The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat.

A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon.

Perinatal high-fat diet exposure alters oxytocin and corticotropin releasing factor inputs onto vagal neurocircuits controlling gastric motility.

Perinatal high-fat diet (pHFD) exposure alters the development of vagal neurocircuits that control gastrointestinal (GI) motility and reduce stress resiliency in offspring. Descending oxytocin (OXT; prototypical anti-stress peptide) and corticotropin releasing factor (CRF; prototypical stress peptide) inputs from the paraventricular nucleus (PVN) of the hypothalamus to the dorsal motor nucleus of the vagus (DMV) modulate the GI stress response. How these descending inputs, and their associated changes to GI motility and stress responses, are altered following pHFD exposure are, however, unknown.

Experimental models of gut-first Parkinson's disease: A systematic review.

Background: There is strong support from studies in humans and in animal models that Parkinson's disease (PD) may begin in the gut. This brings about a unique opportunity for researchers in the field of neurogastroenterology to contribute to advancing the field and making contributions that could lead to the ability to diagnose and treat PD in the premotor stages. Lack of familiarity with some of the aspects of the experimental approaches used in these studies may present a barrier for neurogastroenterology researchers to enter the field.

Brainstem astrocytes control homeostatic regulation of caloric intake.

Prolonged high-fat diet (HFD) exposure is associated with hyperphagia, excess caloric intake and weight gain. After initial exposure to a HFD, a brief (24-48 h) period of hyperphagia is followed by the regulation of caloric intake and restoration of energy balance within an acute (3-5 day) period. Previous studies have demonstrated this occurs via a vagally mediated signalling cascade that increases glutamatergic transmission via activation of NMDA receptors located on gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV).

Stress-induced neuroplasticity in the gastric response to brainstem oxytocin in male rats.

Previous studies have shown that pharmacological manipulations with stress-related hormones such as corticotropin-releasing factor and thyrotropin-releasing hormone induce neuroplasticity in brainstem vagal neurocircuits, which modulate gastric tone and motility. The prototypical antistress hormone oxytocin (OXT) has been shown to modulate gastric tone and motility via vagal pathways, and descending hypothalamic oxytocinergic inputs play a major role in the vagally dependent gastric-related adaptations to stress. The aim of this study was to investigate the possible cellular mechanisms through which OXT modulates central vagal brainstem and peripheral enteric neurocircuits of male Sprague-Dawley rats in response to chronic repetitive stress.

Vagal Tone and Proinflammatory Cytokines Predict Feeding Intolerance and Necrotizing Enterocolitis Risk.

Background: Necrotizing enterocolitis (NEC) is the leading cause of death due to gastrointestinal disease in preterm neonates; yet, clinicians lack reliable and noninvasive predictive tools.

Purpose: We aimed to test that diminished high-frequency heart rate variability (HF-HRV) and elevated levels of proinflammatory cytokines would have utility in NEC prediction.

Methods: In this multisite prospective study, we enrolled 250 preterm (26-34 weeks' postmenstrual age [PMA]) neonates with physiological stability at 72 hours of life.

DMV extrasynaptic NMDA receptors regulate caloric intake in rats.

Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors.

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

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.

Parkinson disease and the gut: new insights into pathogenesis and clinical relevance.

The classic view portrays Parkinson disease (PD) as a motor disorder resulting from loss of substantia nigra pars compacta dopaminergic neurons. Multiple studies, however, describe prodromal, non-motor dysfunctions that affect the quality of life of patients who subsequently develop PD. These prodromal dysfunctions comprise a wide array of gastrointestinal motility disorders including dysphagia, delayed gastric emptying and chronic constipation.

Necrotizing enterocolitis: It's not all in the gut.

Unlabelled: Necrotizing enterocolitis is the leading cause of death due to gastrointestinal disease in preterm neonates, affecting 5–12% of neonates born at a very-low birth weight. Necrotizing enterocolitis can present with a slow and insidious onset, with some neonates displaying early symptoms such as feeding intolerance. Treatment during the early stages includes bowel rest and careful use of antibiotics, but surgery is required if pneumoperitoneum and intestinal perforation occur.

Characterization of the Basic Membrane Properties of Neurons of the Rat Dorsal Motor Nucleus of the Vagus in Paraquat-Induced Models of Parkinsonism.

Most of Parkinson's disease (PD) patients experience gastrointestinal dysfunctions, including gastric hypomotility. The dorsal motor nucleus of the vagus (DMV) modulates the motility of the upper gastrointestinal (GI) tract. Paraquat (P) administration induces Parkinsonism in experimental models, and we have developed recently an environmental model of Parkinsonism in which rats are treated with subthreshold doses of P and lectins (P + L), in both models rats develop reduced gastric motility prodromal to the full extent of motor deficits.

Sex differences in GABAergic neurotransmission to rat DMV neurons.

Functional gastrointestinal disorders, including delayed gastric emptying and decreased gastric motility, are more prevalent in women, suggesting a potential role for circulating gonadal hormones, including estrogen. Gastric motility is tuned by the vagal inputs arising from the dorsal motor nucleus of the vagus (DMV), which is itself controlled by tonic GABAergic inputs. Estrogen increases GABA functions in various central nervous system areas; however, the effect of the estrus cycle in modulating GABAergic inputs onto DMV neurons, hence vagal control of gastric motility, has not been investigated.

Ghrelin ameliorates the phenotype of newborn rats induced with mild necrotizing enterocolitis.

Background: We have shown previously that an attenuated rodent model of mild necrotizing enterocolitis (NEC) increases intestinal histopathological severity grade, prevents typical developmental increases in the high-frequency spectrum of heart rate variability (HF-HRV), alters the nitrergic myenteric phenotype, and increases IL-6 and IL-1β when combined with anterior subdiaphragmatic vagotomy. The aims of the present study were to test the hypotheses that in mild NEC-induced pups, administration of the orexigenic hormone ghrelin (a) reduces the histopathological score, (b) increases the HF-HRV power, (c) improves the altered myenteric phenotype, and (d) subdiaphragmatic vagotomy prevents the effects of ghrelin.

Methods: Newborn Sprague Dawley rats were subjected to seven days of brief periods of cold stress and hypoxia to induce mild NEC with or without anterior subdiaphragmatic vagotomy.

Role of estrogen and stress on the brain-gut axis.

Symptoms of functional gastrointestinal disorders (FGIDs), including fullness, bloating, abdominal pain, and altered gastrointestinal (GI) motility, present a significant clinical problem, with a reported prevalence of 25%-40% within the general population. More than 60% of those affected seek and require healthcare, and affected individuals report a significantly decreased quality of life. FGIDs are highly correlated with episodes of acute and chronic stress and are increased in prevalence and reported severity in women compared with men.

Correlation between the motility of the proximal antrum and the high-frequency power of heart rate variability in freely moving rats.

Background: Cardiac vagal tone can be monitored non-invasively via electrocardiogram measurements of the high-frequency power spectrum of heart rate variability (HF-HRV). Vagal inputs to the upper GI tract are cumbersome to measure non-invasively. Although cardiac and GI vagal outputs arise from distinct brainstem nuclei, the nucleus ambiguus, and the dorsal motor nucleus of the vagus, respectively, we aim to test the hypotheses that in freely moving rats HF-HRV power is correlated to proximal antral motility and can be altered by high levels of circulating estrogen and vagal-selective treatments known to affect antral motility.

Perinatal high-fat diet alters development of GABA receptor subunits in dorsal motor nucleus of vagus.

Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregulation of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABA receptor subunit development. In vivo gastric recordings were made from adult anesthetized Sprague-Dawley rats fed a control or pHFD (14 or 60% kcal from fat, respectively) from embryonic (E13) to postnatal (P42), and response to brainstem microinjection of benzodiazepines was assessed.

Altered gastric tone and motility response to brain-stem dopamine in a rat model of parkinsonism.

The majority of patients with Parkinson's disease (PD) experience gastrointestinal dysfunction. Recently, we described a nigro-vagal pathway that uses dopaminergic (DA) inputs to the dorsal motor nucleus of the vagus (DMV) and A2 area neurons to modulate gastric motility and tone. This pathway is disrupted in a rodent model of PD.

Neurophysiology of the brain stem in Parkinson's disease.

Parkinson's disease (PD) is predominantly idiopathic in origin, and a large body of evidence indicates that gastrointestinal (GI) dysfunctions are a significant comorbid clinical feature; these dysfunctions include dysphagia, nausea, delayed gastric emptying, and severe constipation, all of which occur commonly before the onset of the well-known motor symptoms of PD. Based on a distinct distribution pattern of Lewy bodies (LB) in the enteric nervous system (ENS) and in the preganglionic neurons of the dorsal motor nucleus of the vagus (DMV), and together with the early onset of GI symptoms, it was suggested that idiopathic PD begins in the ENS and spreads to the central nervous system (CNS), reaching the DMV and the substantia nigra pars compacta (SNpc). These two areas are connected by a recently discovered monosynaptic nigro-vagal pathway, which is dysfunctional in rodent models of PD.

Central control of gastrointestinal motility.

Purpose Of Review: This review summarizes the organization and structure of vagal neurocircuits controlling the upper gastrointestinal tract, and more recent studies investigating their role in the regulation of gastric motility under physiological, as well as pathophysiological, conditions.

Recent Findings: Vagal neurocircuits regulating gastric functions are highly plastic, and open to modulation by a variety of inputs, both peripheral and central. Recent research in the fields of obesity, development, stress, and neurological disorders highlight the importance of central inputs onto these brainstem neurocircuits in the regulation of gastric motility.

Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat.

Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson's disease (PD). We tested the hypothesis that gastric co-administration of subthreshold doses of lectins and paraquat can recreate the pathology and behavioral manifestations of PD in rats. A solution containing paraquat + lectin was administered daily for 7 days via gastric gavage, followed by testing for Parkinsonian behavior and gastric dysmotility.

Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats.

Background: We have shown previously that a decreased high-frequency spectrum of heart rate variability (HF-HRV), indicative of reduced vagal tone, shows promise in predicting neonates likely to develop necrotizing enterocolitis (NEC) before its clinical onset. We hypothesized that NEC induction in rat pups decreases HF-HRV power; subdiaphragmatic vagotomy worsens the severity of the NEC phenotype, increases levels of pro-inflammatory cytokines, and alters the myenteric phenotype.

Methods: Newborn Sprague-Dawley rats, representative of preterm human neonates, were subjected to 7-8 days of brief periods of cold stress and hypoxia to induce NEC with or without unilateral subdiaphragmatic vagotomy.

Increased Frequency of Skin-to-Skin Contact Is Associated with Enhanced Vagal Tone and Improved Health Outcomes in Preterm Neonates.

Objective: An estimation of the individual's ability to cope with environmental adversity, that is, stress resiliency, can be extrapolated by measuring cardiac vagal tone, that is, high-frequency heart rate variability (HF-HRV); indeed, higher HF-HRV is associated with health and developmental advantages for preterm neonates. Previous studies show skin-to-skin contact (SSC) improves stress resiliency; however, linkages between SSC and HF-HRV on outcomes have not been assessed. We aimed to test the hypothesis that increased SSC frequency would enhance HF-HRV, reduce neonatal morbidity, and improve developmental outcomes.

Stress Adaptation Upregulates Oxytocin within Hypothalamo-Vagal Neurocircuits.

Stress plays a pivotal role in the development and/or exacerbation of functional gastrointestinal (GI) disorders. The paraventricular nucleus of the hypothalamus (PVN) contains neurons that are part of the hypothalamic-pituitary-adrenal axis as well as preautonomic neurons innervating, among other areas, gastric-projecting preganglionic neurons of the dorsal vagal complex (DVC). The aim of the present study was to test the hypothesis that stress adaptation upregulates oxytocin (OXT) within PVN-brainstem vagal neurocircuitry.

Novel transmitters in brain stem vagal neurocircuitry: new players on the pitch.

The last few decades have seen a major increase in the number of neurotransmitters and neuropeptides recognized as playing a role in brain stem neurocircuits, including those involved in homeostatic functions such as stress responsiveness, gastrointestinal motility, feeding, and/or arousal/wakefulness. This minireview will focus on the known physiological role of three of these novel neuropeptides, i.e.