Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor

Kirsteen Browning, Tanja Babic, Luca Toti, Gregory Holmes, F. Holly Coleman, Renato Alberto Travagli

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Key points: The prototypical stress hormone, corticotropin releasing factor (CRF), and the prototypical anti-stressor hormone, oxytocin (OXT), are known to modulate brainstem neurocircuits involved in visceral reflexes. We demonstrated recently that the brainstem neurocircuits through which OXT exerts its actions are modulated by vagal afferent fibres; however, it is unknown whether the OXT-induced modulation of brainstem vagal neurocircuits is also regulated differentially by CRF. Here we elucidate the cellular mechanisms and the effects on gastric tone of OXT following exposure of vagal brainstem neurones to CRF and report that CRF induces short-term plastic changes in OXT-sensitive vagal neurocircuits. The results presented may represent a possible mechanism through which stress alters the central regulation of gastrointestinal functions and may reflect the vagal dysregulation occurring as a consequence of stress-exacerbated functional dyspepsia. Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT.

Original languageEnglish (US)
Pages (from-to)4591-4605
Number of pages15
JournalJournal of Physiology
Volume592
Issue number20
DOIs
StatePublished - Oct 15 2014

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Corticotropin-Releasing Hormone
Oxytocin
Brain Stem
Stomach
Microinjections
Hormones
Neurons
Synaptic Transmission
Oxytocin Receptors
Metabotropic Glutamate Receptors
Aptitude
Dyspepsia
Gastric Emptying
Motor Neurons
Cyclic AMP-Dependent Protein Kinases
Neuropeptides
Compliance
Reflex

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

@article{9f1f21ae266142dbbc76ee192a912e53,
title = "Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor",
abstract = "Key points: The prototypical stress hormone, corticotropin releasing factor (CRF), and the prototypical anti-stressor hormone, oxytocin (OXT), are known to modulate brainstem neurocircuits involved in visceral reflexes. We demonstrated recently that the brainstem neurocircuits through which OXT exerts its actions are modulated by vagal afferent fibres; however, it is unknown whether the OXT-induced modulation of brainstem vagal neurocircuits is also regulated differentially by CRF. Here we elucidate the cellular mechanisms and the effects on gastric tone of OXT following exposure of vagal brainstem neurones to CRF and report that CRF induces short-term plastic changes in OXT-sensitive vagal neurocircuits. The results presented may represent a possible mechanism through which stress alters the central regulation of gastrointestinal functions and may reflect the vagal dysregulation occurring as a consequence of stress-exacerbated functional dyspepsia. Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT.",
author = "Kirsteen Browning and Tanja Babic and Luca Toti and Gregory Holmes and Coleman, {F. Holly} and Travagli, {Renato Alberto}",
year = "2014",
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Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor. / Browning, Kirsteen; Babic, Tanja; Toti, Luca; Holmes, Gregory; Coleman, F. Holly; Travagli, Renato Alberto.

In: Journal of Physiology, Vol. 592, No. 20, 15.10.2014, p. 4591-4605.

Research output: Contribution to journalArticle

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T1 - Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor

AU - Browning, Kirsteen

AU - Babic, Tanja

AU - Toti, Luca

AU - Holmes, Gregory

AU - Coleman, F. Holly

AU - Travagli, Renato Alberto

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N2 - Key points: The prototypical stress hormone, corticotropin releasing factor (CRF), and the prototypical anti-stressor hormone, oxytocin (OXT), are known to modulate brainstem neurocircuits involved in visceral reflexes. We demonstrated recently that the brainstem neurocircuits through which OXT exerts its actions are modulated by vagal afferent fibres; however, it is unknown whether the OXT-induced modulation of brainstem vagal neurocircuits is also regulated differentially by CRF. Here we elucidate the cellular mechanisms and the effects on gastric tone of OXT following exposure of vagal brainstem neurones to CRF and report that CRF induces short-term plastic changes in OXT-sensitive vagal neurocircuits. The results presented may represent a possible mechanism through which stress alters the central regulation of gastrointestinal functions and may reflect the vagal dysregulation occurring as a consequence of stress-exacerbated functional dyspepsia. Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT.

AB - Key points: The prototypical stress hormone, corticotropin releasing factor (CRF), and the prototypical anti-stressor hormone, oxytocin (OXT), are known to modulate brainstem neurocircuits involved in visceral reflexes. We demonstrated recently that the brainstem neurocircuits through which OXT exerts its actions are modulated by vagal afferent fibres; however, it is unknown whether the OXT-induced modulation of brainstem vagal neurocircuits is also regulated differentially by CRF. Here we elucidate the cellular mechanisms and the effects on gastric tone of OXT following exposure of vagal brainstem neurones to CRF and report that CRF induces short-term plastic changes in OXT-sensitive vagal neurocircuits. The results presented may represent a possible mechanism through which stress alters the central regulation of gastrointestinal functions and may reflect the vagal dysregulation occurring as a consequence of stress-exacerbated functional dyspepsia. Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT.

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