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Hypothalamic-vagal oxytocinergic neurocircuitry modulates gastric emptying and motility following stress.

ABSTRACT:

Key points

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.

Abstract

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 [¹³ C]-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.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC8451654 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The assessment of gastric emptying and motility in humans and animals typically requires radioactive imaging or invasive measurements. Here, we developed a robust strategy to image and characterize gastric emptying and motility in rats based on contrast-enhanced magnetic resonance imaging (MRI) and computer-assisted image processing. The animals were trained to naturally consume a gadolinium-labeled dietgel while bypassing any need for oral gavage. Following this test meal, the animals were scanned under low-dose anesthesia for high-resolution T1-weighted MRI in 7 Tesla, visualizing the time-varying distribution of the meal with greatly enhanced contrast against non-gastrointestinal (GI) tissues. Such contrast-enhanced images not only depicted the gastric anatomy, but also captured and quantified stomach emptying, intestinal filling, antral contraction, and intestinal absorption with fully automated image processing. Over four postingestion hours, the stomach emptied by 27%, largely attributed to the emptying of the forestomach rather than the corpus and the antrum, and most notable during the first 30 min. Stomach emptying was accompanied by intestinal filling for the first 2 h, whereas afterward intestinal absorption was observable as cumulative contrast enhancement in the renal medulla. The antral contraction was captured as a peristaltic wave propagating from the proximal to distal antrum. The frequency, velocity, and amplitude of the antral contraction were on average 6.34 ± 0.07 contractions per minute, 0.67 ± 0.01 mm/s, and 30.58 ± 1.03%, respectively. These results demonstrate an optimized MRI-based strategy to assess gastric emptying and motility in healthy rats, paving the way for using this technique to understand GI diseases, or test new therapeutics in rat models.The assessment of gastric emptying and motility in humans and animals typically requires radioactive imaging or invasive measurements. Here, we developed a robust strategy to image and characterize gastric emptying and motility in rats based on contrast-enhanced magnetic resonance imaging (MRI) and computer-assisted image processing. The animals were trained to naturally consume a gadolinium-labeled dietgel while bypassing any need for oral gavage. Following this test meal, the animals were scanned under low-dose anesthesia for high-resolution T1-weighted MRI in 7 Tesla, visualizing the time-varying distribution of the meal with greatly enhanced contrast against non-gastrointestinal (GI) tissues. Such contrast-enhanced images not only depicted the gastric anatomy, but also captured and quantified stomach emptying, intestinal filling, antral contraction, and intestinal absorption with fully automated image processing. Over four postingestion hours, the stomach emptied by 27%, largely attributed to the emptying of the forestomach rather than the corpus and the antrum, and most notable during the first 30 min. Stomach emptying was accompanied by intestinal filling for the first 2 h, whereas afterward intestinal absorption was observable as cumulative contrast enhancement in the renal medulla. The antral contraction was captured as a peristaltic wave propagating from the proximal to distal antrum. The frequency, velocity, and amplitude of the antral contraction were on average 6.34 ± 0.07 contractions per minute, 0.67 ± 0.01 mm/s, and 30.58 ± 1.03%, respectively. These results demonstrate an optimized MRI-based strategy to assess gastric emptying and motility in healthy rats, paving the way for using this technique to understand GI diseases, or test new therapeutics in rat models.

Project description:Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. The development of gastric symptoms may depend on how humans adapt to the stressful events in their daily lives. Although acute stress delays gastric emptying and alters upper gastrointestinal motility in rodents, the effects of chronic stress on gastric motility and its adaptation mechanism remains unclear. Central oxytocin has been shown to have antistress effects. We studied whether central oxytocin is involved in mediating the adaptation mechanism following chronic repeated stress. Mice were loaded with acute and chronic stress (repeated stress for five consecutive days), and solid gastric emptying and postprandial gastric motility were compared between acute and chronic repeated stress. Expression of oxytocin and CRF mRNA in the hypothalamus was studied following acute and chronic repeated stress. Delayed gastric emptying during acute stress (43.1 +/- 7.8%; n = 6, P < 0.05) was completely restored to normal levels (72.1 +/- 2.4%; n = 6) following chronic repeated stress. Impaired gastric motility induced by acute stress was also restored following chronic repeated stress. Intracerebroventricular injection of oxytocin (0.1 and 0.5 microg) restored the impaired gastric emptying and motility induced by acute stress. The restored gastric emptying and motility following chronic repeated stress were antagonized by intracerebroventricular injection of oxytocin antagonists. Oxytocin mRNA expression in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus was significantly increased following chronic repeated stress. In contrast, increased CRF mRNA expression in the SON and PVN in response to acute stress was significantly reduced following chronic repeated stress. Our study suggests the novel finding that the upregulation of central oxytocin expression is involved in mediating the adaptation mechanism following chronic repeated stress in mice.

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Hypothalamic-vagal oxytocinergic neurocircuitry modulates gastric emptying and motility following stress.

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