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Coverdell TC, Abbott SBG, Campbell JN. Molecular cell types as functional units of the efferent vagus nerve. Semin Cell Dev Biol 2024; 156:210-218. [PMID: 37507330 PMCID: PMC10811285 DOI: 10.1016/j.semcdb.2023.07.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 07/20/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.
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Affiliation(s)
- Tatiana C Coverdell
- Biomedical Sciences Graduate Program, University of Virginia, Charlottesville, VA 22903, USA
| | - Stephen B G Abbott
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA
| | - John N Campbell
- Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
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2
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Verberne AJM, Mussa BM. Neural control of pancreatic peptide hormone secretion. Peptides 2022; 152:170768. [PMID: 35189258 DOI: 10.1016/j.peptides.2022.170768] [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: 01/24/2022] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 11/20/2022]
Abstract
Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.
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Affiliation(s)
- Anthony J M Verberne
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
| | - Bashair M Mussa
- Basic Medical Science Department, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
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3
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Moullé VS. Autonomic control of pancreatic beta cells: What is known on the regulation of insulin secretion and beta-cell proliferation in rodents and humans. Peptides 2022; 148:170709. [PMID: 34896576 DOI: 10.1016/j.peptides.2021.170709] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/17/2021] [Accepted: 12/07/2021] [Indexed: 11/21/2022]
Abstract
Insulin secretion and pancreatic beta-cell proliferation are tightly regulated by several signals such as hormones, nutrients, and neurotransmitters. However, the autonomic control of beta cells is not fully understood. In this review, we describe mechanisms involved in insulin secretion as well as metabolic and mitogenic actions on its target tissues. Since pancreatic islets are physically connected to the brain by nerves, parasympathetic and sympathetic neurotransmitters can directly potentiate or repress insulin secretion and beta-cell proliferation. Finally, we highlight the role of the autonomic nervous system in metabolic diseases such as diabetes and obesity.
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4
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Lkhagvasuren B, Mee-Inta O, Zhao ZW, Hiramoto T, Boldbaatar D, Kuo YM. Pancreas-Brain Crosstalk. Front Neuroanat 2021; 15:691777. [PMID: 34354571 PMCID: PMC8329585 DOI: 10.3389/fnana.2021.691777] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/30/2021] [Indexed: 12/19/2022] Open
Abstract
The neural regulation of glucose homeostasis in normal and challenged conditions involves the modulation of pancreatic islet-cell function. Compromising the pancreas innervation causes islet autoimmunity in type 1 diabetes and islet cell dysfunction in type 2 diabetes. However, despite the richly innervated nature of the pancreas, islet innervation remains ill-defined. Here, we review the neuroanatomical and humoral basis of the cross-talk between the endocrine pancreas and autonomic and sensory neurons. Identifying the neurocircuitry and neurochemistry of the neuro-insular network would provide clues to neuromodulation-based approaches for the prevention and treatment of diabetes and obesity.
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Affiliation(s)
- Battuvshin Lkhagvasuren
- Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Onanong Mee-Inta
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Zi-Wei Zhao
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Tetsuya Hiramoto
- Department of Psychosomatic Medicine, Fukuoka Hospital, National Hospital Organization, Fukuoka, Japan
| | - Damdindorj Boldbaatar
- Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Yu-Min Kuo
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan.,Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan, Taiwan
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5
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Kolben Y, Weksler-Zangen S, Ilan Y. Adropin as a potential mediator of the metabolic system-autonomic nervous system-chronobiology axis: Implementing a personalized signature-based platform for chronotherapy. Obes Rev 2021; 22:e13108. [PMID: 32720402 DOI: 10.1111/obr.13108] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/15/2020] [Accepted: 05/15/2020] [Indexed: 02/07/2023]
Abstract
Adropin is a peptide hormone, which plays a role in energy homeostasis and controls glucose and fatty acid metabolism. Its levels correlate with changes in carbohydrate-lipid metabolism, metabolic diseases, central nervous system function, endothelial function and cardiovascular disease. Both metabolic pathways and adropin are regulated by the circadian clocks. Here, we review the roles of the autonomic nervous system and circadian rhythms in regulating metabolic pathways and energy homeostasis. The beneficial effects of chronotherapy in various systems are discussed. We suggest a potential role for adropin as a mediator of the metabolic system-autonomic nervous system axis. We discuss the possibility of establishing an individualized adropin and circadian rhythm-based platform for implementing chronotherapy, and variability signatures for improving the efficacy of adropin-based therapies are discussed.
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Affiliation(s)
- Yotam Kolben
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Sarah Weksler-Zangen
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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6
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Abstract
At the time of Ivan Pavlov, pancreatic innervation was studied by looking at pancreas secretions in response to electrical stimulation of nerves. Nowadays we have ways to visualize neuronal activity in real time thanks to advances in fluorescent reporters and imaging techniques. We also have very precise optogenetic and pharmacogenetic approaches that allow neuronal manipulations in a very specific manner. These technological advances have been extensively employed for studying the central nervous system and are just beginning to be incorporated for studying visceral innervation. Pancreatic innervation is complex, and the role it plays in physiology and pathophysiology of the organ is still not fully understood. In this review we highlight anatomical aspects of pancreatic innervation, techniques for pancreatic neuronal labeling, and approaches for imaging pancreatic innervation in vitro and in vivo.
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7
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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: 29] [Impact Index Per Article: 4.8] [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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Jin S, Diano S. Mitochondrial Dynamics and Hypothalamic Regulation of Metabolism. Endocrinology 2018; 159:3596-3604. [PMID: 30203064 PMCID: PMC6157417 DOI: 10.1210/en.2018-00667] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 09/02/2018] [Indexed: 01/22/2023]
Abstract
Mitochondria are cellular organelles that play an important role in bioenergetic processes. In the central nervous system, high energy-demanding neurons are critically dependent on mitochondria to fulfill their appropriate functions. The hypothalamus is a key brain area for maintaining glucose and energy homeostasis via the ability of hypothalamic neurons to sense, integrate, and respond to numerous metabolic signals. Mitochondrial function has emerged as an important component in the regulation of hypothalamic neurons controlling glucose and energy homeostasis. Although the underlying mechanisms are not fully understood, emerging evidence indicates that mitochondrial dysfunction in hypothalamic neurons may contribute to the development of various metabolic diseases, including obesity and type 2 diabetes mellitus (T2DM). In this review, we summarize recent studies demonstrating the link between mitochondria and hypothalamic neural control of glucose and energy homeostasis. Finally, this review provides an insight to understand how mitochondria in hypothalamic neurons may contribute to the development of metabolic disorders, such as T2DM and obesity.
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Affiliation(s)
- Sungho Jin
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
| | - Sabrina Diano
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
- Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut
- Department of Clinical Medicine and Surgery, University of Naples “Federico II,” Naples, Italy
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9
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Hogue IB, Card JP, Rinaman L, Staniszewska Goraczniak H, Enquist LW. Characterization of the neuroinvasive profile of a pseudorabies virus recombinant expressing the mTurquoise2 reporter in single and multiple injection experiments. J Neurosci Methods 2018; 308:228-239. [PMID: 30098326 PMCID: PMC6294127 DOI: 10.1016/j.jneumeth.2018.08.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/29/2018] [Accepted: 08/02/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Viral transneuronal tracing has become a well established technology used to define the synaptic architecture of polysynaptic neural networks. NEW METHOD In this report we define the neuroinvasive profile and reporter expression of a new recombinant of the Bartha strain of pseudorabies virus (PRV). The new recombinant, PRV-290, expresses the mTurquoise2 fluorophor and is designed to complement other isogenic recombinants of Bartha that express different reporters of infection. Results & Comparison with Existing Methods: PRV-290 was injected either alone or in combination with isogenic recombinants of PRV that express enhanced green fluorescent protein (EGFP; PRV-152) or monomeric red fluorescent protein (mRFP; PRV-614). Circuits previously defined using PRV-152 and PRV-614 were used for the analysis. The data demonstrate that PRV-290 is a retrograde transneuronal tracer with temporal kinetics similar to those of its isogenic recombinants. Stable expression of the diffusible mTurquoise2 reporter filled infected neurons, with the extent and intensity of labeling increasing with advancing post inoculation survival. In multiple injection experiments, PRV-290 established productive infections in neurons also replicating PRV-152 and/or PRV-614. This novel demonstration of three recombinants infecting individual neurons represents an important advance in the technology. CONCLUSION Collectively, these data demonstrate that PRV-290 is a valuable addition to the viral tracer toolbox for transneuronal tracing of neural circuitry.
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Affiliation(s)
- Ian B Hogue
- Department of Molecular Biology, Neuroscience Institute, Princeton University, Princeton, NJ, 08544, United States.
| | - J Patrick Card
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, United States; Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, FL, 32306, United States.
| | - Linda Rinaman
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, FL, 32306, United States
| | | | - Lynn W Enquist
- Department of Molecular Biology, Neuroscience Institute, Princeton University, Princeton, NJ, 08544, United States
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Carnagarin R, Matthews VB, Herat LY, Ho JK, Schlaich MP. Autonomic Regulation of Glucose Homeostasis: a Specific Role for Sympathetic Nervous System Activation. Curr Diab Rep 2018; 18:107. [PMID: 30232652 DOI: 10.1007/s11892-018-1069-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Cardiometabolic disorders such as obesity, metabolic syndrome and diabetes are increasingly common and associated with adverse cardiovascular outcomes. The mechanisms driving these developments are incompletely understood but likely to include autonomic dysregulation. The latest evidence for such a role is briefly reviewed here. RECENT FINDINGS Recent findings highlight the relevance of autonomic regulation in glucose metabolism and identify sympathetic activation, in concert with parasympathetic withdrawal, as a major contributor to the development of metabolic disorders and an important mediator of the associated adverse cardiovascular consequences. Methods targeting sympathetic overactivity using pharmacological and device-based approaches are available and appear as logical additional approaches to curb the burden of metabolic disorders and alleviate the associated morbidity from cardiovascular causes. While the available data are encouraging, the role of therapeutic inhibition of sympathetic overdrive in the prevention of the metabolic disorders and the associated adverse outcomes requires adequate testing in properly sized randomised controlled trials.
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Affiliation(s)
- Revathy Carnagarin
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia
| | - Vance B Matthews
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia
| | - Lakshini Y Herat
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia
| | - Jan K Ho
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia
| | - Markus P Schlaich
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.
- Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, Australia.
- Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
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11
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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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12
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Seoane-Collazo P, Fernø J, Gonzalez F, Diéguez C, Leis R, Nogueiras R, López M. Hypothalamic-autonomic control of energy homeostasis. Endocrine 2015; 50:276-91. [PMID: 26089260 DOI: 10.1007/s12020-015-0658-y] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 06/06/2015] [Indexed: 10/23/2022]
Abstract
Regulation of energy homeostasis is tightly controlled by the central nervous system (CNS). Several key areas such as the hypothalamus and brainstem receive and integrate signals conveying energy status from the periphery, such as leptin, thyroid hormones, and insulin, ultimately leading to modulation of food intake, energy expenditure (EE), and peripheral metabolism. The autonomic nervous system (ANS) plays a key role in the response to such signals, innervating peripheral metabolic tissues, including brown and white adipose tissue (BAT and WAT), liver, pancreas, and skeletal muscle. The ANS consists of two parts, the sympathetic and parasympathetic nervous systems (SNS and PSNS). The SNS regulates BAT thermogenesis and EE, controlled by central areas such as the preoptic area (POA) and the ventromedial, dorsomedial, and arcuate hypothalamic nuclei (VMH, DMH, and ARC). The SNS also regulates lipid metabolism in WAT, controlled by the lateral hypothalamic area (LHA), VMH, and ARC. Control of hepatic glucose production and pancreatic insulin secretion also involves the LHA, VMH, and ARC as well as the dorsal vagal complex (DVC), via splanchnic sympathetic and the vagal parasympathetic nerves. Muscle glucose uptake is also controlled by the SNS via hypothalamic nuclei such as the VMH. There is recent evidence of novel pathways connecting the CNS and ANS. These include the hypothalamic AMP-activated protein kinase-SNS-BAT axis which has been demonstrated to be a key modulator of thermogenesis. In this review, we summarize current knowledge of the role of the ANS in the modulation of energy balance.
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Affiliation(s)
- Patricia Seoane-Collazo
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain.
| | - Johan Fernø
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain
- Department of Clinical Science, K. G. Jebsen Center for Diabetes Research, University of Bergen, 5021, Bergen, Norway
| | - Francisco Gonzalez
- Department of Surgery, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain
- Service of Ophthalmology, Complejo Hospitalario Universitario de Santiago de Compostela, 15706, Santiago de Compostela, Spain
| | - Carlos Diéguez
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain
| | - Rosaura Leis
- Unit of Investigation in Nutrition, Growth and Human Development of Galicia, Pediatric Department (USC), Complexo Hospitalario Universitario de Santiago (IDIS/SERGAS), Santiago de Compostela, Spain
| | - Rubén Nogueiras
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain
| | - Miguel López
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Santiago de Compostela, Spain.
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13
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Bouret S, Levin BE, Ozanne SE. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiol Rev 2015; 95:47-82. [PMID: 25540138 PMCID: PMC4281588 DOI: 10.1152/physrev.00007.2014] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease.
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Affiliation(s)
- Sebastien Bouret
- The Saban Research Institute, Neuroscience Program, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, California; Inserm U837, Jean-Pierre Aubert Research Center, University Lille 2, Lille, France; Neurology Service, Veterans Administration Medical Center, East Orange, New Jersey; Department of Neurology and Neurosciences, Rutgers, New Jersey Medical School, Newark, New Jersey; and University of Cambridge Institute of Metabolic Science and MRC Metabolic Diseases Unit, Cambridge, United Kingdom
| | - Barry E Levin
- The Saban Research Institute, Neuroscience Program, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, California; Inserm U837, Jean-Pierre Aubert Research Center, University Lille 2, Lille, France; Neurology Service, Veterans Administration Medical Center, East Orange, New Jersey; Department of Neurology and Neurosciences, Rutgers, New Jersey Medical School, Newark, New Jersey; and University of Cambridge Institute of Metabolic Science and MRC Metabolic Diseases Unit, Cambridge, United Kingdom
| | - Susan E Ozanne
- The Saban Research Institute, Neuroscience Program, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, California; Inserm U837, Jean-Pierre Aubert Research Center, University Lille 2, Lille, France; Neurology Service, Veterans Administration Medical Center, East Orange, New Jersey; Department of Neurology and Neurosciences, Rutgers, New Jersey Medical School, Newark, New Jersey; and University of Cambridge Institute of Metabolic Science and MRC Metabolic Diseases Unit, Cambridge, United Kingdom
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14
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Abstract
The autonomic nervous system affects glucose metabolism partly through its connection to the pancreatic islet. Since its discovery by Paul Langerhans, the precise innervation patterns of the islet has remained elusive, mainly because of technical limitations. Using 3-dimensional reconstructions of axonal terminal fields, recent studies have determined the innervation patterns of mouse and human islets. In contrast to the mouse islet, endocrine cells within the human islet are sparsely contacted by autonomic axons. Instead, the invading sympathetic axons preferentially innervate smooth muscle cells of blood vessels. This innervation pattern suggests that, rather than acting directly on endocrine cells, sympathetic nerves may control hormone secretion by modulating blood flow in human islets. In addition to autonomic efferent axons, islets also receive sensory innervation. These axons transmit sensory information to the brain but also have the ability to locally release neuroactive substances that have been suggested to promote diabetes pathogenesis. We discuss recent findings on islet innervation, the connections of the islet with the brain, and the role islet innervation plays during the progression of diabetes.
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Affiliation(s)
- Rayner Rodriguez-Diaz
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Rolf Luft Research Center for Diabetes & Endocrinology, Karolinska Institutet, Stockholm, SE-17177, Sweden; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Alejandro Caicedo
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
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15
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Tsumori T, Oka T, Yokota S, Niu JG, Yasui Y. Intrapancreatic ganglia neurons receive projection fibers from melanocortin-4 receptor-expressing neurons in the dorsal motor nucleus of the vagus nerve of the mouse. Brain Res 2013; 1537:132-42. [PMID: 24028856 DOI: 10.1016/j.brainres.2013.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 08/26/2013] [Accepted: 09/04/2013] [Indexed: 11/19/2022]
Abstract
Melanocortin-4 receptor (MC4R)-expressing neurons are widely distributed in the central nervous system and play a crucial role in a variety of physiological functions including energy and glucose/insulin homeostasis. However, their neural pathways remain to be elucidated. In the present study, we examined a possible pathway from MC4R-expressing neurons in the dorsal motor nucleus of the vagus nerve (DMV) to the intrapancreatic ganglia using transgenic mice that express green fluorescent protein (GFP) under the control of the MC4R-promoter. Using immunofluorescence labeling, we demonstrated that GFP-immunoreactive (ir) nerve fibers were distributed in the intrapancreatic ganglia closely associated with the islets as well as among the acini. These GFP-ir fibers with bouton-like varicosities were frequently observed to surround ganglion cells immunoreactive for vasoactive intestinal polypeptide, a marker for postganglionic parasympathetic neurons. Using the pre-embedding immunoperoxidase method, we clearly showed that GFP-ir terminals formed synapses predominantly with dendrites and additionally with somata of the ganglion cells. Moreover, bilateral subdiaphragmatic vagotomy caused a marked loss of GFP immunoreactivity in the pancreas. Using a combination of retrograde tracing and immunohistochemistry, we finally demonstrated that nearly half of the pancreas-projecting DMV neurons were immunoreactive for GFP. These results suggest that MC4R-expressing DMV neurons may participate in the regulation of glucose/insulin homeostasis through their projections to the intrapancreatic ganglia.
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Affiliation(s)
- Toshiko Tsumori
- Department of Anatomy and Morphological Neuroscience, Shimane University School of Medicine, Izumo 693-8501, Japan
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Babic T, Browning KN, Kawaguchi Y, Tang X, Travagli RA. Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat. J Physiol 2012; 590:3611-22. [PMID: 22711959 DOI: 10.1113/jphysiol.2012.234955] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Brainstem vago-vagal neurocircuits modulate upper gastrointestinal functions. Derangement of these sensory-motor circuits is implicated in several pathophysiological states, such as gastroesophageal reflux disease (GERD), functional dyspepsia and, possibly, pancreatitis. While vagal circuits controlling the stomach have received more attention, the organization of brainstem pancreatic neurocircuits is still largely unknown. We aimed to investigate the in vitro and in vivo modulation of brainstem vagal circuits controlling pancreatic secretion. Using patch clamp techniques on identified vagal pancreas-projecting neurones, we studied the effects of metabotropic glutamate receptor (mGluR) agents in relation to the effects of exendin-4, a glucagon-like peptide 1 analogue, cholecystokinin (CCK) and pancreatic polypeptide (PP). An in vivo anaesthetized rat preparation was used to measure pancreatic exocrine secretion (PES) and plasma insulin following microinjection of metabotropic glutamate receptor (mGluR) agonists and exendin-4 in the brainstem. Group II and III mGluR agonists (2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4), respectively) decreased the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively) in the majority of the neurones tested. All neurones responsive to L-AP4 were also responsive to APDC, but not vice versa. Further, in neurones where L-AP4 decreased mIPSC frequency, exendin-4 increased, while PP had no effect upon, mIPSC frequency. Brainstem microinjection of APDC or L-AP4 decreased plasma insulin secretion, whereas only APDC microinjections increased PES. Exendin-4 microinjections increased plasma insulin. Our results indicate a discrete organization of vagal circuits, which opens up promising avenues of research aimed at investigating the physiology of homeostatic autonomic neurocircuits.
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Affiliation(s)
- Tanja Babic
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, 500 University Drive, MC H109, Hershey, PA 17033, USA
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Mussa BM, Verberne AJM. The dorsal motor nucleus of the vagus and regulation of pancreatic secretory function. Exp Physiol 2012; 98:25-37. [PMID: 22660814 DOI: 10.1113/expphysiol.2012.066472] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Recent investigation of the factors and pathways that are involved in regulation of pancreatic secretory function (PSF) has led to development of a pancreatic vagovagal reflex model. This model consists of three elements, including pancreatic vagal afferents, the dorsal motor nucleus of the vagus (DMV) and pancreatic vagal efferents. The DMV has been recognized as a major component of this model and so this review focuses on the role of this nucleus in regulation of PSF. Classically, the control of the PSF has been viewed as being dependent on gastrointestinal hormones and vagovagal reflex pathways. However, recent studies have suggested that these two mechanisms act synergistically to mediate pancreatic secretion. The DMV is the major source of vagal motor output to the pancreas, and this output is modulated by various neurotransmitters and synaptic inputs from other central autonomic regulatory circuits, including the nucleus of the solitary tract. Endogenously occurring excitatory (glutamate) and inhibitory amino acids (GABA) have a marked influence on DMV vagal output to the pancreas. In addition, a variety of neurotransmitters and receptors for gastrointestinal peptides and hormones have been localized in the DMV, emphasizing the direct and indirect involvement of this nucleus in control of PSF.
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Affiliation(s)
- Bashair M Mussa
- University of Melbourne, Department of Medicine, Clinical Pharmacology & Therapeutics Unit, Austin Health, Heidelberg, Victoria 3084 Australia
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18
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Mussa BM, Sartor DM, Rantzau C, Verberne AJM. Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion. Brain Res 2011; 1394:62-70. [PMID: 21530944 DOI: 10.1016/j.brainres.2011.04.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 03/23/2011] [Accepted: 04/09/2011] [Indexed: 01/13/2023]
Abstract
We and others have previously shown that the dorsal motor nucleus of the vagus (DMV) is involved in regulation of pancreatic exocrine secretion. Many pancreatic preganglionic neurons within the DMV are inhibited by pancreatic secretagogues suggesting that an inhibitory pathway may participate in the control of pancreatic exocrine secretion. Accordingly, the present study examined whether chemical stimulation of the DMV activates the endocrine pancreas and whether an inhibitory pathway is involved in this response. All experiments were conducted in overnight fasted isoflurane/urethane-anesthetized Sprague Dawley rats. Activation of the DMV by bilateral microinjection of bicuculline methiodide (BIM, GABA(A) receptor antagonist, 100 pmol/25 nl; 4 mM) resulted in a significant and rapid increase in glucose-induced insulin secretion (9.2±0.1 ng/ml peak response) compared to control microinjection (4.0±0.6 ng/ml). Activation of glucose-induced insulin secretion by chemical stimulation of the DMV was inhibited (2.1±1.1 ng/ml and 1.6±0.1 ng/ml 5 min later) in the presence of the muscarinic receptor antagonist atropine methonitrate (100 μg/kg/min, i.v.). On the other hand, the nitric oxide (NO) synthesis inhibitor l-nitroarginine methyl ester (30 mg/kg, i.v.) significantly increased the excitatory effect of DMV stimulation on glucose-induced insulin secretion to 15.3±3.0 ng/ml and 16.1±3.1 ng/ml 5 min later. These findings suggest that NO may play an inhibitory role in the central regulation of insulin secretion.
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Affiliation(s)
- Bashair M Mussa
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia
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19
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Mussa BM, Sartor DM, Verberne AJM. Dorsal vagal preganglionic neurons: differential responses to CCK1 and 5-HT3 receptor stimulation. Auton Neurosci 2010; 156:36-43. [PMID: 20346737 DOI: 10.1016/j.autneu.2010.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Revised: 02/11/2010] [Accepted: 03/01/2010] [Indexed: 12/11/2022]
Abstract
The dorsal motor nucleus of the vagus (DMV) is the main source of the vagal innervation of the pancreas. Several studies in vitro have demonstrated that the DMV consists of a heterogeneous population of preganglionic neurons but little is known about their electrophysiological characteristics in vivo. The aims of this study were to (i) identify DMV preganglionic neurons in vivo with axons in the pancreatic vagus and (ii) characterize their responses to stimulation of cholecystokinin (CCK(1)) and serotonin (5-HT(3)) receptors which are major regulators of pancreatic secretion. Male Sprague Dawley rats anaesthetised with isoflurane (1.5%/100% O(2)) were used throughout. Dorsal vagal preganglionic neurons were identified by antidromic activation in response to stimulation of the pancreatic vagus. Dorsal vagal preganglionic neurons had axonal conduction velocities in the C-fibre range (0.7+/-0.03 m/s). Forty-four neurons were identified within the rostral, intermediate and caudal DMV and thirty-eight were tested for responsiveness to CCK-8S (CCK(1) agonist) and phenylbiguanide (PBG; 5-HT(3) receptor agonist). CCK-8S and PBG (0.1-10 microg/kg, i.v.) produced three types of response: (i) preganglionic neurons in the intermediate DMV were inhibited by CCK-8S (n=18) and PBG (n=10), (ii) neurons in the caudal DMV were activated by CCK (n=5) and PBG (n=2) and (iii) CCK-8S (n=9) and PBG (n=7) had no effect on preganglionic neurons in the rostral DMV. CCK-8S and PBG have complex actions on preganglionic neurons in the DMV that may be related to their effects on pancreatic secretion.
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Affiliation(s)
- Bashair M Mussa
- University of Melbourne, Department of Medicine, Clinical Pharmacology and Therapeutics Unit, Austin Health, Heidelberg 3084, Victoria, Australia
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20
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Schloithe AC, Sutherland K, Woods CM, Blackshaw LA, Davison JS, Toouli J, Saccone GTP. A novel preparation to study rat pancreatic spinal and vagal mechanosensitive afferents in vitro. Neurogastroenterol Motil 2008; 20:1060-9. [PMID: 18482253 DOI: 10.1111/j.1365-2982.2008.01141.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The management of pancreatic pain is a significant clinical problem so understanding of how sensory signals are generated in pancreatic tissue is fundamental. We aimed to characterize mechanosensitive and chemosensitive properties of pancreatic spinal and vagal afferents in vitro. Spinal and vagal afferent preparations from Sprague-Dawley rats were established incorporating the left splanchnic nerve or vagus nerves respectively. The common bile duct was cannulated for distension of the pancreatic duct with fluid. Nerve discharge evoked by blunt probing, duct distension or electrical stimulation was obtained from teased nerve bundles using standard extra-cellular recording. Discharge from 197 spinal afferent bundles was recorded, of which 57% displayed spontaneous activity. Blunt probing revealed 61 mechanosensitive receptive fields which were associated primarily with arteries/blood vessels (33/61) and the parenchyma (22/61). All mechanosensitive responses were slowly adapting, with 33% continuing to discharge after termination of the stimulus and 60% displaying a response threshold <10 g. Application of chemical mediators (bradykinin, histamine, 5-hydroxytryptamine, cholecystokinin octapeptide) evoked a response from 31/57 units, with 33% excitatory and 23% inhibitory. Spontaneous discharge was recorded from 72% of 135 vagal bundles. Mechanosensitive receptive fields were not identified in the pancreas but were evident in adjacent organs. No spinal or vagal afferent response to duct distension was obtained. In conclusion, pancreatic mechanosensitive spinal afferents are common, in contrast to pancreatic mechanosensitive vagal afferents indicating that pancreatic sensory innervation is predominantly spinal. Chemosensitive spinal afferent nerve endings are present in the pancreas and respond to a variety of inflammatory and physiological mediators.
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Affiliation(s)
- A C Schloithe
- Department of General and Digestive Surgery, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia
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21
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Young RL, Cooper NJ, Blackshaw LA. Chemical coding and central projections of gastric vagal afferent neurons. Neurogastroenterol Motil 2008; 20:708-18. [PMID: 18266614 DOI: 10.1111/j.1365-2982.2007.01071.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Vagal afferents that innervate gastric muscle or mucosa transmit distinct sensory information from their endings to the nucleus of the tractus solitarius (NTS). While these afferent subtypes are functionally distinct, no neurochemical correlate has been described and it is unknown whether they terminate in different central locations. This study aimed to identify gastric vagal afferent subtypes in the nodose ganglion (NG) of ferrets, their terminal areas in NTS and neurochemistry for isolectin-B4 (IB4) and calcitonin gene-related peptide (CGRP). Vagal afferents were traced from gastric muscle or mucosa and IB4 and CGRP labelling assessed in NG and NTS. 7 +/- 1% and 6 +/- 1% of NG neurons were traced from gastric muscle or mucosa respectively; these were more likely to label for CGRP or for both CGRP and IB4 than other NG neurons (P < 0.01). Muscular afferents were also less likely than others to label with IB4 (P < 0.001). Less than 1% of NG neurons were traced from both muscle and mucosa. Central terminals of both afferent subtypes occurred in the subnucleus gelatinosus of the NTS, but did not overlap completely. This region also labelled for CGRP and IB4. We conclude that while vagal afferents from gastric muscle and mucosa differ little in their chemical coding for CGRP and IB4, they can be traced selectively from their peripheral endings to NG and to overlapping and distinct regions of NTS. Thus, there is an anatomical substrate for convergent NTS integration for both types of afferent input.
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Affiliation(s)
- R L Young
- Nerve-Gut Research Laboratory, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia.
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22
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Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, Yu J, Yang Z, Christiansen LM, Lee CE, Choi CS, Zigman JM, Shulman GI, Sherwin RS, Elmquist JK, Lowell BB. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 2007; 5:383-93. [PMID: 17488640 PMCID: PMC1934926 DOI: 10.1016/j.cmet.2007.04.001] [Citation(s) in RCA: 316] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2007] [Revised: 03/26/2007] [Accepted: 04/11/2007] [Indexed: 10/23/2022]
Abstract
The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia.
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Affiliation(s)
- Qingchun Tong
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - ChianPing Ye
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Rory J. McCrimmon
- Department of Internal Medicine & Endocrinology, Yale University School of Medicine, New Haven, CT, 06520
| | - Harveen Dhillon
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Brian Choi
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Melissa D. Kramer
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Jia Yu
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Zongfang Yang
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Lauryn M. Christiansen
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
| | - Charlotte E. Lee
- Center for Hypothalamic Research, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077
| | - Cheol Soo Choi
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077
| | - Gerald I. Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520
- Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06520
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520
| | - Robert S. Sherwin
- Department of Internal Medicine & Endocrinology, Yale University School of Medicine, New Haven, CT, 06520
| | - Joel K. Elmquist
- Center for Hypothalamic Research, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077
| | - Bradford B. Lowell
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Ave., Boston, MA, 02215
- * To whom correspondence should be addressed (e-mail: ) Ph: 617-667-5954; Fax: 617-667-2927
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23
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Liao Z, Li ZS, Lu Y, Wang WZ. Microinjection of exogenous somatostatin in the dorsal vagal complex inhibits pancreatic secretion via somatostatin receptor-2 in rats. Am J Physiol Gastrointest Liver Physiol 2007; 292:G746-52. [PMID: 17138968 DOI: 10.1152/ajpgi.00174.2006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Previous studies have suggested that somatostatin inhibits pancreatic secretion at a central vagal site, and the dorsal vagal complex (DVC) is involved in central feedback inhibition of the exocrine pancreas. The aim of this study was to investigate the effect of exogenous somatostatin in the DVC on pancreatic secretion and the somatostatin receptor subtype(s) responsible for the effect. The effects of somatostatin microinjected into the DVC on pancreatic secretion stimulated by cholecystokinin octapeptide (CCK-8) or 2-deoxy-d-glucose (2-DG) were examined in anesthetized rats. To investigate the somatostatin inhibitory action site, a somatostatin receptor antagonist [SRA; cyclo(7-aminoheptanoyl-Phe-d-Trp-Lys-Thr)] was microinjected into the DVC before intravenous infusion of somatostatin and CCK-8/2-DG. The effects of injection of a somatostatin receptor-2 agonist (seglitide) and combined injection of somatostatin and a somatostatin receptor-2 antagonist (CYN 154806) in the DVC on the pancreatic secretion were also investigated. Somatostatin injected into the DVC significantly inhibited pancreatic secretion evoked by CCK-8 or 2-DG in a dose-dependent manner. SRA injected into the DVC completely reversed the inhibitory effect of intravenous administration of somatostatin. Seglitide injected into the DVC also inhibited CCK-8/2-DG-induced pancreatic protein secretion. However, combined injection of somatostatin and CYN 154806 did not affect the CCK-8/2-DG-induced pancreatic secretion. Somatostatin in the DVC inhibits pancreatic secretion via somatostatin receptor-2, and the DVC is the action site of somatostatin for its inhibitory effect.
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Affiliation(s)
- Zhuan Liao
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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24
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Love JA, Yi E, Smith TG. Autonomic pathways regulating pancreatic exocrine secretion. Auton Neurosci 2006; 133:19-34. [PMID: 17113358 DOI: 10.1016/j.autneu.2006.10.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2006] [Revised: 09/14/2006] [Accepted: 10/03/2006] [Indexed: 11/24/2022]
Abstract
The parasympathetic (PNS) and sympathetic (SNS) and nervous systems densely innervate the exocrine pancreas. Efferent PNS pathways, consisting of central dorsal motor nucleus of the vagus (DMV) and peripheral pancreatic neurons, stimulate exocrine secretion. The DMV integrates cortical (olfactory, gustatory) and gastric, and intestinal vagal afferent input to determine central PNS outflow during cephalic, gastric and intestinal phases of exocrine secretion. Pancreatic neurons integrate DMV input with peripheral enteric, sympathetic, and, possibly, afferent axon reflexes to determine final PNS input to all exocrine effectors. Gut and islet hormones appear to modulate both central and peripheral PNS pathways. Preganglionic sympathetic neurons in the intermediolateral (IML) column of the spinal cord receive inputs from brain centers, some shared with the PNS, and innervate postganglionic neurons, mainly in prevertebral ganglia. Sympathetic innervation of the exocrine pancreas is primarily indirect, and inhibits secretion by decreasing blood flow and inhibiting transmission in pancreatic ganglia. Interactions between SNS and PNS pathways appear to occur in brain, spinal cord, pancreatic and prevertebral ganglia, and at neuroeffector synapses. Thus, the PNS and SNS pathways regulating the exocrine pancreas are directly or indirectly antagonistic at multiple sites: the state of exocrine secretion reflects the balance of these influences. Despite over a century of study, much remains to be understood about the connections of specific neurons forming pancreatic pathways, their processes of neurotransmission, and how disruption of these pathways contributes to pancreatic disease.
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Affiliation(s)
- Jeffrey A Love
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
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Verberne AJM, McInerney K. Pancreatic vasoconstrictor responses are regulated by neurons in the rostral ventrolateral medulla. Brain Res 2006; 1102:127-34. [PMID: 16781679 DOI: 10.1016/j.brainres.2006.05.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Revised: 04/27/2006] [Accepted: 05/10/2006] [Indexed: 10/24/2022]
Abstract
The pancreas receives sympathetic input which arises from several premotor cell groups in the CNS including the rostral ventrolateral medulla (RVLM). In this study, we examined the influence of electrical stimulation of the RVLM on pancreatic blood flow measured by laser Doppler flowmetry and gastric blood flow measured by ultrasonic Doppler flowmetry in halothane-anesthetized rats. The laser Doppler flow measurement technique was validated by demonstration that pancreatic conductance was reduced by systemic administration of the vasoconstrictor phenylephrine and increased by the vasodilator sodium nitroprusside. Sympathetic vasomotor withdrawal induced by either administration of phenylbiguanide (2 and 10 microg/kg, i.v.) or electrical stimulation of the central end of the cervical vagal trunk (5 Hz, 2 ms, 50-150 microA) produced depressor responses and increases in pancreatic and gastric vascular conductance. Electrical stimulation of the RVLM (50 Hz, 0.5 ms, 25-75 microA) produced pressor and tachycardic responses accompanied by decreases in pancreatic and gastric vascular conductance. All responses to RVLM stimulation were abolished by blockade of ganglionic neurotransmission (hexamethonium bromide, 20 mg/kg, i.v.). These data suggest that RVLM presympathetic vasomotor neurons are a primary source of tonic sympathetic vasomotor drive to the pancreatic and gastric vasculature.
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Affiliation(s)
- Anthony J M Verberne
- Department of Medicine, University of Melbourne, Clinical Pharmacology and Therapeutics Unit, Austin Health, Heidelberg Victoria, Australia.
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26
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Browning KN, Coleman FH, Travagli RA. Effects of pancreatic polypeptide on pancreas-projecting rat dorsal motor nucleus of the vagus neurons. Am J Physiol Gastrointest Liver Physiol 2005; 289:G209-19. [PMID: 15817809 DOI: 10.1152/ajpgi.00560.2004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We investigated the pre- and postsynaptic effects of pancreatic polypeptide (PP) on identified pancreas-projecting neurons of the rat dorsal motor nucleus of the vagus in thin brain stem slices. Perfusion with PP induced a TTX- and apamin-sensitive, concentration-dependent outward (22% of neurons) or inward current (21% of neurons) that was accompanied by a decrease in input resistance; PP was also found to affect the amplitude of the action potential afterhyperpolarization. The remaining 57% of neurons were unaffected. PP induced a concentration-dependent inhibition in amplitude of excitatory (n = 22 of 30 neurons) and inhibitory (n = 13 of 17 neurons) postsynaptic currents evoked by electrical stimulation of the adjacent nucleus of the solitary tract, with an estimated EC(50) of 30 nM for both. The inhibition was accompanied by an alteration in the paired pulse ratio, suggesting a presynaptic site of action. PP also decreased the frequency, but not amplitude, of spontaneous excitatory (n = 6 of 11 neurons) and inhibitory currents (n = 7 of 9 neurons). In five neurons, chemical stimulation of the area postrema (AP) induced a TTX-sensitive inward (n = 3) or biphasic (outward and inward) current (n = 2). Superfusion with PP reversibly reduced the amplitude of these chemically stimulated currents. Regardless of the PP-induced effect, the vast majority of responsive neurons had a multipolar somata morphology with dendrites projecting to areas other than the fourth ventricle or the central canal. These results suggest that pancreas-projecting rat dorsal motor nucleus of the vagus neurons are heterogeneous with respect to their response to PP, which may underlie functional differences in the vagal modulation of pancreatic functions.
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Affiliation(s)
- Kirsteen N Browning
- Dept. of Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
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27
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Browning KN, Coleman FH, Travagli RA. Characterization of pancreas-projecting rat dorsal motor nucleus of vagus neurons. Am J Physiol Gastrointest Liver Physiol 2005; 288:G950-5. [PMID: 15637183 DOI: 10.1152/ajpgi.00549.2004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The electrophysiological and morphological properties of rat dorsal motor nucleus of the vagus (DMV) neurons innervating the pancreas were examined by using whole cell patch clamp recordings from brain stem slices and postfixation morphological reconstructions of Neurobiotin-filled neurons. Recordings were made from 178 DMV neurons whose projections had been identified by previous apposition of the fluorescent neuronal tracer DiI to the body of the pancreas. DMV neurons projecting to the pancreas had an input resistance of 434 +/- 14 M omega, an action potential duration of 3 +/- 0.1 ms, and an afterhyperpolarization of 18 +/- 0.4 mV amplitude and 108 +/- 7 ms time constant of decay; these electrophysiological properties resembled those of gastric-projecting neurons but were significantly different from those of intestinal-projecting neurons. Interestingly, 14 of 178 pancreas-projecting neurons showed the presence of a slowly developing afterhyperpolarization whose presence was not reported in DMV neurons projecting to any other gastrointestinal area. The morphological characteristics of pancreas-projecting neurons (soma area 274 +/- 12 microm2; soma diameter of 25 +/- 0.7 microm; soma form factor 0.74 +/- 0.01; segments 9.7 +/- 0.41), however, were similar to those of intestinal- but differed from those of gastric-projecting neurons. In summary, these results suggest that pancreas-projecting rat DMV neurons are heterogeneous with respect to some electrophysiological and morphological properties. These differences might underlie functional differences in the vagal modulation of pancreatic functions.
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Affiliation(s)
- Kirsteen N Browning
- Department of Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA
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28
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Borsody MK, Weiss JM. The subdiaphragmatic vagus nerves mediate activation of locus coeruleus neurons by peripherally administered microbial substances. Neuroscience 2005; 131:235-45. [PMID: 15680706 DOI: 10.1016/j.neuroscience.2004.09.061] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2004] [Indexed: 11/27/2022]
Abstract
Our earlier studies demonstrated that representative microbial substances--lipopolysaccharide, peptidoglycan, and poly-inosine: poly-cytosine (poly(I):(C))--increased the spontaneous discharge rates and sensory-evoked responses of isolated locus coeruleus (LC) neurons in a dose- and time-related manner after i.p. injection into rats. We then turned our attention to the mechanism by which microbial substances administered into the peritoneal cavity affect the LC neurons. The involvement of the subdiaphragmatic vagus nerves was examined in this regard since several brain responses to peripherally administered lipopolysaccharide have been found to depend upon the integrity of these nerves. The experiments reported here show that lipopolysaccharide, peptidoglycan, and poly(I):(C) all failed to excite LC neurons after i.p. injection into rats that had previously been subjected to complete transection of the subdiaphragmatic vagus nerves. Furthermore, selective transection of the subdiaphragmatic vagus nerve trunks indicated that the dorsal trunk, and not the ventral trunk, was necessary to excite LC neurons in response to i.p. lipopolysaccharide. The inability of LC neurons to respond to i.p. lipopolysaccharide in vagotomized rats is unlikely to be attributed to a desensitization of the neurons to lipopolysaccharide since i.c.v. injection of lipopolysaccharide excited LC neurons in vagotomized rats as it did in vagus-intact rats. These findings suggest that a variety of microbial substances excited LC neurons after administration into the peritoneal cavity in a manner involving the subdiaphragmatic vagus nerves.
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Affiliation(s)
- M K Borsody
- Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Emory West Campus, 1256 Briarcliff Road Northeast, Atlanta, GA 30306, USA.
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Zhang X, Jiang C, Tan Z, Fogel R. Vagal motor neurons in rats respond to noxious and physiological gastrointestinal distention differentially. Eur J Neurosci 2002; 16:2027-38. [PMID: 12473070 DOI: 10.1046/j.1460-9568.2002.02281.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Low-pressure gastrointestinal distention modulates gastrointestinal function by a vago-vagal reflex. Noxious visceral distention, as seen in an obstruction of the gastrointestinal tract, causes abdominal pain, vomiting and affective changes. Using single neuron recording and intracellular injection techniques, we characterized the neuronal responses of neurons in the dorsal motor nucleus of the vagus (DMNV) to low- and high-pressure distensions of stomach and duodenum. Low-pressure gastric distention inhibited the mean activity of the DMNV neurons whereas high-pressure gastric distention excited many neurons. Of 47 DMNV neurons, low-pressure gastric distention inhibited 39, excited four, and did not affect four neurons. High-pressure gastric distention inhibited 26, excited 20, and left one unaffected. Thirteen of the 39 DMNV neurons inhibited by low-pressure distention of the stomach reversed their response to excitation during high-pressure gastric distention. Among 47 DMNV neurons, low-pressure duodenal distention inhibited 30, excited 10, and did not affect the remaining seven neurons. High-pressure distention of the duodenum inhibited 25 and excited 22 neurons. Eight DMNV neurons inhibited by low-pressure duodenal distention were excited in early response to high-pressure distention of the duodenum. High-pressure duodenal distention caused an early excitation and late inhibition in the mean activity of the DMNV neurons while low-pressure duodenal distention only produced late inhibition. These results suggest that different reflexes are present between physiological distention and noxious stimulation of gastrointestinal tract.
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Affiliation(s)
- Xueguo Zhang
- Laboratory of Neurogastroenterology Research, Division of Gastroenterology, Henry Ford Health System, One Ford Place 2D, 6071 Second Avenue, Detroit, MI 48202, USA.
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30
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Nandi J, Meguid MM, Inui A, Xu Y, Makarenko IG, Tada T, Chen C. Central mechanisms involved with catabolism. Curr Opin Clin Nutr Metab Care 2002; 5:407-18. [PMID: 12107377 DOI: 10.1097/00075197-200207000-00010] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Catabolism conjures up an end-metabolic process in which muscle and fat tissue are broken down into their constituent parts to provide nutrients for the body, secondary to a noxious stimulus that prevents the organism from adequately nourishing itself. However, catabolism is a primary event, initiated in the brain in response to perceived or real stresses or noxious stimuli, which has a secondary effect of inhibiting food intake and consequently the break down of skeletal muscle and adipose tissues to provide nutrients for the body to survive. RECENT FINDINGS This is achieved via a cascade of neurohormonal monoaminergic and peptidergic mediators in the central nervous system, invoking the cortex, the limbic system and the hypothalamus. Among the most detailed mediators studied are corticotropin-releasing factor and serotonin which, via the hypothalamic-pituitary-adrenal axis and the sympathetic and parasympathetic nervous system, stimulate catecholamines and cortisol and inhibit anabolic hormones, insulin, leptin, ghrelin, including neuropeptide Y and other neuropeptides, among them the paracrine-acting cytokines. Simultaneously, there occurs stimulation of the counter-regulatory hormones cortisol, glucagon and the melanocortin family of neuropeptides. SUMMARY The net effect is anorexia, with the inhibition of food intake, body weight loss, delayed gastric emptying and functions, the stimulation of gluconeogenesis, glycogenolysis and ketogenesis as sources of metabolic fuel, which if unabated leads ultimately to cachexia. The use of antagonists and the removal of stress or noxious stimuli experimentally test different pathways of this dynamic metabolic picture. Several studies have demonstrated important progress towards our understanding of the central mechanisms involved in anorexia and weight loss, which we summarize in this review.
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Affiliation(s)
- Jyotirmoy Nandi
- Department of Medicine, Gastroenterology Division, University Hospital, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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31
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Gilon P, Henquin JC. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr Rev 2001; 22:565-604. [PMID: 11588141 DOI: 10.1210/edrv.22.5.0440] [Citation(s) in RCA: 181] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In beta-cells, ACh binds to muscarinic M(3) receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)-induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA(2) produces arachidonic acid and lysophosphatidylcholine. These phospholipid-derived messengers, particularly diacylglycerol, activate PKC, thereby increasing the efficiency of free cytosolic Ca(2+) concentration ([Ca(2+)](c)) on exocytosis of insulin granules. IP3, also produced by PLC, causes a rapid elevation of [Ca(2+)](c) by mobilizing Ca(2+) from the endoplasmic reticulum; the resulting fall in Ca(2+) in the organelle produces a small capacitative Ca(2+) entry. ACh also depolarizes the plasma membrane of beta-cells by a Na(+)- dependent mechanism. When the plasma membrane is already depolarized by secretagogues such as glucose, this additional depolarization induces a sustained increase in [Ca(2+)](c). Surprisingly, ACh can also inhibit voltage-dependent Ca(2+) channels and stimulate Ca(2+) efflux when [Ca(2+)](c) is elevated. However, under physiological conditions, the net effect of ACh on [Ca(2+)](c) is always positive. The insulinotropic effect of ACh results from two mechanisms: one involves a rise in [Ca(2+)](c) and the other involves a marked, PKC-mediated increase in the efficiency of Ca(2+) on exocytosis. The paper also discusses the mechanisms explaining the glucose dependence of the effects of ACh on insulin release.
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Affiliation(s)
- P Gilon
- Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, B-1200 Brussels, Belgium.
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Viñuela MC, Larsen PJ. Identification of NPY-induced c-Fos expression in hypothalamic neurones projecting to the dorsal vagal complex and the lower thoracic spinal cord. J Comp Neurol 2001; 438:286-99. [PMID: 11550173 DOI: 10.1002/cne.1316] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Neuropeptide Y exerts profound effects on body weight and glucose homeostasis. We have investigated the effect of centrally administered neuropeptide Y on the activity of descending neurones of the hypothalamic paraventricular nucleus by combining retrograde tract tracing with c-Fos immunocytochemistry. Male rats were injected with True Blue into the dorsal vagal complex and with FluoroGold into the intermediolateral column of the lower thoracic spinal cord. One week after the last surgical procedure, animals were injected centrally with an orexigenic dose of neuropeptide Y (5 microg) and sacrificed 60 to 240 minutes following this injection. Temporal analysis of NPY-induced c-Fos expression showed a peak at 90 minutes, which was nearly returned to basal levels between 120 and 240 minutes. Expression of c-Fos was prominent in several of the subnuclei of the paraventricular nucleus and in the adjacent perifornical nucleus. Neurones projecting to the spinal cord were prominent in the dorsal, lateral, and ventral portion of the medial parvicellular subnuclei of the PVN. About 15% of IML projecting neurones of the medial parvicellular subnucleus were Fos-positive, whereas less than 5% of IML projecting neurones from other subnuclei were Fos-positive. Hardly any PVN neurones projecting to the dorsal vagal complex were concomitantly Fos-positive. A considerably larger (>10%) proportion of perifornical neurones projecting to the nucleus of the solitary tract were c-Fos-immunopositive. In conclusion, NPY induces c-Fos in paraventricular neurones projecting to intermediolateral column of the spinal cord and in neurones of the perifornical nucleus projecting to the dorsal vagal complex.
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Affiliation(s)
- M C Viñuela
- Department of Physiology, Faculty of Medicine, University of Cadiz, Cadiz, Spain
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Deng X, Guarita DR, Pedroso MR, Kreiss C, Wood PG, Sved AF, Whitcomb DC. PYY inhibits CCK-stimulated pancreatic secretion through the area postrema in unanesthetized rats. Am J Physiol Regul Integr Comp Physiol 2001; 281:R645-53. [PMID: 11448870 DOI: 10.1152/ajpregu.2001.281.2.r645] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Peptide YY (PYY) inhibits CCK-8-secretin-stimulated pancreatic secretion in vivo. To investigate whether CCK-8-secretin-stimulated pancreatic secretion is mediated through a vago-vagal pathway and whether PYY inhibits this pathway through the area postrema (AP), chronic pancreatic, biliary, and duodenal catheters were implanted in AP-lesioned (APX) or sham-operated rats. The effects of APX on pancreatic secretion stimulated by bethanechol, pancreatic juice diversion (PJD), or CCK-8-secretin, were tested, with and without background PYY infusion, in unanesthetized rats. APX reduced basal pancreatic secretion by 15-20% (P < 0.01). APX had no effect on bethanechol-stimulated secretion and potentiated protein secretion stimulated by PJD (396 vs. 284%) and exogenous CCK-8-secretin. In sham-operated rats, background PYY potently inhibited CCK-8-secretin-stimulated pancreatic fluid (1.8 vs. 48.2%) and protein secretion (3.7 vs. 45.8%) but potentiated fluid (52.9 vs. 43.1%) and protein (132.9 vs. 68.9%) secretion in APX rats. Our findings demonstrate that PYY inhibits CCK-8-secretin-stimulated pancreatic secretion through an AP-dependent mechanism in sham-operated rats. The AP also contributes to basal pancreatic secretion.
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Affiliation(s)
- X Deng
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261, USA
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Bouryi VA, Lewis DI. Adrenaline modulates multiple conductances in rat vagal motoneurones in vitro. Neuroreport 2001; 12:1709-13. [PMID: 11409744 DOI: 10.1097/00001756-200106130-00038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Whole cell recordings were undertaken from vagal motoneurones, including identified gastric vagal motoneurones, located within the medial regions of the dorsal vagal motonucleus of the rat medulla in vitro. The actions of adrenaline on individual channels expressed by these neurones were investigated. Adrenaline directly inhibits Ca2+ currents and delayed rectifier K+ currents and activates a sustained Na+ current. It also inhibits both Ca2+ activated non-selective cationic currents and Ca2+ activated K+ currents, the latter via inhibition of the underlying activating Ca2+ current. Since different sub-populations of vagal motoneurones express different complements of ion channels, this selective modulation of specific conductances by adrenaline may provide a mechanism by which adrenergic inputs, which project non-selectively throughout the DMV, could selectively control different aspects of vagal function.
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Affiliation(s)
- V A Bouryi
- School of Biomedical Sciences, University of Leeds, UK
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35
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Berthoud HR, Patterson LM, Zheng H. Vagal-enteric interface: vagal activation-induced expression of c-Fos and p-CREB in neurons of the upper gastrointestinal tract and pancreas. THE ANATOMICAL RECORD 2001; 262:29-40. [PMID: 11146426 DOI: 10.1002/1097-0185(20010101)262:1<29::aid-ar1008>3.0.co;2-b] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Many gastrointestinal and pancreatic functions are under strong modulatory control by the brain via the vagus nerve. To start identifying location and neurochemical phenotype of the enteric neurons receiving functional vagal efferent input, we activated vagal preganglionic neurons either by electrical or chemical stimulation and examined the expression of phosphorylated CREB (c-AMP response element binding protein) and the immediate early gene c-Fos. There was no spontaneous expression of both markers in the pancreas and considerable spontaneous expression of p-CREB but not Fos in the upper GI-tract. Unilateral electrical vagal stimulation-induced p-CREB was found in 40% of neurons in the head of the pancreas. Fos expression was found in 70-90% of neurons in the esophagus and stomach, in 20-30% of myenteric plexus neurons and 5-15% in submucosal neurons of the proximal duodenum. Double-labeling experiments showed that a majority of pancreatic neurons and about 25-35% of neurons in the stomach and duodenum contain NADPH-diaphorase and that many of these receive functional vagal input. Other neurons that can be vagally activated contain gastrin-releasing peptide or calretinin. Chemical stimulation of the dorsal surface of the caudal brainstem with the stable TRH analog RX77368 resulted in selective activation of vagal efferents with expression of Fos in a small number of gastric myenteric plexus neurons. The results demonstrate the suitability of this method to investigate magnitude and local distribution of vagal input to the enteric nervous system as well as specificity of its neurochemically coded pathways. They represent the first step in the identification of function-specific units of parasympathetic vagal outflow.
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Affiliation(s)
- H R Berthoud
- Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA.
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Zhang X, Renehan WE, Fogel R. Vagal innervation of the rat duodenum. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 2000; 79:8-18. [PMID: 10683501 DOI: 10.1016/s0165-1838(99)00093-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Electrophysiologic and anterograde tract tracing studies have demonstrated that the vagus nerve innervates the duodenum. These studies, however, have provided little information regarding the finer anatomic topography within the vagal complex. In this study, the retrograde neuronal tracers WGA-HRP or DiI, applied to the duodenum, were used to characterize the vagal afferent and efferent innervation of this portion of the gastrointestinal tract. This approach labeled a substantial number of motor neurons in both the medial and lateral columns of the dorsal motor nucleus of the vagus (DMNV). Vagal motor neurons innervating the duodenum were seen across the medial-lateral extent of the DMNV and between 600 microm rostral to obex and 1600 microm caudal to obex. The three branches of the vagus nerve contained efferent fibers to the duodenum. The gastric branch of the vagus nerve was the pathway that connected the majority of DMNV neurons with the duodenum. These neurons were located in the medial and middle thirds of the DMNV. The celiac branch to the duodenum was composed of axons from the majority of lateral column neurons but also contained axons from neurons in the medial column. The hepatic branch of the vagus nerve contained only a small number of cell axons. Some neurons were located medially whereas others were in the lateral third of the duodenum. Although central terminations of vagal primary afferents from the duodenum were not found in previous tract tracing studies, we observed a large number of terminals in the subpostremal/commissural region of the nucleus of the solitary tract. Similar to the motor fibers, most afferent fibers from the duodenum were located in the gastric branch of the vagus nerve, although the hepatic and celiac branches also contained afferent neurons. These results demonstrate that the vagal innervation of the duodenum is unique, being an amalgam of what would be expected following labeling of more proximal and distal portions of the GI tract. The uniqueness of the sensory and motor innervation to the duodenum has implications for hypotheses regarding the organization of vagovagal reflexes controlling gastrointestinal function.
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Affiliation(s)
- X Zhang
- Neurogastroenterology Laboratory, Division of Gastroenterology, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202, USA
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37
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Chapter VI Nitric oxide systems in the medulla oblongata and their involvement in autonomic control. ACTA ACUST UNITED AC 2000. [DOI: 10.1016/s0924-8196(00)80060-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Wang J, Zheng H, Berthoud HR. Functional vagal input to chemically identified neurons in pancreatic ganglia as revealed by Fos expression. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 277:E958-64. [PMID: 10567025 DOI: 10.1152/ajpendo.1999.277.5.e958] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The importance of neural elements in the control of both endocrine and exocrine pancreatic secretory functions and their coordination with gastrointestinal, hepatic, and general homeostatic functions is increasingly recognized. To better characterize the vagal efferent input to the pancreas, the capacity of electrical vagal stimulation to induce expression of c-Fos in neurochemically identified neurons of intrapancreatic ganglia was investigated. At optimal stimulation parameters, unilateral stimulation of either the left or right cervical vagus induced Fos expression in approximately 30% of neurons in the head and 10-20% of neurons in the body and tail of the pancreas. There was no Fos expression if no stimulation or stimulation with a distally cut vagus was applied. Large proportions of neurons contained nitric oxide synthase as assessed with NADPH diaphorase histochemistry (88%) and choline acetyltransferase. The proportion of nitrergic and nonnitrergic neurons receiving vagal input was not different. It is concluded that a significant proportion of pancreatic neurons receives excitatory synaptic input from vagal preganglionic axons and that many of these vagal postganglionic neurons can produce nitric oxide and acetylcholine.
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Affiliation(s)
- J Wang
- Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA
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Streefland C, Maes FW, Bohus B. Autonomic brainstem projections to the pancreas: a retrograde transneuronal viral tracing study in the rat. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1998; 74:71-81. [PMID: 9915620 DOI: 10.1016/s0165-1838(98)00047-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The present study describes brainstem nuclei that participate in the autonomic innervation of the pancreas, using a retrograde viral transneuronal tracing technique. It aimed at identifying the neuronal architecture of the parasympathetic, gustatory-induced insulin release by the endocrine pancreas (preabsorptive insulin response, PIR). Autonomic pathways organized for reflex adjustments of the end organ, as it happens in the PIR, involve relatively simple circuits. This implies a short brainstem circuit from the rostral gustatory nucleus of the solitary tract to the dorsal motor nucleus of the vagus. The present findings confirm projections to the pancreas, originating from preganglionic neurons in the dorsal motor nucleus of the vagus. Transneuronal labeling was detected in the medial, and to a lesser extent in the lateral nucleus of the solitary tract mainly at caudal and intermediate levels. Furthermore, infected neurons were seen in the brainstem in the dorsal and ventral part of the medullary reticular formation, in the area postrema and in the raphe nuclei. Sparse labeling was found in the gustatory zone of the nucleus tractus solitarius. These results indicate that a direct connection between the rostral nucleus tractus solitarius and the medial dorsal motor nucleus of the vagus is very unlikely, so that one or more intermediate stations may be involved. Candidates to complete this pathway are the intermediate or caudal nucleus tractus solitarius, the medullary reticular formation or the parabrachial nucleus.
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Affiliation(s)
- C Streefland
- Groningen Graduate School for Behavioral and Cognitive Neurosciences, Department of Animal Physiology, University of Groningen, Haren, The Netherlands.
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Wang HF, Shortland P, Park MJ, Grant G. Retrograde and transganglionic transport of horseradish peroxidase-conjugated cholera toxin B subunit, wheatgerm agglutinin and isolectin B4 from Griffonia simplicifolia I in primary afferent neurons innervating the rat urinary bladder. Neuroscience 1998; 87:275-88. [PMID: 9722157 DOI: 10.1016/s0306-4522(98)00061-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
In the present study, we investigated and compared the ability of the cholera toxin B subunit, wheat germ agglutinin and isolectin B4 from Griffonia simplicifolia I conjugated to horseradish peroxidase, to retrogradely and transganglionically label visceral primary afferents after unilateral injections into the rat urinary bladder wall. Horseradish peroxidase histochemical or lectin-immunofluorescence histochemical labelling of bladder afferents was seen in the L6-S1 spinal cord segments and in the T13-L2 and L6-S1 dorsal root ganglia. In the lumbosacral spinal cord, the most intense and extensive labelling of bladder afferents was seen when cholera toxin B subunit-horseradish peroxidase was injected. Cholera toxin B subunit-horseradish peroxidase-labelled fibres were found in Lissauer's tract, its lateral and medial collateral projections, and laminae I and IV-VI of the spinal gray matter. Labelled fibres were numerous in the lateral collateral projection and extended into the spinal parasympathetic nucleus. Labelling from both the lateral and medial projections extended into the dorsal grey commissural region. Wheat germ agglutinin-horseradish peroxidase labelling produced a similar pattern but was not as dense and extensive as that of cholera toxin B subunit-horseradish peroxidase. The isolectin B4 from Griffonia simplicifolia I-horseradish peroxidase-labelled fibres, on the other hand, were fewer and only observed in the lateral collateral projection and occasionally in lamina I. Cell profile counts showed that a larger number of dorsal root ganglion cells were labelled with cholera toxin B subunit-horseradish peroxidase than with wheat germ agglutinin- or isolectin B4-horseradish peroxidase. In the L6-S1 dorsal root ganglia, the majority (81%) of the cholera toxin B subunit-, and almost all of the wheat germ agglutinin- and isolectin B4-immunoreactive cells were RT97-negative (an anti-neurofilament antibody that labels dorsal root ganglion neurons with myelinated fibres). Double labelling with other neuronal markers showed that 71%, 43% and 36% of the cholera toxin B subunit-immunoreactive cells were calcitonin gene-related peptide-, isolectin B4-binding- and substance P-positive, respectively. A few cholera toxin B subunit cells showed galanin-immunoreactivity, but none were somatostatin-, vasoactive intestinal polypeptide-, or neuropeptide Y-immunoreactive or contained fluoride-resistant acid phosphatase. The results show that cholera toxin B subunit-horseradish peroxidase is a more effective retrograde and transganglionic tracer for pelvic primary afferents from the urinary bladder than wheat germ agglutinin-horseradish peroxidase and isolectin B4-horseradish peroxidase, but in contrast to somatic nerves, it is transported mainly by unmyelinated fibres in the visceral afferents.
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Affiliation(s)
- H F Wang
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Hsieh JH, Chen RF, Wu JJ, Yen CT, Chai CY. Vagal innervation of the gastrointestinal tract arises from dorsal motor nucleus while that of the heart largely from nucleus ambiguus in the cat. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1998; 70:38-50. [PMID: 9686902 DOI: 10.1016/s0165-1838(98)00027-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The origin of medullary cells that form the cardiac vagal branch and the vagal branches in the lower thorax innervating the gastrointestinal (GI) tract was studied using horseradish peroxidase (HRP), a retrograde transport tracer in the cat. The distributions of parasympathetic postganglionic neurons of the heart were studied with acetylcholinesterase histochemistry. Intracardiac ganglionic neurons were found mainly in the connective tissue surrounding the base of the pulmonary arteries and in an area in and dorsal to the interatrial septum. Following injection of HRP into the subepicardum where most of the cardiac postganglionic neurons reside, 91% of the labelled neurons were found bilaterally distributed in the nucleus ambiguus (NA). A small population of labelled neurons was found in the dorsal motor nucleus of the vagus (DMV) and an intermediate zone (IZ) between the two nuclei. When HRP was injected into the left or right cardiopulmonary vagus branch, labelled neurons were found exclusively in the ipsilateral NA, DMV and IZ with a predominance in the NA. In the thorax, after they course around the heart, the left and right thoracic vagus nerves divides into a left and a right branch, respectively. The left branch of the left thoracic vagus joins the left branch of the right thoracic vagus to form the anterior vagus nerve at 3 cm above the diaphragm. The right branch of the right thoracic vagus nerve joins the right branch of the left thoracic vagus to form the posterior vagus nerve. After application of HRP into the right or the left branch of the left thoracic vagus, HRP labelled cells were found in the left DMV. Similarly, after application of HRP into the left or the right branch of the right thoracic vagus, labelled cells were found in the right DMV. On the other hand, when HRP was injected into the anterior vagus, labelled neurons were found bilaterally in the DMV. This suggests that all rostral branches of the thoracic vagus have their origin in the ipsilateral DMV, and intermixing occurs only at the caudal level near the diaphragm. Findings of the present experiments suggest that parasympathetic preganglionic neurons innervating the GI tract are located exclusively in the DMV while those of the heart are located mainly in the NA. Within the DMV, GI vagal neurons were found medially from the level 0-2.5 mm rostral to the obex. In contrast, cardiac vagal neurons were found in the lateral edge of the DMV at the level 0-1 mm rostral to the obex.
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Affiliation(s)
- J H Hsieh
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Won MH, Matsuo K, Oh YS, Kitoh J. Brainstem topology of the vagal motoneurons projecting to the esophagus and stomach in the house musk shrew, Suncus murinus. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1998; 68:171-81. [PMID: 9626945 DOI: 10.1016/s0165-1838(97)00123-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The central origin of vagal efferents innervating the esophagus and stomach in the house musk shrew, Suncus murinus, was studied using the retrograde tracing technique. The animals were perfused with fixative 48-72 h after HRP injection and sections were processed by HRP histochemistry. HRP application into the gastroesophagus resulted in bilateral labelling of neurons in the dorsal motor nucleus of the vagus nerve (DMX) and ambiguous nucleus (AN). Labelled neurons in the DMX were observed from all regions except from the cervical esophagus, while ones in the AN were seen from the esophagus and cardia. The more labelled neurons were observed on the right DMX from subdiaphragmatic esophagus, cardia, lesser curvature and ventral corpus, while on the left DMX from the dorsal corpus labelled neurons in the longitudinal extent of the DMX were generally located at the dorsal and dorsomedial part, and those in the middle part were scattered. Labelled neurons in the AN were located restricted in the rostral part. Our results suggest that in the Suncus murinus the rostrocaudal site-specific localization within the DMX was not found, but it was prominent in the AN. In addition, while the majority of neurons which supply the esophagus and stomach were located in the DMX, only a small number was found in the AN.
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Affiliation(s)
- M H Won
- Department of Anatomy, College of Medicine, Hallym University, Chunchon, South Korea.
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Krowicki ZK, Sharkey KA, Serron SC, Nathan NA, Hornby PJ. Distribution of nitric oxide synthase in rat dorsal vagal complex and effects of microinjection of nitric oxide compounds upon gastric motor function. J Comp Neurol 1997; 377:49-69. [PMID: 8986872 DOI: 10.1002/(sici)1096-9861(19970106)377:1<49::aid-cne6>3.0.co;2-j] [Citation(s) in RCA: 107] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Nitric oxide (NO) has received attention as a vagal nonadrenergic-noncholinergic (NANC) mediator of gastrointestinal relaxation. The dorsal vagal complex (DVC) is the primary hindbrain site of vagal control of the gastrointestinal tract, and yet the subnuclear distribution of NO and its physiological effects have not been analyzed in this nucleus. Therefore, this study estimates the relative number of NO synthase (NOS)-containing neurons in subnuclear regions of the DVC, identifies NOS-containing vagal abdominal preganglionic neurons in the dorsal motor nucleus of the vagus, and defines a role of NO in the DVC in control of gastric motor function. The location of NADPH-diaphorase-positive staining (a marker of NOS activity) and NOS immunoreactivity overlap in the DVC. In the dorsal motor nucleus of the vagus there are positively stained cells caudal to the obex and at its most rostral extent, but not at the intermediate level. Intraperitoneal fluorogold combined with NADPH-diaphorase activity labels approximately 5% and 15% of fluorogold-immunoreactive cells in the caudal and rostral dorsal motor nucleus of the vagus, respectively. Thus, a portion of NOS-containing neurons are preganglionic vagal neurons projecting to the abdominal viscera. In the nucleus tractus solitarius, the majority of NADPH-diaphorase-positive cells are within the centralis, medial, and ventral/ventrolateral subnuclei. Fiber/terminal staining is present in the subnucleus centralis, subnucleus gelatinosus, subpostremal zone, and the medial nucleus tractus solitarius. The presence of NOS terminal staining implicates NO in afferent control of gastric function in the DVC (e.g., vago-vagal circuits in subnucleus gelatinosus). To determine a role of NO in the DVC, NO-related agents were microinjected into the DVC in alpha-chloralose-anesthetized rats while recording indices of gastric motor function. L-Arginine, microinjected into the DVC, significantly decreases intragastric pressure (-2.2 +/- 0.4 cm2, N = 12), and this effect is abolished by vagotomy. Microinjection of an NOS inhibitor, NG-nitro-L-arginine methyl ester, increases intragastric pressure (1.9 +/- 0.7 cm2, N = 10), with the greatest effect in the DVC rostral to the obex. Overall, it was concluded that tonic release of NO in the DVC mediates gastric relaxation, at least in anesthetized animals, and NOS-containing preganglionic neurons in the dorsal motor nucleus of the vagus may be "command" NANC neurons which control a variety of gastrointestinal functions.
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Affiliation(s)
- Z K Krowicki
- Department of Pharmacology, Louisiana State University Medical Center, New Orleans 70112, USA
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Chen XH, Itoh M, Sun W, Miki T, Takeuchi Y. Localization of sympathetic and parasympathetic neurons innervating pancreas and spleen in the cat. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1996; 59:12-6. [PMID: 8816360 DOI: 10.1016/0165-1838(95)00136-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The localization of sympathetic and parasympathetic neurons innervating the pancreas and spleen was studied in the cat utilizing retrograde transport of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP). Injection of WGA-HRP into the pancreas resulted in retrograde labeling in the whole of the solar plexus, while injection of WGA-HRP into the spleen also resulted in heavy labeling in the celiac ganglia bilaterally. Only a few labeled neurons were distributed in the superior mesenteric ganglion. With respect to parasympathetic innervation, HRP-labeled pancreatic and splenic neurons were found throughout the rostrocaudal extent of the dorsal motor nucleus of the vagus nerve (DMV) bilaterally. Although pancreatic neurons in the DMV were mainly observed in limits rostral to the obex, splenic neurons were centered at the level of the obex.
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Affiliation(s)
- X H Chen
- Department of Anatomy, Kagawa Medical School, Japan
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Portillo F, Carrasco M, Vallo JJ. Hypothalamic neuron projection to autonomic preganglionic levels related with glucose metabolism: a fluorescent labelling study in the rat. Neurosci Lett 1996; 210:197-200. [PMID: 8805129 DOI: 10.1016/0304-3940(96)12690-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The location of hypothalamic paraventricular neurons projecting to sympathetic preganglionic levels and related to the autonomic regulation of various organs involved in glucose metabolism (OGM) was determined by ipsilateral injections of two fluorescent tracers, Diamidino Yellow into the left dorsal motor nucleus of the vagus and Fast Blue into the left intermediolateral cell column of the T8-T9 spinal cord. Hypothalamospinal neurons were mainly located in the dorsal part of the paraventricular hypothalamic nucleus (PVH) and the hypothalamobulbar neurons were most abundant in the ventral, medial and extreme lateral parts of the PVH. No double-labelled neurons were found in the hypothalamus. These results can help the knowledge of the neural hypothalamic network related with the autonomic hypothalamic control.
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Affiliation(s)
- F Portillo
- Departamento de Fisiología, Facultad de Medicina, Cádiz, Spain
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Fogel R, Zhang X, Renehan WE. Relationships between the morphology and function of gastric and intestinal distention-sensitive neurons in the dorsal motor nucleus of the vagus. J Comp Neurol 1996; 364:78-91. [PMID: 8789277 DOI: 10.1002/(sici)1096-9861(19960101)364:1<78::aid-cne7>3.0.co;2-p] [Citation(s) in RCA: 54] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The activity of vagal motor neurons is influenced by sensory information transmitted to the brainstem. In particular, there is evidence that distention of the stomach increases activity of motor neurons in the dorsal vagal motor nucleus, whereas distention of the duodenum, small intestine, and colon reduces neuron firing. In this study, we determined 1) the response of vagal motor neurons to distention of the stomach and duodenum and 2) whether the response properties were associated with specific morphological features. Using the single-cell recording and iontophoretic injection technique, we identified four groups of vagal motor neurons affected by gastric and/or duodenal distention. Group 1 neurons responded to either gastric or duodenal stimulation. Neurons in groups 2, 3, and 4 were affected by both gastric and duodenal distention. Group 2 neurons were excited by duodenal distention and were inhibited by gastric distention. Group 3 neurons were inhibited by duodenal distention and were excited by gastric distention. Most neurons belonged to group 4. Neurons in this group were inhibited by both gastric and duodenal distention. Our analyses revealed that the neurons affected by both stimuli had distinctive structural features. Neurons in group 2 had the largest somata, the most dendritic branches, and the greatest cell surface area. Neurons in group 3 were the smallest and had the shortest dendritic length. In addition, we were able to demonstrate that the neurons in group 4 had a smaller total dendritic length and a smaller cell volume than neurons in group 2 and had more dendritic branch segments than neurons in group 3. These results suggest that morphological features are associated with specific response properties of vagal motor neurons.
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Affiliation(s)
- R Fogel
- Division of Gastroenterology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA
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Krowicki ZK, Hornby PJ. Pancreatic polypeptide, microinjected into the dorsal vagal complex, potentiates glucose-stimulated insulin secretion in the rat. REGULATORY PEPTIDES 1995; 60:185-92. [PMID: 8746545 DOI: 10.1016/0167-0115(95)00130-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Specific binding sites for circulating pancreatic polypeptide (PP) have been found within the dorsal vagal complex (DVC) in the caudal medulla oblongata. Therefore, the effects of rat PP on pancreatic hormone secretion upon its microinjection into the DVC in halothane-anesthetized rats at doses of 0.4-40 pmol were investigated. At this range of doses, the changes in plasma concentrations of insulin, glucagon and glucose over basal levels did not differ from those after vehicle microinjection. In a separate series of experiments, vehicle and PP at doses of 0.4 and 4 pmol were microinjected into the right DVC 40 min after the continuous infusion of D-glucose had been started. In animals receiving continuous infusion of D-glucose, PP microinjected into the DVC (4 pmol), resulted in markedly higher insulin levels at corresponding time points compared to those with vehicle microinjected into the DVC. These data indicate, for the first time, that microinjection of PP into the DVC may potentiate glucose-stimulated insulin secretion in halothane-anesthetized rats.
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Affiliation(s)
- Z K Krowicki
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans 70112, USA
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Krowicki ZK, Hornby PJ. The nucleus raphe obscurus controls pancreatic hormone secretion in the rat. THE AMERICAN JOURNAL OF PHYSIOLOGY 1995; 268:E1128-34. [PMID: 7611388 DOI: 10.1152/ajpendo.1995.268.6.e1128] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Until recently, the dorsal vagal complex (DVC) was considered as the only brain stem regulatory center for the vagal control of the endocrine pancreas. Because the nucleus raphe obscurus (NRO) maintains anatomic connections via the DVC to the pancreas, a functional significance of these findings was investigated in the present study. Kainic acid and vehicle were microinjected into the right DVC and the NRO of alpha-chloralose-anesthetized rats, and plasma concentrations of rat insulin, glucagon, and glucose were determined before and 5, 15, 30, and 60 min after injections. Chemical stimulation of neurons in the DVC by kainic acid at a dose of 200 pmol evoked increases in concentrations of insulin, with a peak at 15 min, and glucagon, with a peak at 30 min. Microinjection of kainic acid into the NRO at a dose of 200 pmol, but not at a dose of 20 pmol, produced increases in plasma concentrations of insulin, with a peak at 30 min, and glucagon, with a peak at 60 min. Plasma glucose levels on microinjection of kainic acid into the NRO at a dose of 20 pmol were decreased, whereas no changes on microinjection of kainic acid at a dose of 200 pmol were observed. The effects of kainic acid on insulin and glucagon secretion in the NRO were abolished by bilateral vagotomy. The study demonstrates for the first time that the NRO can contribute to vagal control of pancreatic endocrine function, although the exact circuitry and neurotransmitters involved in this response remain unknown.
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Affiliation(s)
- Z K Krowicki
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans 70112, USA
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Feldman PD, Galiano FJ. Evidence against a hemodynamic role for serotonin in the dorsal motor nucleus of the vagus. Brain Res Bull 1995; 37:457-62. [PMID: 7633893 DOI: 10.1016/0361-9230(95)00024-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
This study was performed to investigate the potential role of serotonin (5-HT) in the dorsal motor nucleus of the vagus (dmnX) in regulating peripheral hemodynamics. Microinjections (5 or 25 nmol in 50 nl) of the monoaminergic neurotransmitter were made into the dorsomedial medulla of the urethaneanesthetized rat during continuous recording of femoral arterial blood pressure. Heart rate was extracted electronically from the pressure waveform. Discrete injections of 5-HT placed directly in the dmnX were found to be entirely without effect on peripheral hemodynamics. In contrast, injections placed in the solitary tract nucleus, lying immediately above the dmnX, were found to have profound depressor and bradycardic effects, while the immediately subjacent hypoglossal nucleus appeared to contain both depressor and unresponsive sites. These findings cast doubt on the involvement of serotonin in the dmnX in the regulation of cardiovascular hemodynamics.
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Affiliation(s)
- P D Feldman
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans 70112-1393, USA
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