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Wang YB, Dow KE, Boychuk CR. GABA AR-δ-subunit mediates increased GABAergic inhibition in cardiac DMV neurons after high-fat diet. iScience 2025; 28:112268. [PMID: 40264791 PMCID: PMC12013407 DOI: 10.1016/j.isci.2025.112268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 12/20/2024] [Accepted: 03/18/2025] [Indexed: 04/24/2025] Open
Abstract
Activity of cardiac-projecting neurons in the dorsal motor nucleus of the vagus (CVNDMV) is vital in cardiac reflexes contributing to maintaining cardiovascular health. However, how this population adapts to metabolic challenges, such as high-fat diet (HFD), is unclear. This study aimed to identify neuroplasticity changes induced by HFD in CVNDMV. Using whole-cell patch-clamp electrophysiology, we found that 15-day HFD feeding increased tonic, but not phasic, gamma-aminobutyric acid type A (GABAA) inhibitory neurotransmission, exclusive to CVNDMV. Single-cell quantitative reverse-transcription PCR (scRT-qPCR) analysis revealed a higher number of CVNDMV expressing GABAA receptor δ-subunit (GABAA(δ)R) in HFD compared to normal fat diet (NFD). Deletion of GABAA(δ)R in ChAT-positive motor neurons abolished HFD-induced increased tonic GABAA neurotransmission in CVNDMV. Altogether, this evidence suggests that CVNDMV exhibits early onset HFD-induced increased GABAergic neurotransmission, likely mediated by GABAA(δ)R. This increased inhibitory tone could explain previously reported reduced cardiac vagal motor output, thus contributing to poor cardiometabolic health after HFD.
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Affiliation(s)
- Yoko Brigitte Wang
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Kaylie E. Dow
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Carie R. Boychuk
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
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Su Y, Xu J, Zhu Z, Chin J, Xu L, Yu H, Nudell V, Dash B, Moya EA, Ye L, Nimmerjahn A, Sun X. Brainstem Dbh+ Neurons Control Chronic Allergen-Induced Airway Hyperreactivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.02.04.527145. [PMID: 36778350 PMCID: PMC9915738 DOI: 10.1101/2023.02.04.527145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic exposure of the lung to irritants such as allergen is a primary cause of asthma characterized by exaggerated airway constriction, also called hyperreactivity, which can be life-threatening. Aside from immune cells, vagal sensory neurons are important for airway hyperreactivity 1-4 . However, the identity and signature of the downstream nodes of this adaptive circuit remains poorly understood. Here we show that a single population of Dbh + neurons in the nucleus of the solitary tract (nTS) of the brainstem, and downstream neurons in the nucleus ambiguous (NA), are both necessary and sufficient for chronic allergen-induced airway hyperreactivity. We found that repeated exposures of mice to inhaled allergen activates nTS neurons in a mast cell-, interleukin 4 (IL-4)-and vagal nerve-dependent manner. Single-nucleus RNA-seq of the nTS at baseline and following allergen challenges reveals that a Dbh + population is preferentially activated. Ablation or chemogenetic inactivation of Dbh + nTS neurons blunted, while chemogenetic activation promoted hyperreactivity. Viral tracing indicates that Dbh + nTS neurons, capable of producing norepinephrine, project to the NA, and NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that then directly drive airway constriction. Focusing on transmitters, delivery of norepinephrine antagonists to the NA blunted allergen-induced hyperreactivity. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. The knowledge opens the possibility of targeted neural modulation as an approach to control refractory allergen-induced airway constriction.
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Juras JA, Pitra S, Smith BN. Systemic Glucose Regulation by a Hindbrain Inhibitory Circuit in a Mouse Model of Type 1 Diabetes. Neuroendocrinology 2024; 114:302-312. [PMID: 38194945 DOI: 10.1159/000536142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/04/2024] [Indexed: 01/11/2024]
Abstract
INTRODUCTION Previous work showed that increasing the electrical activity of inhibitory neurons in the dorsal vagal complex (DVC) is sufficient to increase whole-body glucose concentration in normoglycemic mice. Here we tested the hypothesis that deactivating GABAergic neurons in the dorsal hindbrain of hyperglycemic mice decreases synaptic inhibition of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) and reduces systemic glucose levels. METHODS Chemogenetic activation or inactivation of GABAergic neurons in the nucleus tractus solitarius (NTS) was used to assess effects of modulating parasympathetic output on blood glucose concentration in normoglycemic and hyperglycemic mice. Patch-clamp electrophysiology in vitro was used to assess cellular effects of chemogenetic manipulation of NTS GABA neurons. RESULTS Chemogenetic activation of GABAergic NTS neurons in normoglycemic mice increased their action potential firing, resulting in increased inhibitory synaptic input to DMV motor neurons and elevated blood glucose concentration. Deactivation of GABAergic DVC neurons in normoglycemic mice altered their electrical activity but did not alter systemic glucose levels. Conversely, stimulation of GABAergic DVC neurons in mice that were hyperglycemic subsequent to treatment with streptozotocin changed their electrical activity but did not alter whole-body glucose concentration, while deactivation of this inhibitory circuit significantly decreased circulating glucose concentration. Peripheral administration of a brain impermeant muscarinic acetylcholine receptor antagonist abolished these effects. CONCLUSION Disinhibiting vagal motor neurons decreases hyperglycemia in a mouse model of type 1 diabetes. This inhibitory brainstem circuit emerges as a key parasympathetic regulator of whole-body glucose homeostasis that undergoes functional plasticity in hyperglycemic conditions.
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Affiliation(s)
- J Anna Juras
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA
| | - Soledad Pitra
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Bret N Smith
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA
- Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
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Xing T, Nanni G, Burkholder CR, Browning KN, Travagli RA. The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat. J Physiol 2023; 601:4751-4766. [PMID: 37772988 PMCID: PMC10873099 DOI: 10.1113/jp284238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 09/08/2023] [Indexed: 09/30/2023] Open
Abstract
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. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.
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Affiliation(s)
| | | | | | - Kirsteen N. Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA and Neurobiology Research, Newport, NC
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Cao Y, Wang W, Chen J, Jiang B, Liang S, Chen X, Dong H. A case of comorbidity of schizophrenic catatonia and chronic intestinal pseudo-obstruction Successfully managed with lorazepam. Heliyon 2023; 9:e21067. [PMID: 37916112 PMCID: PMC10616325 DOI: 10.1016/j.heliyon.2023.e21067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 10/12/2023] [Accepted: 10/13/2023] [Indexed: 11/03/2023] Open
Abstract
It is challenging to manage schizophrenic catatonia and comorbid chronic intestinal pseudo-obstruction (CIPO). The pathology of catatonia is unclear. There are few reports or research on this issue. In this case, we present a middle-aged woman diagnosed with schizophrenia with catatonic features and comorbid CIPO. In the treatment process, modified electroconvulsive therapy (mECT) improved her stupor and CIPO partially. Lorazepam alleviated her stupor and CIPO completely. It is the first report describing complete remission with lorazepam in patient suffering from comorbid schizophrenic catatonia and CIPO, which may benefit the exploration of pathophysiology and treatment of comorbidity of schizophrenia with catatonia and CIPO.
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Affiliation(s)
- Yang Cao
- Zhejiang Provincial Mental Health Institute, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Weixin Wang
- Zhejiang Provincial Mental Health Institute, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Jiong Chen
- Zhejiang Provincial Mental Health Institute, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Bo Jiang
- Zhejiang Provincial Mental Health Institute, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Sugai Liang
- Zhejiang University School of Medicine Affiliated Mental Health Center, Hangzhou Seventh People's Hospital Hangzhou, China
| | - Xianyu Chen
- Psychiatry Department, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hui Dong
- Gastroenterology Department, Zhejiang Hospital, Hangzhou, China
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Zhou H, Rao Z, Zhang Z, Zhou J. Function of the GABAergic System in Diabetic Encephalopathy. Cell Mol Neurobiol 2023; 43:605-619. [PMID: 35460435 PMCID: PMC11415196 DOI: 10.1007/s10571-022-01214-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 03/17/2022] [Indexed: 11/03/2022]
Abstract
Diabetes is a common metabolic disease characterized by loss of blood sugar control and a high rate of complications. γ-Aminobutyric acid (GABA) functions as the primary inhibitory neurotransmitter in the adult mammalian brain. The normal function of the GABAergic system is affected in diabetes. Herein, we summarize the role of the GABAergic system in diabetic cognitive dysfunction, diabetic blood sugar control disorders, diabetes-induced peripheral neuropathy, diabetic central nervous system damage, maintaining diabetic brain energy homeostasis, helping central control of blood sugar and attenuating neuronal oxidative stress damage. We show the key regulatory role of the GABAergic system in multiple comorbidities in patients with diabetes and hope that further studies elucidating the role of the GABAergic system will yield benefits for the treatment and prevention of comorbidities in patients with diabetes.
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Affiliation(s)
- Hongli Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Zhili Rao
- Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, People's Republic of China
| | - Zuo Zhang
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Jiyin Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China.
- Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, People's Republic of China.
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Jaffey DM, McAdams JL, Baronowsky EA, Black D, Powley TL. Vagal preganglionic axons arborize in the myenteric plexus into two types: nitrergic and non-nitrergic postganglionic motor pools? Am J Physiol Regul Integr Comp Physiol 2023; 324:R305-R316. [PMID: 36622086 PMCID: PMC9942884 DOI: 10.1152/ajpregu.00260.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 01/03/2023] [Indexed: 01/10/2023]
Abstract
Vagal preganglionic neurons innervate myenteric ganglia. These autonomic efferents are distributed so densely within the ganglia that it has been impractical to track individual vagal axons through the myenteric plexus with tracer labeling. To evaluate whether vagal efferent axons evidence selectivity, particularly for nitrergic or non-nitrergic myenteric neurons within the plexus, we limited the numbers and volumes of brainstem dextran biotin tracer injections per animal. Reduced labeling and the use of immunohistochemistry generated cases in which some individual axons could be distinguished and traced in three dimensions (Neurolucida) within and among successive (up to 46) myenteric ganglia. In the myenteric plexus of all stomach regions, the majority (∼86%) of vagal efferents were organized into two distinct subtypes. One subtype (∼24% of dextran-labeled efferents, designated "primarily nitrergic") selectively contacted and linked-both within and between ganglia-nitric oxide synthase positive (nNOS+) neurons into presumptive motor modules. A second subtype (∼62% of efferents, designated "primarily non-nitrergic") appeared to selectively contact and link-both within and between ganglia-non-nitrergic enteric neurons into a second type of effector ensemble. A third candidate type (∼14% of labeled preganglionics), appeared to lack "nitrergic selectivity" and to contact both nNOS+ and nNOS- enteric neurons. In addition to the quantitative assessment of the efferent axons in stomach, qualitative observations of the proximal duodenum indicated similar selective vagal efferent projections, in proportions comparable with those evaluated in the stomach. Limited injections of tracer, three-dimensional (3-D) tracing of individual axons, and histochemistry of myenteric neurons might distinguish additional efferent phenotypes.NEW & NOTEWORTHY The present study highlights the following: 1) one type of vagal efferent axon selectively innervates nitrergic upper gastrointestinal myenteric neurons; 2) a second type of vagal efferent selectively innervates non-nitrergic gastrointestinal myenteric neurons; and 3) the two types of vagal efferents might modulate peristalsis reciprocally and cooperatively.
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Affiliation(s)
- D M Jaffey
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - J L McAdams
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - E A Baronowsky
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - D Black
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - T L Powley
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
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8
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Wang H, Liu WJ, Wang XY, Chen XQ, Cai RL, Zhang MT, Wang HT, He GW, Zhang Z, Shen GM. A central amygdala input to the dorsal vagal complex controls gastric motility in mice under restraint stress. Front Physiol 2023; 14:1074979. [PMID: 36875016 PMCID: PMC9975572 DOI: 10.3389/fphys.2023.1074979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 02/02/2023] [Indexed: 02/22/2023] Open
Abstract
Background/aims: Psychological and physiological stress can cause gastrointestinal motility disorders. Acupuncture has a benign regulatory effect on gastrointestinal motility. However, the mechanisms underlying these processes remain unclear. Methods: Herein, we established a gastric motility disorder (GMD) model in the context of restraint stress (RS) and irregular feeding. The activity of emotional center-central amygdala (CeA) GABAergic neurons and gastrointestinal center-dorsal vagal complex (DVC) neurons were recorded by electrophysiology. Virus tracing and patch clamp analysis of the anatomical and functional connection between the CeAGABA → dorsal vagal complex pathways were performed. Optogenetics inhibiting or activating CeAGABA neurons or the CeAGABA → dorsal vagal complex pathway were used to detect changes in gastric function. Results: We found that restraint stress induced delayed gastric emptying and decreased gastric motility and food intake. Simultaneously, restraint stress activated CeA GABAergic neurons, inhibiting dorsal vagal complex neurons, with electroacupuncture (EA) reversing this phenomenon. In addition, we identified an inhibitory pathway in which CeA GABAergic neurons project into the dorsal vagal complex. Furthermore, the use of optogenetic approaches inhibited CeAGABA neurons and the CeAGABA → dorsal vagal complex pathway in gastric motility disorder mice, which enhanced gastric movement and gastric emptying, whereas activation of the CeAGABA and CeAGABA → dorsal vagal complex pathway mimicked the symptoms of weakened gastric movement and delayed gastric emptying in naïve mice. Conclusion: Our findings indicate that the CeAGABA → dorsal vagal complex pathway may be involved in regulating gastric dysmotility under restraint stress conditions, and partially reveals the mechanism of electroacupuncture.
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Affiliation(s)
- Hao Wang
- College of Integrated Chinese and Western Medicine (School of Life Sciences), Anhui University of Chinese Medicine, Hefei, Anhui, China
- Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, Anhui, China
| | - Wen-Jian Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xi-Yang Wang
- College of Integrated Chinese and Western Medicine (School of Life Sciences), Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Xiao-Qi Chen
- College of Integrated Chinese and Western Medicine (School of Life Sciences), Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Rong-Lin Cai
- Research Institute of Acupuncture and Meridian, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Meng-Ting Zhang
- College of Integrated Chinese and Western Medicine (School of Life Sciences), Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Hai-Tao Wang
- College of Integrated Chinese and Western Medicine (School of Life Sciences), Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Guang-Wei He
- Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, Anhui, China
| | - Zhi Zhang
- Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui, China
| | - Guo-Ming Shen
- College of Integrated Chinese and Western Medicine (School of Life Sciences), Anhui University of Chinese Medicine, Hefei, Anhui, China
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Baumer-Harrison C, Breza JM, Sumners C, Krause EG, de Kloet AD. Sodium Intake and Disease: Another Relationship to Consider. Nutrients 2023; 15:535. [PMID: 36771242 PMCID: PMC9921152 DOI: 10.3390/nu15030535] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/14/2023] [Accepted: 01/15/2023] [Indexed: 01/22/2023] Open
Abstract
Sodium (Na+) is crucial for numerous homeostatic processes in the body and, consequentially, its levels are tightly regulated by multiple organ systems. Sodium is acquired from the diet, commonly in the form of NaCl (table salt), and substances that contain sodium taste salty and are innately palatable at concentrations that are advantageous to physiological homeostasis. The importance of sodium homeostasis is reflected by sodium appetite, an "all-hands-on-deck" response involving the brain, multiple peripheral organ systems, and endocrine factors, to increase sodium intake and replenish sodium levels in times of depletion. Visceral sensory information and endocrine signals are integrated by the brain to regulate sodium intake. Dysregulation of the systems involved can lead to sodium overconsumption, which numerous studies have considered causal for the development of diseases, such as hypertension. The purpose here is to consider the inverse-how disease impacts sodium intake, with a focus on stress-related and cardiometabolic diseases. Our proposition is that such diseases contribute to an increase in sodium intake, potentially eliciting a vicious cycle toward disease exacerbation. First, we describe the mechanism(s) that regulate each of these processes independently. Then, we highlight the points of overlap and integration of these processes. We propose that the analogous neural circuitry involved in regulating sodium intake and blood pressure, at least in part, underlies the reciprocal relationship between neural control of these functions. Finally, we conclude with a discussion on how stress-related and cardiometabolic diseases influence these circuitries to alter the consumption of sodium.
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Affiliation(s)
- Caitlin Baumer-Harrison
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32603, USA
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL 32610, USA
- Center for Smell and Taste, University of Florida, Gainesville, FL 32610, USA
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
| | - Joseph M. Breza
- Department of Psychology, College of Arts and Sciences, Eastern Michigan University, Ypsilanti, MI 48197, USA
| | - Colin Sumners
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32603, USA
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL 32610, USA
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
| | - Eric G. Krause
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL 32610, USA
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
| | - Annette D. de Kloet
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32603, USA
- Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL 32610, USA
- Center for Smell and Taste, University of Florida, Gainesville, FL 32610, USA
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA
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Jiang Y, Zimmerman JE, Browning KN, Travagli RA. Stress-induced neuroplasticity in the gastric response to brainstem oxytocin in male rats. Am J Physiol Gastrointest Liver Physiol 2022; 322:G513-G522. [PMID: 35170350 PMCID: PMC8993533 DOI: 10.1152/ajpgi.00347.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
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. After chronic (5 consecutive days) of homotypic or heterotypic stress load, the response to exogenous brainstem administration of OXT was examined using whole cell patch-clamp recordings from gastric-projecting vagal motoneurons and in vivo recordings of gastric tone and motility. GABAergic currents onto vagal motoneurons were decreased by OXT in stressed, but not in naïve rats. In naïve rats, microinjections of OXT in vagal brainstem nuclei-induced gastroinhibition via peripheral release of nitric oxide (NO). In stressed rats, however, the OXT-induced gastroinhibition was determined by the release of both NO and vasoactive intestinal peptide (VIP). Taken together, our data indicate that stress induces neuroplasticity in the response to OXT in the neurocircuits, which modulate gastric tone and motility. In particular, stress uncovers the OXT-mediated modulation of brainstem GABAergic currents and alters the peripheral gastric response to vagal stimulation.NEW & NOTEWORTHY The prototypical antistress hormone, oxytocin (OXT), modulates gastric tone and motility via vagal pathways, and descending hypothalamic-brainstem OXT neurocircuits play a major role in the vagally dependent adaptation of gastric motility and tone to stress. The current study suggests that in the neurocircuits, which modulate gastric tone and motility, stress induces neuroplasticity in the response to OXT and may reflect the dysregulation observed in stress-exacerbated functional motility disorders.
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Affiliation(s)
- Yanyan Jiang
- 1Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | | | - Kirsteen N. Browning
- 1Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - R. Alberto Travagli
- 1Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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Liang SL, Tong YS, Hwang LL, Huang YZ, Chen CY. CART Peptides Differently Regulate Firing Rates and GABAergic Synaptic Inputs of DMV Neurons Innervating the Stomach Antrum and Cecum of Adult Male Rats. Neuroendocrinology 2022; 112:555-570. [PMID: 34348334 DOI: 10.1159/000518690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 07/23/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIM Central administration of cocaine- and amphetamine-regulated transcript peptides (CARTp) alters gastrointestinal motility and reduces food intake in rats. Since neurons in the dorsal motor nucleus of the vagus (DMV) receive GABAergic and glutamatergic inputs and innervate the smooth muscle of gastrointestinal organs, we hypothesized that CARTp acts on the DMV or presynaptic neurons. METHODS We used 3,3'-dioctadecyloxa-carbocyanine perchlorate (DiO) retrograde tracing with electrophysiological methods to record DMV neurons innervating the stomach antrum or cecum in brainstem slices from adult rats. RESULTS DiO application did not change the electrophysiological properties of DMV neurons. CART55-102 had no effect on the basal firing rates of neurons in either the stomach antrum-labeled group (SLG) or cecum-labeled group (CLG). When presynaptic inputs were blocked, CART55-102 further increased the firing rates of the SLG, suggesting a direct excitatory effect. Spontaneous inhibitory postsynaptic currents (sIPSCs) occurred at a higher frequency in SLG neurons than in CLG neurons. CART55-102 reduced the amplitude and the frequency of sIPSCs in SLG neurons dose-dependently, with higher doses also reducing spontaneous excitatory postsynaptic currents (sEPSCs). Higher doses of CART55-102 reduced sIPSC and sEPSC amplitudes in CLG neurons, suggesting a postsynaptic effect. In response to incremental current injections, the SLG neurons exhibited less increases in firing activity. Simultaneous applications of current injections and CART55-102 decreased the firing activity of the CLG. Therefore, stomach antrum-projecting DMV neurons possess a higher gating ability to stabilize firing activity. CONCLUSION The mechanism by which CARTp mediates anorectic actions may be through a direct reduction in cecum-projecting DMV neuron excitability and, to a lesser extent, that of antrum-projecting DMV neurons, by acting on receptors of these neurons.
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Affiliation(s)
- Shu-Ling Liang
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Yong-Sheng Tong
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ling-Ling Hwang
- Department of Physiology, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ying-Zu Huang
- Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Yen Chen
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Faculty of Medicine, Institute of Emergency and Critical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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12
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Littlejohn EL, Boychuk CR. Protein Kinase C-Dependent Effects of Neurosteroids on Synaptic GABA A Receptor Inhibition Require the δ-Subunit. Front Physiol 2021; 12:742838. [PMID: 34759836 PMCID: PMC8573421 DOI: 10.3389/fphys.2021.742838] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/25/2021] [Indexed: 11/13/2022] Open
Abstract
The dorsal motor nucleus of the vagus (DMV) contains preganglionic motor neurons important for interpreting sensory input from the periphery, integrating that information, and coding the appropriate parasympathetic (vagal) output to target organs. Despite the critical role of hormonal regulation of vagal motor output, few studies examine the role of neurosteroids in the regulation of the DMV. Of the few examinations, no studies have investigated the potential impact of allopregnanolone (Allo), a neuroactive progesterone-derivative, in the regulation of neurotransmission on the DMV. Since DMV neuronal function is tightly regulated by GABAA receptor activity and Allo is an endogenous GABAA receptor ligand, the present study used in vitro whole cell patch clamp to investigate whether Allo alters GABAergic neurotransmission to DMV neurons. Although Allo did not influence GABAergic neurotransmission during initial application (5-20 min), a TTX-insensitive prolongment of decay time and increase in frequency of GABAergic currents was established after Allo was removed from the bath for at least 30 min (LtAllo). Inhibition of protein kinase C (PKC) abolished these effects, suggesting that PKC is largely required to mediate Allo-induced inhibition of the DMV. Using mice that lack the δ-subunit of the GABAA receptor, we further confirmed that PKC-dependent activity of LtAllo required this subunit. Allo also potentiated GABAA receptor activity after a repeated application of δ-subunit agonist, suggesting that the presence of Allo encodes stronger δ-subunit-mediated inhibition over time. Using current clamp recording, we demonstrated that LtAllo-induced inhibition is sufficient to decrease action potential firing and excitability within DMV neurons. We conclude that the effects of LtAllo on GABAergic inhibition are dependent on δ-subunit and PKC activation. Taken together, DMV neurons can undergo long lasting Allo-dependent GABAA receptor plasticity.
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Affiliation(s)
| | - Carie R. Boychuk
- Department of Cellular and Integrative Physiology, Long College of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
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13
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Borgmann D, Ciglieri E, Biglari N, Brandt C, Cremer AL, Backes H, Tittgemeyer M, Wunderlich FT, Brüning JC, Fenselau H. Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism. Cell Metab 2021; 33:1466-1482.e7. [PMID: 34043943 PMCID: PMC8280952 DOI: 10.1016/j.cmet.2021.05.002] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 02/23/2021] [Accepted: 05/03/2021] [Indexed: 01/26/2023]
Abstract
Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.
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Affiliation(s)
- Diba Borgmann
- Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Translational Neurocircuitry Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Anatomy II, Neuroanatomy, University Hospital Cologne, Joseph-Stelzmann Str. 9, 50937 Cologne, Germany
| | - Elisa Ciglieri
- Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50937 Cologne, Germany
| | - Nasim Biglari
- Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Strasse 50, 50931 Cologne, Germany
| | - Claus Brandt
- Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Strasse 50, 50931 Cologne, Germany
| | - Anna Lena Cremer
- Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Strasse 50, 50931 Cologne, Germany
| | - Heiko Backes
- Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Strasse 50, 50931 Cologne, Germany
| | - Marc Tittgemeyer
- Translational Neurocircuitry Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, Cologne 50931, Germany
| | - F Thomas Wunderlich
- Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50937 Cologne, Germany; Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Strasse 50, 50931 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, Cologne 50931, Germany; Center of Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Straße 21, 50931 Cologne, Germany
| | - Jens C Brüning
- Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50937 Cologne, Germany; Max Planck Institute for Metabolism Research, Department of Neuronal Control of Metabolism, Gleueler Strasse 50, 50931 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, Cologne 50931, Germany; Center of Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Straße 21, 50931 Cologne, Germany
| | - Henning Fenselau
- Synaptic Transmission in Energy Homeostasis Group, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50937 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Straße 26, Cologne 50931, Germany.
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14
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Clyburn C, Browning KN. Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions. Am J Physiol Gastrointest Liver Physiol 2021; 320:G880-G887. [PMID: 33730858 PMCID: PMC8202199 DOI: 10.1152/ajpgi.00014.2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The meticulous regulation of the gastrointestinal (GI) tract is required for the coordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders and the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second-order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of GI functions.
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Affiliation(s)
- Courtney Clyburn
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
| | - Kirsteen N. Browning
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
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15
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Browning KN, Carson KE. Central Neurocircuits Regulating Food Intake in Response to Gut Inputs-Preclinical Evidence. Nutrients 2021; 13:nu13030908. [PMID: 33799575 PMCID: PMC7998662 DOI: 10.3390/nu13030908] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/02/2021] [Accepted: 03/07/2021] [Indexed: 02/07/2023] Open
Abstract
The regulation of energy balance requires the complex integration of homeostatic and hedonic pathways, but sensory inputs from the gastrointestinal (GI) tract are increasingly recognized as playing critical roles. The stomach and small intestine relay sensory information to the central nervous system (CNS) via the sensory afferent vagus nerve. This vast volume of complex sensory information is received by neurons of the nucleus of the tractus solitarius (NTS) and is integrated with responses to circulating factors as well as descending inputs from the brainstem, midbrain, and forebrain nuclei involved in autonomic regulation. The integrated signal is relayed to the adjacent dorsal motor nucleus of the vagus (DMV), which supplies the motor output response via the efferent vagus nerve to regulate and modulate gastric motility, tone, secretion, and emptying, as well as intestinal motility and transit; the precise coordination of these responses is essential for the control of meal size, meal termination, and nutrient absorption. The interconnectivity of the NTS implies that many other CNS areas are capable of modulating vagal efferent output, emphasized by the many CNS disorders associated with dysregulated GI functions including feeding. This review will summarize the role of major CNS centers to gut-related inputs in the regulation of gastric function with specific reference to the regulation of food intake.
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16
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Yang NN, Yang JW, Ye Y, Huang J, Wang L, Wang Y, Su XT, Lin Y, Yu FT, Ma SM, Qi LY, Lin LL, Wang LQ, Shi GX, Li HP, Liu CZ. Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus. Theranostics 2021; 11:4078-4089. [PMID: 33754049 PMCID: PMC7977469 DOI: 10.7150/thno.52574] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 01/24/2021] [Indexed: 12/17/2022] Open
Abstract
Inflammatory cytokines produced by muscularis macrophages largely contribute to the pathological signs of postoperative ileus (POI). Electroacupuncture (EA) can suppress inflammation, mainly or partly via activation of vagal efferent. The goal of this study was to investigate the mechanisms by which EA stimulation at an hindlimb region ameliorates inflammation in POI. Methods: Intestinal motility and inflammation were examined after 24 h after intestinal manipulation (IM)-induced POI in mice. Local immune response in the intestinal muscularis, expression of macrophages, α7 nicotinic acetylcholine receptor (α7nAChR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined by flow cytometry, Western Blot, qPCR and immunofluorescence. The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. In the parasympathetic pathways, intestinal motility and inflammation were determined after cervical vagotomy and sub-diaphragmatic vagotomy. The expression of gamma absorptiometry aminobutyric acid (GABAA) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABAA receptor) or muscimol (agonist of GABAA receptor) were assessed. Results: EA suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABAA receptor in DMV to ameliorate inflammation. Conclusions: The present study revealed that EA of hindlimb regions inhibited the expression of GABAA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.
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Affiliation(s)
- Na-Na Yang
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Jing-Wen Yang
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Yang Ye
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jin Huang
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Lu Wang
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Yu Wang
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Xin-Tong Su
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Ying Lin
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Fang-Ting Yu
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Si-Ming Ma
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Ling-Yu Qi
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Lu-Lu Lin
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Li-Qiong Wang
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Guang-Xia Shi
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Hong-Ping Li
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
| | - Cun-Zhi Liu
- International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine
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17
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Wean JB, Smith BN. Fibroblast Growth Factor 19 Increases the Excitability of Pre-Motor Glutamatergic Dorsal Vagal Complex Neurons From Hyperglycemic Mice. Front Endocrinol (Lausanne) 2021; 12:765359. [PMID: 34858337 PMCID: PMC8632226 DOI: 10.3389/fendo.2021.765359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/26/2021] [Indexed: 01/14/2023] Open
Abstract
Intracerebroventricular administration of the protein hormone fibroblast growth factor 19 (FGF19) to the hindbrain produces potent antidiabetic effects in hyperglycemic mice that are likely mediated through a vagal parasympathetic mechanism. FGF19 increases the synaptic excitability of parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) from hyperglycemic, but not normoglycemic, mice but the source of this synaptic input is unknown. Neurons in the area postrema (AP) and nucleus tractus solitarius (NTS) express high levels of FGF receptors and exert glutamatergic control over the DMV. This study tested the hypothesis that FGF19 increases glutamate release in the DMV by increasing the activity of glutamatergic AP and NTS neurons in hyperglycemic mice. Glutamate photoactivation experiments confirmed that FGF19 increases synaptic glutamate release from AP and NTS neurons that connect to the DMV in hyperglycemic, but not normoglycemic mice. Contrary to expectations, FGF19 produced a mixed effect on intrinsic membrane properties in the NTS with a trend towards inhibition, suggesting that another mechanism was responsible for the observed effects on glutamate release in the DMV. Consistent with the hypothesis, FGF19 increased action potential-dependent glutamate release in the NTS in hyperglycemic mice only. Finally, glutamate photoactivation experiments confirmed that FGF19 increases the activity of glutamatergic AP neurons that project to the NTS in hyperglycemic mice. Together, these results support the hypothesis that FGF19 increases glutamate release from AP and NTS neurons that project to the DMV in hyperglycemic mice. FGF19 therefore modifies the local vago-vagal reflex circuitry at several points. Additionally, since the AP and NTS communicate with several other metabolic regulatory nuclei in the brain, FGF19 in the hindbrain may alter neuroendocrine and behavioral aspects of metabolism, in addition to changes in parasympathetic output.
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Affiliation(s)
- Jordan B. Wean
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Bret N. Smith
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States
- *Correspondence: Bret N. Smith,
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18
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Yu Z. Neuromechanism of acupuncture regulating gastrointestinal motility. World J Gastroenterol 2020; 26:3182-3200. [PMID: 32684734 PMCID: PMC7336328 DOI: 10.3748/wjg.v26.i23.3182] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/29/2020] [Accepted: 05/23/2020] [Indexed: 02/06/2023] Open
Abstract
Acupuncture has been used in China for thousands of years and has become more widely accepted by doctors and patients around the world. A large number of clinical studies and animal experiments have confirmed that acupuncture has a benign adjustment effect on gastrointestinal (GI) movement; however, the mechanism of this effect is unclear, especially in terms of neural mechanisms, and there are still many areas that require further exploration. This article reviews the recent data on the neural mechanism of acupuncture on GI movements. We summarize the neural mechanism of acupuncture on GI movement from four aspects: acupuncture signal transmission, the sympathetic and parasympathetic nervous system, the enteric nervous system, and the central nervous system.
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Affiliation(s)
- Zhi Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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19
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Littlejohn EL, Fedorchak S, Boychuk CR. Sex-steroid-dependent plasticity of brain-stem autonomic circuits. Am J Physiol Regul Integr Comp Physiol 2020; 319:R60-R68. [PMID: 32493037 DOI: 10.1152/ajpregu.00357.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
In the central nervous system (CNS), nuclei of the brain stem play a critical role in the integration of peripheral sensory information and the regulation of autonomic output in mammalian physiology. The nucleus tractus solitarius of the brain stem acts as a relay center that receives peripheral sensory input from vagal afferents of the nodose ganglia, integrates information from within the brain stem and higher central centers, and then transmits autonomic efferent output through downstream premotor nuclei, such as the nucleus ambiguus, the dorsal motor nucleus of the vagus, and the rostral ventral lateral medulla. Although there is mounting evidence that sex and sex hormones modulate autonomic physiology at the level of the CNS, the mechanisms and neurocircuitry involved in producing these functional consequences are poorly understood. Of particular interest in this review is the role of estrogen, progesterone, and 5α-reductase-dependent neurosteroid metabolites of progesterone (e.g., allopregnanolone) in the modulation of neurotransmission within brain-stem autonomic neurocircuits. This review will discuss our understanding of the actions and mechanisms of estrogen, progesterone, and neurosteroids at the cellular level of brain-stem nuclei. Understanding the complex interaction between sex hormones and neural signaling plasticity of the autonomic nervous system is essential to elucidating the role of sex in overall physiology and disease.
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Affiliation(s)
- Erica L Littlejohn
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas
| | - Stephanie Fedorchak
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas
| | - Carie R Boychuk
- Department of Cellular and Integrative Physiology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, Texas
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20
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Fortin SM, Lipsky RK, Lhamo R, Chen J, Kim E, Borner T, Schmidt HD, Hayes MR. GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats. Sci Transl Med 2020; 12:eaay8071. [PMID: 32132220 PMCID: PMC7211411 DOI: 10.1126/scitranslmed.aay8071] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/22/2019] [Accepted: 02/13/2020] [Indexed: 01/04/2023]
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is approved for the treatment of obesity; however, there is still much to be learned regarding the neuronal sites of action that underlie its suppressive effects on food intake and body weight. Peripherally administered liraglutide in rats acts in part through central GLP-1Rs in both the hypothalamus and the hindbrain. Here, we extend findings supporting a role for hindbrain GLP-1Rs in mediating the anorectic effects of liraglutide in male rats. To dissociate the contribution of GLP-1Rs in the area postrema (AP) and the nucleus tractus solitarius (NTS), we examined the effects of liraglutide in both NTS AAV-shRNA-driven Glp1r knockdown and AP-lesioned animals. Knockdown of NTS GLP-1Rs, but not surgical lesioning of the AP, attenuated the anorectic and body weight-reducing effects of acutely delivered liraglutide. In addition, NTS c-Fos responses were maintained in AP-lesioned animals. Moreover, NTS Glp1r knockdown was sufficient to attenuate the intake- and body weight-reducing effects of chronic daily administered liraglutide over 3 weeks. Development of improved obesity pharmacotherapies requires an understanding of the cellular phenotypes targeted by GLP-1R agonists. Fluorescence in situ hybridization identified Glp1r transcripts in NTS GABAergic neurons, which when inhibited using chemogenetics, attenuated the food intake- and body weight-reducing effects of liraglutide. This work demonstrates the contribution of NTS GLP-1Rs to the anorectic potential of liraglutide and highlights a phenotypically distinct (GABAergic) population of neurons within the NTS that express the GLP-1R and are involved in the mediation of liraglutide signaling.
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Affiliation(s)
- Samantha M Fortin
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rachele K Lipsky
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rinzin Lhamo
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jack Chen
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eun Kim
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tito Borner
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Heath D Schmidt
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew R Hayes
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
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21
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Littlejohn EL, Espinoza L, Lopez MM, Smith BN, Boychuk CR. GABA A receptor currents in the dorsal motor nucleus of the vagus in females: influence of ovarian cycle and 5α-reductase inhibition. J Neurophysiol 2019; 122:2130-2141. [PMID: 31596653 PMCID: PMC6879959 DOI: 10.1152/jn.00039.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 09/23/2019] [Accepted: 10/07/2019] [Indexed: 11/22/2022] Open
Abstract
The dorsal motor nucleus of the vagus (DMV) contains the preganglionic motor neurons important in the regulation of glucose homeostasis and gastrointestinal function. Despite the role of sex in the regulation of these processes, few studies examine the role of sex and/or ovarian cycle in the regulation of synaptic neurotransmission to the DMV. Since GABAergic neurotransmission is critical to normal DMV function, the present study used in vitro whole cell patch-clamping to investigate whether sex differences exist in GABAergic neurotransmission to DMV neurons. It additionally investigated whether the ovarian cycle plays a role in those sex differences. The frequency of phasic GABAA receptor-mediated inhibitory postsynaptic currents in DMV neurons from females was lower compared with males, and this effect was TTX sensitive and abolished by ovariectomy (OVX). Amplitudes of GABAergic currents (both phasic and tonic) were not different. However, females demonstrated significantly more variability in the amplitude of both phasic and tonic GABAA receptor currents. This difference was eliminated by OVX in females, suggesting that these differences were related to reproductive hormone levels. This was confirmed for GABAergic tonic currents by comparing females in two ovarian stages, estrus versus diestrus. Female mice in diestrus had larger tonic current amplitudes compared with those in estrus, and this increase was abolished after administration of a 5α-reductase inhibitor but not modulation of estrogen. Taken together, these findings demonstrate that DMV neurons undergo GABAA receptor activity plasticity as a function of sex and/or sex steroids.NEW & NOTEWORTHY Results show that GABAergic signaling in dorsal vagal motor neurons (DMV) demonstrates sex differences and fluctuates across the ovarian cycle in females. These findings are the first to demonstrate that female GABAA receptor activity in this brain region is modulated by 5α-reductase-dependent hormones. Since DMV activity is critical to both glucose and gastrointestinal homeostasis, these results suggest that sex hormones, including those synthesized by 5α-reductase, contribute to visceral, autonomic function related to these physiological processes.
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Affiliation(s)
- Erica L Littlejohn
- Department of Cellular and Integrative Physiology, College of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Liliana Espinoza
- Department of Cellular and Integrative Physiology, College of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Monica M Lopez
- Department of Cellular and Integrative Physiology, College of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Bret N Smith
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Carie R Boychuk
- Department of Cellular and Integrative Physiology, College of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas
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Goyal RK, Cristofaro V, Sullivan MP. Rapid gastric emptying in diabetes mellitus: Pathophysiology and clinical importance. J Diabetes Complications 2019; 33:107414. [PMID: 31439470 PMCID: PMC7707148 DOI: 10.1016/j.jdiacomp.2019.107414] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/20/2019] [Accepted: 08/07/2019] [Indexed: 12/23/2022]
Abstract
Although slow gastric emptying (gastroparesis) is a well-known complication of chronic hyperglycemia in diabetes mellitus (DM), it recently has become clear that rapid gastric emptying also is a frequent and important diabetic complication. In contrast, acute hyperglycemia causes slow gastric emptying, and acute hypoglycemia causes rapid gastric emptying. Rapid gastric emptying is frequent in T2DM; however, it may also occur in T1DM, particularly in the early stages of the disease, but may persist even into late stages. Recent studies suggest that usually, the stomach restricts the emptying of nutrients to 1-4 kcals/min. This restriction is due to the action of the gastric 'braking' hormones such as GLP-1, leptin, and amylin acting via the gastric inhibitory vagal motor circuit (GIVMC). Disruption of this braking system leads to rapid gastric emptying. Acute hyperglycemia also slows gastric emptying by stimulating the GIVMC, while acute hypoglycemia causes rapid gastric emptying by stimulating the gastric excitatory vagal motor circuit (GEVMC). In contrast, chronic hyperglycemia causes rapid gastric emptying by inducing oxidative stress in the stomach wall that disrupts inhibitory neuromuscular transmission and increases the contractility of the smooth muscle, while chronic hyperglycemia may also cause slow gastric emptying via severe inflammatory stress caused by proinflammatory macrophages and reduce contractility of the smooth muscle. There is a bidirectional relationship between blood glucose and gastric emptying. Thus, rapid gastric emptying may lead to a sizeable postprandial spike, and slow gastric emptying may blunt it. Postprandial hyperglycemia is involved in the development, progression, and complications of DM. Correction of fast gastric emptying involves agents that activate GIVMC and the use of gastric 'braking' hormones or their analogs. Recognition and treatment of rapid gastric emptying may contribute to better management of postprandial hyperglycemia and prevention of some diabetic complications.
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Affiliation(s)
- Raj K Goyal
- Departments of Medicine and Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States of America.
| | - Vivian Cristofaro
- Departments of Medicine and Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States of America
| | - Maryrose P Sullivan
- Departments of Medicine and Surgery, VA Boston Healthcare System and Harvard Medical School, Boston, MA, United States of America
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23
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Jiang Y, Babic T, Travagli RA. Sex differences in GABAergic neurotransmission to rat DMV neurons. Am J Physiol Gastrointest Liver Physiol 2019; 317:G476-G483. [PMID: 31393788 PMCID: PMC6842985 DOI: 10.1152/ajpgi.00112.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
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. The aim of the present study was to test the hypothesis that GABAergic tone to DMV neurons, hence the vagal output to the stomach, varies according to sex and the estrus cycle. Experiments were performed on age-matched Sprague-Dawley male and virgin female rats; females were subdivided according to the high-estrogen (HE) or low-estrogen (LE) period of their cycle. Whole-cell patch-clamp recordings were made from gastric-projecting DMV neurons, and the response to perfusion with the GABAA receptor antagonist bicuculline was examined. The response of corpus and antrum tone and motility to bicuculline microinjected in the dorsal vagal complex, recorded via strain gauges sewn to the anterior gastric surface, was also assessed. Bicuculline increased the firing rate of DMV neurons, as well as gastric tone and motility, to a larger extent in HE compared with LE or male rats, suggesting a higher GABAergic tone in HE female rats. Taken together, the data support the hypothesis that GABAergic tone to DMV neurons varies according to sex and estrus cycle.NEW & NOTEWORTHY GABAergic neurotransmission to the dorsal motor nucleus of the vagus (DMV) plays a pivotal role in the modulation of gastric tone and motility. Gastric motility is reduced in women and may contribute to the higher incidence of functional gastrointestinal disorders. In the present study, we report that GABAergic tone to rat DMV neurons, hence vagal output to the stomach, varies according to sex and estrus cycle, and the GABAergic tone is increased during the high-estrogen period of the estrus cycle.
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Affiliation(s)
- Yanyan Jiang
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - Tanja Babic
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - R. Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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24
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Horita T, Koyama K, Takemi S, Tanaka T, Sakai T, Sakata I. GABAergic and glutamatergic neurons in the brain regulate phase II of migrating motor contractions in the Suncus murinus. J Smooth Muscle Res 2019; 54:91-99. [PMID: 30787212 PMCID: PMC6380905 DOI: 10.1540/jsmr.54.91] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Gastric contractions exhibit characteristic motor patterns in the fasted state, known as
migrating motor contractions (MMC). MMC consist of three periodically repeated phases
(phase I, II and III) and are known to be regulated by hormones and the autonomic and
enteric nervous systems. However, the central regulation of gastric contractions in the
fasted state is not completely understood. Here, we have examined the central effects of
motilin, ghrelin, γ-aminobutyric acid (GABA) and L-glutamate signaling on gastric MMC by
using suncus (Suncus murinus) as an animal model, because of their
similar gastric motor patterns to those observed in humans and dogs.
Intracerebroventricular (i.c.v.) administration of motilin and ghrelin had no effect on
phase I and II contractions, respectively. Conversely, i.c.v. administration of
GABAA receptor antagonist, during phase I of the MMC, evoked phase II-like
contractions and significantly increased the motility index (MI). This was compared with
the i.c.v. administration of GABA which inhibited spontaneous phase II contractions with a
significantly decreased MI. In addition, i.c.v. administration of L-glutamate during phase
I also induced phase II-like irregular contractions with a significant increase in the MI.
Taken together with previous findings, these results suggest that central GABAergic and
glutamatergic signaling, with the coordination of both peripheral motilin and ghrelin,
regulate phase II contractions of MMC in the fasted state.
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Affiliation(s)
- Taichi Horita
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Kouhei Koyama
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Toru Tanaka
- Faculty of Pharmaceutical Sciences, Department of Pharmaceutical and Health Sciences, Josai University, 1-1 Keiyaki dai, Sakado, Saitama 350-0295, Japan
| | - Takafumi Sakai
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan.,Area of Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
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25
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Extensive Inhibitory Gating of Viscerosensory Signals by a Sparse Network of Somatostatin Neurons. J Neurosci 2019; 39:8038-8050. [PMID: 31471471 DOI: 10.1523/jneurosci.3036-18.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 08/07/2019] [Accepted: 08/10/2019] [Indexed: 01/07/2023] Open
Abstract
Integration and modulation of primary afferent sensory information begins at the first terminating sites within the CNS, where central inhibitory circuits play an integral role. Viscerosensory information is conveyed to the nucleus of the solitary tract (NTS) where it initiates neuroendocrine, behavioral, and autonomic reflex responses that ensure optimal internal organ function. This excitatory input is modulated by diverse, local inhibitory interneurons, whose functions are not clearly understood. Here we show that, in male rats, 65% of somatostatin-expressing (SST) NTS neurons also express GAD67, supporting their likely role as inhibitory interneurons. Using whole-cell recordings of NTS neurons, from horizontal brainstem slices of male and female SST-yellow fluorescent protein (YFP) and SST-channelrhodopsin 2 (ChR2)-YFP mice, we quantified the impact of SST-NTS neurons on viscerosensory processing. Light-evoked excitatory photocurrents were reliably obtained from SST-ChR2-YFP neurons (n = 16) and the stimulation-response characteristics determined. Most SST neurons (57%) received direct input from solitary tract (ST) afferents, indicating that they form part of a feedforward circuit. All recorded SST-negative NTS neurons (n = 72) received SST-ChR2 input. ChR2-evoked PSCs were largely inhibitory and, in contrast to previous reports, were mediated by both GABA and glycine. When timed to coincide, the ChR2-activated SST input suppressed ST-evoked action potentials at second-order NTS neurons, demonstrating strong modulation of primary viscerosensory input. These data indicate that the SST inhibitory network innervates broadly within the NTS, with the potential to gate viscerosensory input to powerfully alter autonomic reflex function and other behaviors.SIGNIFICANCE STATEMENT Sensory afferent input is modulated according to state. For example the baroreflex is altered during a stress response or exercise, but the basic mechanisms underpinning this sensory modulation are not fully understood in any sensory system. Here we demonstrate that the neuronal processing of viscerosensory information begins with synaptic gating at the first central synapse with second-order neurons in the NTS. These data reveal that the somatostatin subclass of inhibitory interneurons are driven by visceral sensory input to play a major role in gating viscerosensory signals, placing them within a feedforward circuit within the NTS.
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EA at PC6 Promotes Gastric Motility: Role of Brainstem Vagovagal Neurocircuits. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:7457485. [PMID: 31379967 PMCID: PMC6662446 DOI: 10.1155/2019/7457485] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 05/28/2019] [Accepted: 07/03/2019] [Indexed: 12/14/2022]
Abstract
Background We aimed to assess whether electroacupuncture (EA) at PC6 affects gastric motility via the vagovagal reflex and if so whether brainstem vagovagal neurocircuits and related transmitters are involved. Methods Gastric motility was measured in male Sprague-Dawley (SD) rats by placing a small manometric balloon in the gastric antrum. The rats were subjected to control, sham surgery, vagotomy, sympathectomy, and microinjection group, including artificial cerebrospinal fluid, gamma-aminobutyric acid (GABA), and glutamic acid (L-Glu). The effect of EA at PC6 on gastric motility was measured. Moreover, electrophysiological testing was used to measure the effect of EA at PC6 on the parasympathetic and sympathetic nerves. In addition, artificial cerebrospinal fluid, L-Glu, and GABA have been microinjected into the dorsal motor nucleus of the vagus (DMV) to measure the changes in gastric motility and parasympathetic nerve discharge induced by EA at PC6. Key Results EA facilitated the gastric motility in control group. In the vagotomy group, gastric motility was not affected by EA at PC6. However, in the sympathectomy group, gastric motility was similar to control group. Acupuncture at PC6 increased parasympathetic nerve discharge but not sympathetic nerve discharge. Furthermore, the microinjection of L-Glu into the DMV increased gastric motility, although EA at PC6 showed no remarkable change in this group. The injection of GABA reduced gastric motility and parasympathetic nerve discharge, but EA at PC6 significantly increased gastric motility and the parasympathetic nerve discharge in this group. Conclusions and Inferences EA at PC6—primarily by inhibiting GABA transmission to DMV—reduced the inhibition of efferent vagal motor fibers and thus promoted efferent vagus nerve activity and increased gastric motility.
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Clyburn C, Howe CA, Arnold AC, Lang CH, Travagli RA, Browning KN. Perinatal high-fat diet alters development of GABA A receptor subunits in dorsal motor nucleus of vagus. Am J Physiol Gastrointest Liver Physiol 2019; 317:G40-G50. [PMID: 31042399 PMCID: PMC6689732 DOI: 10.1152/ajpgi.00079.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/22/2019] [Accepted: 04/29/2019] [Indexed: 01/31/2023]
Abstract
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 GABAA 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 day 13 (E13) to postnatal day 42 (P42), and response to brainstem microinjection of benzodiazepines was assessed. Whole cell patch clamp recordings from DMV neurons assessed the functional expression of GABAA α subunits, whereas mRNA and protein expression were measured via qPCR and Western blotting, respectively. pHFD decreased basal antrum and corpus motility, whereas brainstem microinjection of L838,417 (positive allosteric modulator of α2/3 subunit-containing GABAA receptors) produced a larger decrease in gastric tone and motility. GABAergic miniature inhibitory postsynaptic currents in pHFD DMV neurons were responsive to L838,417 throughout development, unlike control DMV neurons, which were responsive only at early postnatal timepoints. Brainstem mRNA and protein expression of the GABAA α1,2, and 3 subunits, however, did not differ between control and pHFD rats. This study suggests that pHFD exposure arrests the development of synaptic GABAA α2/3 receptor subunits on DMV neurons and that functional synaptic expression is maintained into adulthood, although cellular localization may differ. The tonic activation of slower GABAA α2/3 subunit-containing receptors implies that such developmental changes may contribute to the observed decreased gastric motility. NEW & NOTEWORTHY Vagal neurocircuits involved in the control of gastric functions, satiation, and food intake are subject to significant developmental regulation postnatally, with immature GABAA receptors expressing slower α2/3-subunits, whereas mature GABAA receptor express faster α1-subunits. After perinatal high-fat diet exposure, this developmental regulation of dorsal motor nucleus of the vagus (DMV) neurons is disrupted, increasing their tonic GABAergic inhibition, decreasing efferent output, and potentially decreasing gastric motility.
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Affiliation(s)
- Courtney Clyburn
- Department of Neural and Behavioral Sciences, Penn State College of Medicine , Hershey, Pennsylvania
| | - Caitlin A Howe
- Department of Neural and Behavioral Sciences, Penn State College of Medicine , Hershey, Pennsylvania
| | - Amy C Arnold
- Department of Neural and Behavioral Sciences, Penn State College of Medicine , Hershey, Pennsylvania
| | - Charles H Lang
- Department of Cellular and Molecular Physiology, Penn State College of Medicine , Hershey, Pennsylvania
| | - R Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State College of Medicine , Hershey, Pennsylvania
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine , Hershey, Pennsylvania
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28
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Lu MJ, Yu Z, He Y, Yin Y, Xu B. Electroacupuncture at ST36 modulates gastric motility via vagovagal and sympathetic reflexes in rats. World J Gastroenterol 2019; 25:2315-2326. [PMID: 31148903 PMCID: PMC6529886 DOI: 10.3748/wjg.v25.i19.2315] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/22/2019] [Accepted: 05/03/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Electroacupuncture (EA) at ST36 can significantly improve gastrointestinal symptoms, especially in promoting gastrointestinal motility. The automatic nervous system plays a main role in EA, but few studies exist on how vagovagal and sympathetic reflexes affect EA to regulate gastrointestinal motility.
AIM To study the role of vagovagal and sympathetic reflexes in EA at ST36, as well as the associated receptor subtypes that are involved.
METHODS Gastric motility was measured with a manometric balloon placed in the gastric antrum area in anesthetized animals. The peripheral nervous discharge was measured using a platinum electrode hooking the vagus or greater splanchnic nerve, and the central nervous discharge was measured with a glass microelectrode in the dorsal motor nucleus of the vagus (DMV). The effects and mechanisms of EA at ST36 were explored in male Sprague-Dawley rats which were divided in to a control group, vagotomy group, sympathectomy group, and microinjection group [including an artificial cerebrospinal fluid group, glutamate (L-Glu) group, and γ-aminobutyric acid (GABA) group] and in genetically modified male mice [β1β2 receptor-knockout (β1β2-/-) mice, M2M3 receptor-knockout (M2M3-/-) mice, and wild-type control mice].
RESULTS EA at ST36 promoted gastric motility during 30-120 s. During EA, both vagus and sympathetic nerve discharges increased, with a much higher frequency of vagus nerve discharge than sympathetic discharge. The gastric motility mediated by EA at ST36 was interdicted by vagotomy. However, gastric motility mediated by EA at ST36 was increased during 0-120 s by sympathectomy, which eliminated the delay effect of EA during 0-30 s, but it was lower than the control group during 30-120 s. Using gene knockout mice and their wild-type controls to explore the receptor mechanisms, we found that EA at ST36 decreased gastric motility in M2/3-/- mice, and promoted gastric motility in β1/2-/- mice. Extracellular recordings showed that EA at ST36 increased spikes of the DMV. Microinjection of L-Glu into the DMV increased gastric motility, while EA at ST36 decreased gastric motility during 0-60 s, and promoted gastric motility during 60-120 s. Injection of GABA reduced or increased gastric motility, and reduced the promoting gastric motility effect of EA at ST36.
CONCLUSION These data suggest that EA at ST36 modulates gastric motility via vagovagal and sympathetic reflexes mediated through M2/3 and β1/2 receptors, respectively. Sympathetic nerve activity mediated through β1/2 receptors is associated with an early delay in modulation of gastric motility by EA at ST36.
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Affiliation(s)
- Meng-Jiang Lu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zhi Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Yan He
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Yin Yin
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Bin Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Goyal RK, Guo Y, Mashimo H. Advances in the physiology of gastric emptying. Neurogastroenterol Motil 2019; 31:e13546. [PMID: 30740834 PMCID: PMC6850045 DOI: 10.1111/nmo.13546] [Citation(s) in RCA: 203] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/29/2018] [Accepted: 12/16/2018] [Indexed: 12/16/2022]
Abstract
There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits. The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP-1 inhibit gastric emptying via the GIVMC, and in the inter-digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.
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Affiliation(s)
- Raj K. Goyal
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
| | - Yanmei Guo
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
| | - Hiroshi Mashimo
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
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30
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McMenamin CA, Clyburn C, Browning KN. High-Fat Diet During the Perinatal Period Induces Loss of Myenteric Nitrergic Neurons and Increases Enteric Glial Density, Prior to the Development of Obesity. Neuroscience 2019; 393:369-380. [PMID: 30454864 DOI: 10.1016/j.neuroscience.2018.09.033] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 09/19/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Diet-induced obesity induces peripheral inflammation accompanied by a loss of myenteric neurons. Few studies, however, have investigated the effects of a high-fat diet (HFD) on either the development of myenteric neurons or prior to the occurrence of obesity. The present study assessed the effects of maternal HFD on the density and neurochemical phenotype of myenteric ganglia in the upper gastrointestinal tract. Sprague-Dawley rats were fed either a control or HFD (14% or 60% kcal from fat, respectively) from embryonic day 13; the fundus, corpus and duodenum were fixed thereafter at postnatal 2, 4, 6 and 12 weeks of age for subsequent immunohistochemical studies. While myenteric ganglion size did not differ throughout the study, HFD exposure decreased the number of nitrergic neurons by 6 weeks of age in all regions. This decrease was accompanied by a loss of PGP-immunoreactive neurons, suggesting a decline in myenteric neuronal number. HFD also increased myenteric plexus glial cell density in all regions by 4 weeks of age. These changes occurred in the absence of an increase in serum or gastric inflammatory markers. The present study suggests that exposure to a HFD during the perinatal time period results in glial proliferation and loss of inhibitory nitrergic neurons prior to the onset of obesity, suggesting that dietary alterations may affect gastrointestinal functions independently of increased adiposity or glycemic dysregulation.
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Affiliation(s)
- Caitlin A McMenamin
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Courtney Clyburn
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, United States
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, United States.
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31
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A hindbrain inhibitory microcircuit mediates vagally-coordinated glucose regulation. Sci Rep 2019; 9:2722. [PMID: 30804396 PMCID: PMC6389891 DOI: 10.1038/s41598-019-39490-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
Neurons in the brainstem dorsal vagal complex integrate neural and humoral signals to coordinate autonomic output to viscera that regulate a variety of physiological functions, but how this circuitry regulates metabolism is murky. We tested the hypothesis that premotor, GABAergic neurons in the nucleus tractus solitarius (NTS) form a hindbrain micro-circuit with preganglionic parasympathetic motorneurons of the dorsal motor nucleus of the vagus (DMV) that is capable of modulating systemic blood glucose concentration. In vitro, neuronal activation or inhibition using either excitatory or inhibitory designer receptor exclusively activated by designer drugs (DREADDs) constructs expressed in GABAergic NTS neurons increased or decreased, respectively, action potential firing of GABAergic NTS neurons and downstream synaptic inhibition of the DMV. In vivo, DREADD-mediated activation of GABAergic NTS neurons increased systemic blood glucose concentration, whereas DREADD-mediated silencing of these neurons was without effect. The DREADD-induced hyperglycemia was abolished by blocking peripheral muscarinic receptors, consistent with the hypothesis that altered parasympathetic drive mediated the response. This effect was paralleled by elevated serum glucagon and hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK1) expression, without affecting insulin levels or muscle metabolism. Activity in a hindbrain inhibitory microcircuit is sufficient to modulate systemic glucose concentration, independent of insulin secretion or utilization.
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Abstract
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. SUMMARY Recognition of the pivotal role that the central nervous system exerts in the regulation, integration, and modulation of gastric motility should serve to encourage research into central mechanisms regulating peripheral motility disorders.
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Affiliation(s)
- Kirsteen N Browning
- Department of Neural and Behavioral Science, Penn State College of Medicine, Hershey, Pennsylvania, USA
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33
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Peng M, Coutts D, Wang T, Cakmak YO. Systematic review of olfactory shifts related to obesity. Obes Rev 2019; 20:325-338. [PMID: 30450791 DOI: 10.1111/obr.12800] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 10/07/2018] [Indexed: 02/01/2023]
Abstract
OBJECTIVE The modern food environment is a key driver of rising levels of obesity. While olfaction is known to play a major role in food choice; however, its relationship to obesity is yet to be understood. This review assesses current knowledge of the interaction between obesity and olfaction. METHODS This review is based on observational studies comparing olfactory abilities across weight groups (N = 10) and clinical studies evaluating olfactory changes following bariatric surgery (N = 9). Meta-analyses were performed on data collected by a standard olfactory assessment tool (Sniffin΄ Sticks), to test whether olfaction has any association with body weight or bariatric surgery. RESULTS This review synthesizes findings derived from 38 datasets, with a total of 1432 individual olfactory assessments. The meta-analyses suggest that olfactory function is negatively correlated with body weight. In addition, Roux-en-Y gastric bypass patients frequently report olfactory changes, yet more pronounced and immediate shifts have been observed among sleeve gastrectomy recipients. CONCLUSIONS Our review finds strong evidence for the link between olfaction and obesity and indicates that bariatric surgery (particularly the sleeve gastrectomy) is effective in reversing olfactory decline associated with obesity. In conclusion, we present mechanistic models to underpin the observed relationship between olfaction and obesity.
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Affiliation(s)
- Mei Peng
- Sensory Neuroscience Laboratory, Department of Food Science, University of Otago, Dunedin, New Zealand
| | - Duncan Coutts
- Sensory Neuroscience Laboratory, Department of Food Science, University of Otago, Dunedin, New Zealand
| | - Ting Wang
- Department of Mathematics and Statistics, University of Otago, Dunedin, New Zealand
| | - Yusuf O Cakmak
- Department of Anatomy, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, Dunedin, New Zealand.,Medical Technologies Centre of Research Excellence, Auckland, New Zealand
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Mussa BM, Sood S, Verberne AJM. Implication of neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function in diabetic gastroparesis. World J Gastroenterol 2018; 24:3821-3833. [PMID: 30228777 PMCID: PMC6141338 DOI: 10.3748/wjg.v24.i34.3821] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Recently, diabetic gastroparesis (DGP) has received much attention as its prevalence is increasing in a dramatic fashion and management of patients with DGP represents a challenge in the clinical practice due to the limited therapeutic options. DGP highlights an interrelationship between the gastric emptying and pancreatic secretory function that regulate a wide range of digestive and metabolic functions, respectively. It well documented that both gastric emptying and pancreatic secretion are under delicate control by multiple neurohormonal mechanisms including extrinsic parasympathetic pathways and gastrointestinal (GI) hormones. Interestingly, the latter released in response to various determinants that related to the rate and quality of gastric emptying. Others and we have provided strong evidence that the central autonomic nuclei send a dual output (excitatory and inhibitory) to the stomach and the pancreas in response to a variety of hormonal signals from the abdominal viscera. Most of these hormones released upon gastric emptying to provide feedback, and control this process and simultaneously regulate pancreatic secretion and postprandial glycemia. These findings emphasize an important link between gastric emptying and pancreatic secretion and its role in maintaining homeostatic processes within the GI tract. The present review deals with the neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function that implicated in DGP and this provides new insights in our understanding of the pathophysiology of DGP. This also enhances the process of identifying potential therapeutic targets to treat DGP and limit the complications of current management practices.
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Affiliation(s)
- Bashair M Mussa
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sanjay Sood
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anthony JM Verberne
- Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia
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Clyburn C, Travagli RA, Browning KN. Acute high-fat diet upregulates glutamatergic signaling in the dorsal motor nucleus of the vagus. Am J Physiol Gastrointest Liver Physiol 2018; 314:G623-G634. [PMID: 29368945 PMCID: PMC6008060 DOI: 10.1152/ajpgi.00395.2017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Obesity is associated with dysregulation of vagal neurocircuits controlling gastric functions, including food intake and energy balance. In the short term, however, caloric intake is regulated homeostatically although the precise mechanisms responsible are unknown. The present study examined the effects of acute high-fat diet (HFD) on glutamatergic neurotransmission within central vagal neurocircuits and its effects on gastric motility. Sprague-Dawley rats were fed a control or HFD diet (14% or 60% kcal from fat, respectively) for 3-5 days. Whole cell patch-clamp recordings and brainstem application of antagonists were used to assess the effects of acute HFD on glutamatergic transmission to dorsal motor nucleus of the vagus (DMV) neurons and subsequent alterations in gastric tone and motility. After becoming hyperphagic initially, caloric balance was restored after 3 days following HFD exposure. In control rats, the non- N-methyl-d-aspartate (NMDA) receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), but not the NMDA receptor antagonist, amino-5-phosphonopentanoate (AP5), significantly decreased excitatory synaptic currents and action potential firing rate in gastric-projecting DMV neurons. In contrast, both AP5 and DNQX decreased excitatory synaptic transmission and action potential firing in acute HFD neurons. When microinjected into the brainstem, AP5, but not DNQX, decreased gastric motility and tone in acute HFD rats only. These results suggest that acute HFD upregulates NMDA receptor-mediated currents, increasing DMV neuronal excitability and activating the vagal efferent cholinergic pathway, thus increasing gastric tone and motility. Although such neuroplasticity may be a persistent adaptation to the initial exposure to HFD, it may also be an important mechanism in homeostatic regulation of energy balance. NEW & NOTEWORTHY Vagal neurocircuits are critical to the regulation of gastric functions, including satiation and food intake. Acute high-fat diet upregulates glutamatergic signaling within central vagal neurocircuits via activation of N-methyl-d-aspartate receptors, increasing vagal efferent drive to the stomach. Although it is possible that such neuroplasticity is a persistent adaptation to initial exposure to the high-fat diet, it may also play a role in the homeostatic control of feeding.
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Affiliation(s)
- Courtney Clyburn
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - R. Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - Kirsteen N. Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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Jiang Y, Browning KN, Toti L, Travagli RA. Vagally mediated gastric effects of brain stem α 2-adrenoceptor activation in stressed rats. Am J Physiol Gastrointest Liver Physiol 2018; 314:G504-G516. [PMID: 29351390 PMCID: PMC5966751 DOI: 10.1152/ajpgi.00382.2017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 01/05/2018] [Accepted: 01/09/2018] [Indexed: 02/07/2023]
Abstract
Chronic stress exerts vagally dependent effects to disrupt gastric motility; previous studies have shown that, among other nuclei, A2 neurons are involved in mediating these effects. Several studies have also shown robust in vitro and in vivo effects of α2-adrenoceptor agonists on vagal motoneurons. We have demonstrated previously that brainstem vagal neurocircuits undergo remodeling following acute stress; however, the effects following brief periods of chronic stress have not been investigated. Our aim, therefore, was to test the hypothesis that different types of chronic stress influence gastric tone and motility by inducing plasticity in the response of vagal neurocircuits to α2-adrenoreceptor agonists. In rats that underwent 5 days of either homotypic or heterotypic stress loading, we applied the α2-adrenoceptor agonist, UK14304, either by in vitro brainstem perfusion to examine its ability to modulate GABAergic synaptic inputs to vagal motoneurons or in vivo brainstem microinjection to observe actions to modulate antral tone and motility. In neurons from naïve rats, GABAergic currents were unresponsive to exogenous application of UK14304. In contrast, GABAergic currents were inhibited by UK14304 in all neurons from homotypic and, in a subpopulation of neurons, heterotypic stressed rats. In control rats, UK14304 microinjection inhibited gastric tone and motility via withdrawal of vagal cholinergic tone; in heterotypic stressed rats, the larger inhibition of antrum tone was due to a concomitant activation of peripheral nonadrenergic, noncholinergic pathways. These data suggest that stress induces plasticity in brainstem vagal neurocircuits, leading to an upregulation of α2-mediated responses. NEW & NOTEWORTHY Catecholaminergic neurons of the A2 area play a relevant role in stress-related dysfunction of the gastric antrum. Brief periods of chronic stress load induce plastic changes in the actions of adrenoceptors on vagal brainstem neurocircuits.
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Affiliation(s)
- Yanyan Jiang
- Department of Neural and Behavioral Sciences, Penn State, College of Medicine , Hershey, Pennsylvania
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State, College of Medicine , Hershey, Pennsylvania
| | - Luca Toti
- Department of Neural and Behavioral Sciences, Penn State, College of Medicine , Hershey, Pennsylvania
| | - R Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State, College of Medicine , Hershey, Pennsylvania
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Bülbül M, Sinen O, Gök M, Travagli RA. Apelin-13 inhibits gastric motility through vagal cholinergic pathway in rats. Am J Physiol Gastrointest Liver Physiol 2018; 314:G201-G210. [PMID: 29025730 PMCID: PMC5866420 DOI: 10.1152/ajpgi.00223.2017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The expression of apelin and its receptors (APJ) in central autonomic networks suggests that apelin may regulate gastrointestinal motor functions. In rodents, central administration of apelin-13 has been shown to inhibit gastric emptying; however, the mechanisms involved remain to be determined. Using male adult Sprague-Dawley rats, the aims of the present study were 1) to determine the expression of APJ receptor in the dorsal vagal complex (DVC), 2) to assess the effects of central application of apelin-13 into the DVC on gastric tone and motility, and 3) to investigate the neuronal pathways responsible for apelin-induced alterations. APJ receptor immunoreactivity was detected in gastric-projecting and choline acetyltransferase-positive neurons of the DVC. Microinjection of apelin-13 into the DVC significantly decreased gastric tone and motility in both corpus and antrum. The apelin-induced reduction in gastric tone and motility was prevented by surgical vagotomy or fourth ventricular application of the APJ receptor antagonist, [Ala13]apelin-13 (F13A). Systemic administration of the muscarinic receptor antagonist atropine, but not the nitric oxide synthase inhibitor nitro-l-arginine methyl ester (l-NAME), abolished the apelin-induced inhibitory responses. The present results indicate a central modulatory role of apelin in the vagal neurocircuitry that controls gastric motor functions via withdrawal of the tonically active cholinergic pathway. NEW & NOTEWORTHY This is the first study investigating the effects induced by brain stem application of apelin-13 while monitoring gastric tone and motility in rats. We have found that gastric-projecting neurons of the dorsal vagal complex express apelin receptors (APJ), which mediate the inhibitory actions of apelin-13. The inhibitory effects of apelin were abolished by systemic preadministration of atropine, but not nitro-l-arginine methyl ester (l-NAME). Apelin seems to modulate gastric motility via withdrawal of the tonically active vagal cholinergic pathway.
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Affiliation(s)
- Mehmet Bülbül
- 1Department of Neural and Behavioral Neurosciences, Penn State University College of Medicine, Hershey, Pennsylvania,2Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Osman Sinen
- 2Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Melahat Gök
- 2Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - R. Alberto Travagli
- 1Department of Neural and Behavioral Neurosciences, Penn State University College of Medicine, Hershey, Pennsylvania
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McMenamin CA, Travagli RA, Browning KN. Perinatal high fat diet increases inhibition of dorsal motor nucleus of the vagus neurons regulating gastric functions. Neurogastroenterol Motil 2018; 30:10.1111/nmo.13150. [PMID: 28762595 PMCID: PMC5739938 DOI: 10.1111/nmo.13150] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 06/07/2017] [Indexed: 01/02/2023]
Abstract
BACKGROUND Previous studies suggest an increased inhibition of dorsal motor nucleus of the vagus (DMV) neurons following exposure to a perinatal high fat diet (PNHFD); the underlying neural mechanisms, however, remain unknown. This study assessed the effects of PNHFD on inhibitory synaptic inputs to DMV neurons and the vagally dependent control of gastric tone and motility. METHODS Whole-cell patch clamp recordings were made from DMV neurons in thin brainstem slices from Sprague-Dawley rats fed either a control diet or HFD (14 or 60% kcal from fat, respectively) from embryonic day 13 onwards; gastric tone and motility were recorded in in vivo anesthetized rats. KEY RESULTS The non-selective GABAA antagonist, BIC (10 μmol L-1 ), induced comparable inward currents in PNHFD and control DMV neurons, but a larger current in PNHFD neurons at higher concentrations (50 μmol L-1 ). Differences were not apparent in neuronal responses to the phasic GABAA antagonist, gabazine (GBZ), the extrasynaptic GABAA agonist, THIP, the GABA transport blocker, nipecotic acid, or the gliotoxin, fluoroacetate, suggesting that PNHFD altered inhibitory transmission but not GABAA receptor density or function, GABA uptake or glial modulation of synaptic strength. Similarly, the increase in gastric motility and tone following brainstem microinjection of low doses of BIC (1-10 pmoles) and GBZ (0.01-0.1 pmoles) were unchanged in PNHFD rats while higher doses of BIC (25 pmoles) induced a significantly larger increase in gastric tone compared to control. CONCLUSIONS AND INFERENCES These studies suggest that exposure to PNHFD increases the tonic inhibition of DMV neurons, possibly contributing to dysregulated vagal control of gastric functions.
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Affiliation(s)
| | | | - Kirsteen N. Browning
- Address for correspondence: Kirsteen N Browning, PhD, Department of Neural and Behavioral Science, Penn State College of Medicine, 500 University Drive, MC H109, Hershey, PA 17033, Tel: 717 531 8267,
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Boychuk CR, Smith KC, Smith BN. Functional and molecular plasticity of γ and α1 GABA A receptor subunits in the dorsal motor nucleus of the vagus after experimentally induced diabetes. J Neurophysiol 2017; 118:2833-2841. [PMID: 28835522 DOI: 10.1152/jn.00085.2017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 08/17/2017] [Accepted: 08/17/2017] [Indexed: 12/13/2022] Open
Abstract
Chronic experimentally induced hyperglycemia augments subunit-specific γ-aminobutyric acid A (GABAA) receptor-mediated inhibition of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). However, the contribution of α1 or γ GABAA receptor subunits, which are ubiquitously expressed on central nervous system neurons, to this elevation in inhibitory tone have not been determined. This study investigated the effect of chronic hyperglycemia/hypoinsulinemia on α1- and γ-subunit-specific GABAA receptor-mediated inhibition using electrophysiological recordings in vitro and quantitative RT-PCR. DMV neurons from streptozotocin-treated mice demonstrated enhancement of both phasic and tonic inhibitory currents in response to application of the α1-subunit-selective GABAA receptor-positive allosteric modulator zolpidem. Responses to low concentrations of the GABAA receptor antagonist gabazine suggested an additional increased contribution of γ-subunit-containing receptors to tonic currents in DMV neurons. Consistent with the functional elevation in α1- and γ-subunit-dependent activity, transcription of both the α1- and γ2-subunits was increased in the dorsal vagal complex of streptozotocin-treated mice. Overall, these findings suggest an increased sensitivity to both zolpidem and gabazine after several days of hyperglycemia/hypoinsulinemia, which could contribute to altered parasympathetic output from DMV neurons in diabetes.NEW & NOTEWORTHY Glutamate and GABA signaling in the dorsal vagal complex is elevated after several days of chronic hyperglycemia in a mouse model of type 1 diabetes. We report persistently enhanced GABAA receptor-mediated responses to the somnolescent zolpidem in preganglionic vagal motor neurons. These results imply a broader impact of chronic hyperglycemia on central vagal function than previously appreciated and reinforce the hypothesis that diabetes effects in the brain can impact regulation of metabolic homeostasis.
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Affiliation(s)
- Carie R Boychuk
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Katalin C Smith
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Bret N Smith
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
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McMenamin CA, Travagli RA, Browning KN. Inhibitory neurotransmission regulates vagal efferent activity and gastric motility. Exp Biol Med (Maywood) 2017; 241:1343-50. [PMID: 27302177 DOI: 10.1177/1535370216654228] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The gastrointestinal tract receives extrinsic innervation from both the sympathetic and parasympathetic nervous systems, which regulate and modulate the function of the intrinsic (enteric) nervous system. The stomach and upper gastrointestinal tract in particular are heavily influenced by the parasympathetic nervous system, supplied by the vagus nerve, and disruption of vagal sensory or motor functions results in disorganized motility patterns, disrupted receptive relaxation and accommodation, and delayed gastric emptying, amongst others. Studies from several laboratories have shown that the activity of vagal efferent motoneurons innervating the upper GI tract is inhibited tonically by GABAergic synaptic inputs from the adjacent nucleus tractus solitarius. Disruption of this influential central GABA input impacts vagal efferent output, hence gastric functions, significantly. The purpose of this review is to describe the development, physiology, and pathophysiology of this functionally dominant inhibitory synapse and its role in regulating vagally determined gastric functions.
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Affiliation(s)
- Caitlin A McMenamin
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
| | - R Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA 17033, USA
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McMenamin CA, Anselmi L, Travagli RA, Browning KN. Developmental regulation of inhibitory synaptic currents in the dorsal motor nucleus of the vagus in the rat. J Neurophysiol 2016; 116:1705-1714. [PMID: 27440241 DOI: 10.1152/jn.00249.2016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/14/2016] [Indexed: 01/14/2023] Open
Abstract
Prior immunohistochemical studies have demonstrated that at early postnatal time points, central vagal neurons receive both glycinergic and GABAergic inhibitory inputs. Functional studies have demonstrated, however, that adult vagal efferent motoneurons receive only inhibitory GABAergic synaptic inputs, suggesting loss of glycinergic inhibitory neurotransmission during postnatal development. The purpose of the present study was to test the hypothesis that the loss of glycinergic inhibitory synapses occurs in the immediate postnatal period. Whole cell patch-clamp recordings were made from dorsal motor nucleus of the vagus (DMV) neurons from postnatal days 1-30, and the effects of the GABAA receptor antagonist bicuculline (1-10 μM) and the glycine receptor antagonist strychnine (1 μM) on miniature inhibitory postsynaptic current (mIPSC) properties were examined. While the baseline frequency of mIPSCs was not altered by maturation, perfusion with bicuculline either abolished mIPSCs altogether or decreased mIPSC frequency and decay constant in the majority of neurons at all time points. In contrast, while strychnine had no effect on mIPSC frequency, its actions to increase current decay time declined during postnatal maturation. These data suggest that in early postnatal development, DMV neurons receive both GABAergic and glycinergic synaptic inputs. Glycinergic neurotransmission appears to decline by the second postnatal week, and adult neurons receive principally GABAergic inhibitory inputs. Disruption of this developmental switch from GABA-glycine to purely GABAergic transmission in response to early life events may, therefore, lead to adverse consequences in vagal efferent control of visceral functions.
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Affiliation(s)
- Caitlin A McMenamin
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - Laura Anselmi
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - R Alberto Travagli
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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Boychuk CR, Smith BN. Glutamatergic drive facilitates synaptic inhibition of dorsal vagal motor neurons after experimentally induced diabetes in mice. J Neurophysiol 2016; 116:1498-506. [PMID: 27385796 DOI: 10.1152/jn.00325.2016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 07/01/2016] [Indexed: 12/31/2022] Open
Abstract
The role of central regulatory circuits in modulating diabetes-associated glucose dysregulation has only recently been under rigorous investigation. One brain region of interest is the dorsal motor nucleus of the vagus (DMV), which contains preganglionic parasympathetic motor neurons that regulate subdiaphragmatic visceral function. Previous research has demonstrated that glutamatergic and GABAergic neurotransmission are independently remodeled after chronic hyperglycemia/hypoinsulinemia. However, glutamatergic circuitry within the dorsal brain stem impinges on GABAergic regulation of the DMV. The present study investigated the role of glutamatergic neurotransmission in synaptic GABAergic control of DMV neurons after streptozotocin (STZ)-induced hyperglycemia/hypoinsulinemia by using electrophysiological recordings in vitro. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was elevated in DMV neurons from STZ-treated mice. The effect was abolished in the presence of the ionotropic glutamate receptor blocker kynurenic acid or the sodium channel blocker tetrodotoxin, suggesting that after STZ-induced hyperglycemia/hypoinsulinemia, increased glutamatergic receptor activity occurs at a soma-dendritic location on local GABA neurons projecting to the DMV. Although sIPSCs in DMV neurons normally demonstrated considerable amplitude variability, this variability was significantly increased after STZ-induced hyperglycemia/hypoinsulinemia. The elevated amplitude variability was not related to changes in quantal release, but rather correlated with significantly elevated frequency of sIPSCs in these mice. Taken together, these findings suggest that GABAergic regulation of central vagal circuitry responsible for the regulation of energy homeostasis undergoes complex functional reorganization after several days of hyperglycemia/hypoinsulinemia, including both glutamate-dependent and -independent forms of plasticity.
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Affiliation(s)
- Carie R Boychuk
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Bret N Smith
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
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Abstract
A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.
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He F, Ai HB. Effects of electrical stimulation at different locations in the central nucleus of amygdala on gastric motility and spike activity. Physiol Res 2016; 65:693-700. [PMID: 26988148 DOI: 10.33549/physiolres.933125] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The aim of the study was to determine the effects of electrical stimulation of different locations in the central nucleus of amygdala (CNA) on gastric motility and spike activity in dorsal vagal complex. Gastric motility index (GMI) and firing rate (FR) of dorsal vagal complex neurons were measured in adult Wistar rats respectively. Neuronal spikes in dorsal vagal complex (DVC) were recorded extracellularly with single-barrel glass microelectrodes. Each type of responses elicited by electrical stimulation in medial (CEM) and lateral (CEL) subdivisions of CNA were recorded, respectively. GMI was significantly increased after stimulation of CEM (p<0.01), and significantly decreased in response to CEL stimulation (p<0.01). After stimulation of CEM, FR in medial nucleus of the solitary tract (mNST) decreased by 31.6 % (p<0.01) and that in dorsal motor nucleus of the vagus (DMNV) increased by 27.1 % (p<0.01). On the contrary, FR in mNST increased (p<0.01) and that in DMNV decreased in response to CEL stimulation (p<0.05). In conclusions, our findings indicated that different loci of CNA may mediate differential effects on gastric activity via changes in the firing of brainstem neurons controlling gut activity.
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Affiliation(s)
- Feng He
- Key Laboratory of Animal Resistance of Shandong Province, College of Life Sciences, Shandong Normal University, Lixia District, Jinan, P. R. China.
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Presynaptic ionotropic glutamate receptors modulate GABA release in the mouse dorsal motor nucleus of the vagus. Neuroscience 2015; 308:95-105. [PMID: 26343294 DOI: 10.1016/j.neuroscience.2015.09.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/25/2015] [Accepted: 09/02/2015] [Indexed: 11/21/2022]
Abstract
Regulation of GABA release in the dorsal motor nucleus of the vagus (DMV) potently influences vagal output to the viscera. The presence of functional ionotropic glutamate receptors (iGluRs) on GABAergic terminals that rapidly alter GABA release onto DMV motor neurons has been suggested previously, but the receptor subtypes contributing to the response are unknown. We examined the effect of selective activation and inhibition of iGluRs on tetrodotoxin-insensitive, miniature inhibitory postsynaptic currents (mIPSCs) in DMV neurons using patch-clamp recordings in brainstem slices from mice. Capsaicin, which activates transient receptor potential vanilloid type 1 (TRPV1) receptors and increases mIPSC frequency in the DMV via an iGluR-mediated, heterosynaptic mechanism, was also applied to assess GABA release subsequent to capsaicin-stimulated glutamate release. Application of glutamate, N-methyl-d-aspartate (NMDA), or kainic acid (KA), but not AMPA, resulted in increased mIPSC frequency in most neurons. Inhibition of AMPA/KA receptors reduced mIPSC frequency, but selective antagonism of AMPA receptors did not alter GABA release, implicating the presence of presynaptic KA receptors on GABAergic terminals. Whereas NMDA application increased mIPSC frequency, blocking NMDA receptors was without effect, indicating that presynaptic NMDA receptors were present, but not activated by ambient glutamate levels in the slice. The effect of NMDA was prevented by AMPA/KA receptor blockade, suggesting indirect involvement of NMDA receptors. The stimulatory effect of capsaicin on GABA release was prevented when AMPA/KA or NMDA, but not AMPA receptors were blocked. Results of these studies indicate that presynaptic NMDAR and KA receptors regulate GABA release in the DMV, representing a heterosynaptic arrangement for rapidly modulating parasympathetic output, especially when synaptic excitation is elevated.
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Steinbusch L, Labouèbe G, Thorens B. Brain glucose sensing in homeostatic and hedonic regulation. Trends Endocrinol Metab 2015; 26:455-66. [PMID: 26163755 DOI: 10.1016/j.tem.2015.06.005] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 06/15/2015] [Accepted: 06/16/2015] [Indexed: 11/21/2022]
Abstract
Glucose homeostasis as well as homeostatic and hedonic control of feeding is regulated by hormonal, neuronal, and nutrient-related cues. Glucose, besides its role as a source of metabolic energy, is an important signal controlling hormone secretion and neuronal activity, hence contributing to whole-body metabolic integration in coordination with feeding control. Brain glucose sensing plays a key, but insufficiently explored, role in these metabolic and behavioral controls, which when deregulated may contribute to the development of obesity and diabetes. The recent introduction of innovative transgenic, pharmacogenetic, and optogenetic techniques allows unprecedented analysis of the complexity of central glucose sensing at the molecular, cellular, and neuronal circuit levels, which will lead to a new understanding of the pathogenesis of metabolic diseases.
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Affiliation(s)
- Laura Steinbusch
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Gwenaël Labouèbe
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
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Abstract
Spinal cord injury (SCI) results not only in motor and sensory deficits but also in autonomic dysfunctions. The disruption of connections between higher brain centers and the spinal cord, or the impaired autonomic nervous system itself, manifests a broad range of autonomic abnormalities. This includes compromised cardiovascular, respiratory, urinary, gastrointestinal, thermoregulatory, and sexual activities. These disabilities evoke potentially life-threatening symptoms that severely interfere with the daily living of those with SCI. In particular, high thoracic or cervical SCI often causes disordered hemodynamics due to deregulated sympathetic outflow. Episodic hypertension associated with autonomic dysreflexia develops as a result of massive sympathetic discharge often triggered by unpleasant visceral or sensory stimuli below the injury level. In the pelvic floor, bladder and urethral dysfunctions are classified according to upper motor neuron versus lower motor neuron injuries; this is dependent on the level of lesion. Most impairments of the lower urinary tract manifest in two interrelated complications: bladder storage and emptying. Inadequate or excessive detrusor and sphincter functions as well as detrusor-sphincter dyssynergia are examples of micturition abnormalities stemming from SCI. Gastrointestinal motility disorders in spinal cord injured-individuals are comprised of gastric dilation, delayed gastric emptying, and diminished propulsive transit along the entire gastrointestinal tract. As a critical consequence of SCI, neurogenic bowel dysfunction exhibits constipation and/or incontinence. Thus, it is essential to recognize neural mechanisms and pathophysiology underlying various complications of autonomic dysfunctions after SCI. This overview provides both vital information for better understanding these disorders and guides to pursue novel therapeutic approaches to alleviate secondary complications.
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Affiliation(s)
- Shaoping Hou
- Spinal Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
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48
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Browning KN, Travagli RA. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr Physiol 2015; 4:1339-68. [PMID: 25428846 DOI: 10.1002/cphy.c130055] [Citation(s) in RCA: 359] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Although the gastrointestinal (GI) tract possesses intrinsic neural plexuses that allow a significant degree of autonomy over GI functions, the central nervous system (CNS) provides extrinsic neural inputs that regulate, modulate, and control these functions. While the intestines are capable of functioning in the absence of extrinsic inputs, the stomach and esophagus are much more dependent upon extrinsic neural inputs, particularly from parasympathetic and sympathetic pathways. The sympathetic nervous system exerts a predominantly inhibitory effect upon GI muscle and provides a tonic inhibitory influence over mucosal secretion while, at the same time, regulates GI blood flow via neurally mediated vasoconstriction. The parasympathetic nervous system, in contrast, exerts both excitatory and inhibitory control over gastric and intestinal tone and motility. Although GI functions are controlled by the autonomic nervous system and occur, by and large, independently of conscious perception, it is clear that the higher CNS centers influence homeostatic control as well as cognitive and behavioral functions. This review will describe the basic neural circuitry of extrinsic inputs to the GI tract as well as the major CNS nuclei that innervate and modulate the activity of these pathways. The role of CNS-centered reflexes in the regulation of GI functions will be discussed as will modulation of these reflexes under both physiological and pathophysiological conditions. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide these answers.
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Affiliation(s)
- Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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Boychuk CR, Gyarmati P, Xu H, Smith BN. Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii. J Neurophysiol 2015; 114:999-1007. [PMID: 26084907 DOI: 10.1152/jn.00310.2015] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 06/15/2015] [Indexed: 12/23/2022] Open
Abstract
Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated.
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Affiliation(s)
- Carie R Boychuk
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Peter Gyarmati
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Hong Xu
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
| | - Bret N Smith
- Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky
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50
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Abstract
The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.
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Affiliation(s)
- Bernard Thorens
- Center for Integrative Genomics, University of Lausanne, Genopode Building, 1015, Lausanne, Switzerland,
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