Neural Pathway for Gut Feelings: Vagal Interoceptive Feedback From the Gastrointestinal Tract Is a Critical Modulator of Anxiety-like Behavior

Krieger, Jean‐Philippe; Asker, Mohammed; Pauline, Van der Velden; Börchers, Stina; Jennifer, Richard E.; Maric, Ivana; Longo, Francesco; Singh, Avninder; Guillaume, De Lartigue; Karolina, Skibicka P.

doi:10.1016/j.biopsych.2022.04.020

Cited by 22 publications

(14 citation statements)

References 48 publications

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“…Of interest, acute stress elevates blood pressure via CRF-dependent projections to the NTS and subsequent alterations to sympathetic cardiac outflow (Wang et al ., 2019) although it remains to be determined whether cardiovascular autonomic outputs are similarly uncoupled following pHFD. Additionally, while the current study has suggested that pHFD disrupts hypothalamic-brainstem stress neurocircuits that impact GI functions, investigation of limbic regions (the central amygdala and anterior cingulate cortex) and higher order regions involved in executive function (prefrontal cortex) would be required to assess the role of descending inputs to the hypothalamus as additional potential drivers of this neural dysfunction, given their roles in anxiety (Krieger et al ., 2022) and pain perception (Silverman et al ., 1997). These are also sources of extrahypothalamic CRF production (Merchenthaler et al ., 1982; Bhatia & Tandon, 2005) and could explain the dissonance between PVN CRF levels, CRF fiber density in the DMV, and CRF concentration in the CSF identified in the current study.…”

Section: Discussionmentioning

confidence: 99%

Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Carson

Alvarez

Mackley

et al. 2022

Preprint

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Perinatal high fat diet (pHFD) exposure is known to affect 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. However, how these descending inputs, and their associated changes to GI motility and stress responses, are altered following pHFD exposure are unknown. The present study usedin vivorecordings of gastric tone and motility,in vivoassays of gastric emptying rates,in vitroelectrophysiological recordings from brainstem slice preparations, and retrograde neuronal tracing experiments to investigate the hypothesis that pHFD alters descending PVN-DMV inputs, dysregulating DMV neuronal responses and subsequent gastric motility. Basal gastric emptying rates were found to be significantly delayed in pHFD rats, which also demonstrating an inability to mount an appropriate response to acute stress with a further delay in gastric emptying. Neuronal tracing experiments suggested that pHFD reduced PVNOXTneurons that project to the DMV but increased PVNCRFprojections. Whole cell patch clamp recordings of DMV neurons demonstrated that, following pHFD, PVNCRFprojections are tonically active, altering GABAergic inputs to DMV neurons. Lastly, blocking DMV CRF receptors in pHFD rats restored the appropriate gastric response to brainstem oxytocin application. Taken together, these results indicate that pHFD exposure leads to an upregulating of CRF inputs to the DMV, resulting in tonic CRF activation on the system and altering gastric motility. These results suggest that pHFD exposure leads gastric dysmotility, leading to a maladaptive gastric stress response and reduced stress resiliency.

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Section: Discussionmentioning

confidence: 99%

Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Carson

Alvarez

Mackley

et al. 2022

Preprint

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“…From a neural perspective, insomnia caused by GERD may be attributed to the interplay of various neural pathways. The excitement of the vagus nerve caused by gastroesophageal reflux may lead to dysfunction in the hypothalamus and amygdala ( 49 – 51 ), two brain regions involved in regulating sleep stability, emotion, and cognition. This can result in unstable sleep and increased susceptibility to external factors that disturb sleep.…”

Section: Discussionmentioning

confidence: 99%

Causal association of gastroesophageal reflux disease with obstructive sleep apnea and sleep-related phenotypes: a bidirectional two-sample Mendelian randomization study

Qin,

Wang,

Wang

et al. 2023

Front. Neurol.

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BackgroundThe interactions and associations between obstructive sleep apnea (OSA), sleep-related phenotypes (SRPs), and gastroesophageal reflux disease (GERD) are complex, thus it is hard to explore the effect and direction of causalities.Study objectivesA bidirectional Mendelian randomization (MR) study was performed to explore causal associations of GERD with OSA and SRPs (including insomnia, morningness, sleep duration, ease of getting up, daytime napping, daytime dozing, and snoring).MethodsFirst, we gathered summary statistics from publicly available databases. Subsequently, we identified single-nucleotide polymorphisms without strong linkage (r2 ≤ 0.001) by referencing relevant genome-wide association studies that met genome-wide significance criteria. Our primary analysis relied on inverse variance weighted to estimate the causal relationship. To ensure the validity of our findings, we also conducted several sensitivity analyses. These included MR Pleiotropy RESidual Sum and Outlier to detect and correct for potential pleiotropic effects, MR-Egger to assess directional pleiotropy, and weighted median analysis to further evaluate heterogeneity and pleiotropy. For the initial MR analysis, when causality was indicated by the results, instrumental variables that were significantly linked to the aforementioned confounding factors were removed. We will re-analyze the data after excluding outcome-related single nucleotide polymorphisms to confirm that the results are still consistent with the previous results.ResultsGERD was found to increase the risk of OSA (OR = 1.53, 95% CI = 1.37–1.70, p = 5.3 × 10−15), insomnia (OR = 1.14, 95% CI = 1.10–1.19, p = 1.3 × 10−10), snoring (OR = 1.09, 95% CI = 1.04–1.13, p = 6.3 × 10−5) and less sleep duration (OR = 0.94, 95% CI = 0.91–0.97, p = 3.7 × 10−4). According to the reverse-direction analysis, there is an elevated risk of GERD associated with OSA (OR = 1.07, 95% CI = 1.02–1.12, p = 0.005), insomnia (OR = 1.95, 95% CI = 1.60–2.37, p = 1.92 × 10−11) and snoring (OR = 1.74, 95% CI = 1.37–2.21, p = 4.4 × 10−6).ConclusionGenetic susceptibility to GERD can elevate the likelihood of experiencing insomnia, snoring, and OSA, in addition to diminishing sleep duration. Conversely, a reverse MR analysis indicates that ameliorating any one of insomnia, snoring, or OSA can mitigate the risk of developing GERD.

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“…Of interest, acute stress elevates blood pressure via CRF-dependent projections to the NTS and subsequent alterations to sympathetic cardiac outflow (Wang et al, 2019) although it remains to be determined whether cardiovascular autonomic outputs are similarly uncoupled following pHFD. Additionally, while the current study has suggested that pHFD disrupts hypothalamic-brainstem stress neurocircuits that impact GI functions, investigation of limbic regions (the central amygdala and anterior cingulate cortex) and higher order regions involved in executive function (prefrontal cortex) would be required to assess the role of descending inputs to the hypothalamus as additional potential drivers of this neural dysfunction, given their roles in anxiety (Krieger et al, 2022) and pain perception (Silverman et al, 1997). These are also sources of extrahypothalamic CRF production (Bhatia & Tandon, 2005;Merchenthaler et al, 1982) and could explain the dissonance between PVN CRF levels, CRF fibre density in the DMV and CRF concentration in the CSF identified in the current study.…”

Section: Discussionmentioning

confidence: 97%

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

Carson

Alvarez

Mackley

et al. 2023

The Journal of Physiology

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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. The present study used retrograde neuronal tracing experiments, cerebrospinal fluid extraction, in vivo recordings of gastric tone, motility and gastric emptying rates, and in vitro electrophysiological recordings from brainstem slice preparations to investigate the hypothesis that pHFD alters descending PVN–DMV inputs and dysregulates vagal brain–gut responses to stress. Compared to controls, rats exposed to pHFD had slower gastric emptying rates and did not respond to acute stress with the expected delay in gastric emptying. Neuronal tracing experiments demonstrated that pHFD reduced the number of PVNOXT neurons that project to the DMV, but increased PVNCRF neurons. Both in vitro electrophysiology recordings of DMV neurons and in vivo recordings of gastric motility and tone demonstrated that, following pHFD, PVNCRF–DMV projections were tonically active, and that pharmacological antagonism of brainstem CRF1 receptors restored the appropriate gastric response to brainstem OXT application. These results suggest that pHFD exposure disrupts descending PVN–DMV inputs, leading to a dysregulated vagal brain–gut response to stress. Key points Maternal high‐fat diet exposure is associated with gastric dysregulation and stress sensitivity in offspring. The present study demonstrates that perinatal high‐fat diet exposure downregulates hypothalamic–vagal oxytocin (OXT) inputs but upregulates hypothalamic–vagal corticotropin releasing factor (CRF) inputs. Both in vitro and in vivo studies demonstrated that, following perinatal high‐fat diet, CRF receptors were tonically active at NTS–DMV synapses, and that pharmacological antagonism of these receptors restored the appropriate gastric response to OXT. The current study suggests that perinatal high‐fat diet exposure disrupts descending PVN–DMV inputs, leading to a dysregulated vagal brain–gut response to stress.

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Neural Pathway for Gut Feelings: Vagal Interoceptive Feedback From the Gastrointestinal Tract Is a Critical Modulator of Anxiety-like Behavior

Cited by 22 publications

References 48 publications

Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Perinatal High Fat Diet Exposure Alters Oxytocin and Corticotropin Releasing Factor Inputs onto Vagal Neurocircuits Controlling Gastric Motility

Causal association of gastroesophageal reflux disease with obstructive sleep apnea and sleep-related phenotypes: a bidirectional two-sample Mendelian randomization study

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

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