & Anselmi, 2016; Jiang et al. 2018a,b), and we have shown recently that acute stress or pretreatment with CRF induces a cAMP‐dependent translocation of OXT receptors to the terminals of previous unresponsive GABAergic NTS‐DMV synapses (Browning et al. 2014).
The anti‐stressor effects of central OXT in GI function was demonstrated by its reversal of the gastric dysmotility that occurs during acute and chronic variable stress (i.e. chronic heterotypic stress, CHe) (Zheng et al. 2010). Furthermore, both systemic administration of OXT antagonists or knockout of OXT receptors has been shown to prevent the adaptive GI motility in response to chronic repetitive stress (i.e. chronic homotypic stress, CHo) (Zheng et al. 2010; Babygirija et al. 2010a,b, 2011). Whether the beneficial effect of OXT in regulating GI motility is attributed to modulation of the HPA axis or to the direct influence of OXT on vagal neurocircuitry innervating the GI tract is still unclear. In this study, we used different established models of stress, i.e. acute stress, CHo, in which Sprague–Dawley rats show an attenuated response or an adaptation to the stressor, and CHe, in which the rats do not adapt to the variable stressors.
The aim of the present study was to test the hypothesis that the activity of hypothalamic–vagal oxytocinergic neurocircuits plays a major role in the gastric response to stress.