Integration of Peripheral and Central Appetite Signals by Brainstem Neurons

Summary

Principal Investigator: Suzanne M Appleyard
Abstract: DESCRIPTION (provided by applicant): Obesity is a major health problem in the United States and is a leading contributor to cardiovascular disease, diabetes mellitus and stroke. One of the less well understood areas of obesity research are the mechanisms by which neurons respond to, integrate and pass on central and peripheral signals about energy state and how these signaling pathways are altered in obesity. Our long-range goal is to understand the molecular and cellular mechanisms by which neurons in the nucleus of the solitary tract (NTS) of the brainstem control body- weight and how these mechanisms are altered in obesity. Visceral afferents, including gastric afferents, carrying information about satiety terminate in the NTS. As such, NTS neurons act as gates, determining what information contained in afferents is passed onto other brain regions. Ablation of NTS neurons expressing catecholamines (NTS-CA neurons) disrupts control of food intake by several hormones, including ghrelin and cholecystokinin (CCK). The overall objective of this proposal is to identify the mechanisms by which NTS-CA neurons respond to appetite-regulating inputs under normal and obese conditions. Our central hypothesis is that the output of NTS-CA neurons is an integration of afferent and hormonal inputs and that it is altered by different energy states, such as fasting or obesity. We will test this hypothesis with the following three specific aims. (1) Determine how afferent inputs regulate NTS-CA neurons. Our working hypothesis for this aim is that the firing rate of NTS-CA neurons is controlled by visceral afferents, including gastric afferents, both through direct and indirect inputs. (2) Identify mechanism(s) by which key hormonal appetite modulators regulate NTS- CA neurons. Our working hypothesis for this aim is that CCK, which inhibits food intake and ghrelin, which stimulates food intake, regulate the output of NTS-CA neurons. (3) Determine how NTS-CA neurons adapt to different energy states. Our working hypothesis for this aim is that NTS-CA neurons adapt to prolonged exposure to hormones or conditions of altered energy states. We are well prepared to undertake the proposed research because we have developed a mouse horizontal brain slice that allows us to selectively stimulate visceral afferents while recording from identified NTS-CA neurons using electrophysiological patch clamp techniques. This is an extremely powerful system to address the cellular and molecular mechanisms by which NTS-CA neurons integrate neuronal and hormonal responses and how these mechanisms are altered in obesity. In addition, we will use labeling techniques to specifically identify NTS-CA neurons receiving gastric afferent inputs, pharmacology to dissect out molecular signaling pathways and behavioral paradigms to examine how these pathways/mechanisms are altered in different energy states. The contribution of this work is expected to be significant, because increasing our understanding of the molecular mechanisms underlying appetite control and how these mechanisms are altered in different energy states, will lead to more precisely targeted approaches for the prevention treatment of obesity.
Funding Period: 2009-04-15 - 2014-03-31
more information: NIH RePORT

Top Publications

  1. pmc Ghrelin inhibits visceral afferent activation of catecholamine neurons in the solitary tract nucleus
    Ran Ji Cui
    Program in Neuroscience, Department of Veterinary Comparative Anatomy, Washington State University, Pullman, Washington 99164, USA
    J Neurosci 31:3484-92. 2011
  2. pmc Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus
    R J Cui
    Department of Veterinary Comparative Anatomy, Physiology and Pharmacology, Washington State University, Pullman, WA 99164, USA
    Neuroscience 222:181-90. 2012
  3. pmc Serotonin activates catecholamine neurons in the solitary tract nucleus by increasing spontaneous glutamate inputs
    Ran Ji Cui
    Program in Neuroscience, Department of Veterinary Comparative Anatomy, Physiology and Pharmacology, Washington State University, Pullman, Washington 99164, USA
    J Neurosci 32:16530-8. 2012

Detail Information

Publications4

  1. pmc Ghrelin inhibits visceral afferent activation of catecholamine neurons in the solitary tract nucleus
    Ran Ji Cui
    Program in Neuroscience, Department of Veterinary Comparative Anatomy, Washington State University, Pullman, Washington 99164, USA
    J Neurosci 31:3484-92. 2011
    ..These results demonstrate a potential mechanism by which ghrelin inhibits NTS TH neurons through a pathway whose responsiveness is increased during fasting...
  2. pmc Opioids inhibit visceral afferent activation of catecholamine neurons in the solitary tract nucleus
    R J Cui
    Department of Veterinary Comparative Anatomy, Physiology and Pharmacology, Washington State University, Pullman, WA 99164, USA
    Neuroscience 222:181-90. 2012
    ....
  3. pmc Serotonin activates catecholamine neurons in the solitary tract nucleus by increasing spontaneous glutamate inputs
    Ran Ji Cui
    Program in Neuroscience, Department of Veterinary Comparative Anatomy, Physiology and Pharmacology, Washington State University, Pullman, Washington 99164, USA
    J Neurosci 32:16530-8. 2012
    ....

Research Grants62

  1. CSF Neuropeptide, Hormonal and Metabolomic Analysis in Human Energy Balance
    Sharon L Wardlaw; Fiscal Year: 2013
    ..An important goal is to identify biomarkers in CSF that could predict responses to dieting and to pharmacotherapy for obesity that target the melanocortin system. ..
  2. Leptin and Central Control of Thermoregulation
    HEIKE MUENZBERG-GRUENING; Fiscal Year: 2013
    ..In leptin deficient ob/ob mice with LepRb-driven cre/EGFP expression potential thermoregulatory defects (e.g. LepRb expression, neuronal projections) in POA &DMH/DHA neurons are investigated. ..
  3. Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders
    Brian P Sorrentino; Fiscal Year: 2013
    ..abstract_text> ..
  4. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  5. Mechanisms of Fatty Acid Control of Feeding Behavior
    W SUE RITTER; Fiscal Year: 2013
    ..I addition, some results may have translational significance for diabetes, where beta cell GPR40 is already a target for drug development. ..
  6. Neural Functioning of Feeding Centers in Obese Youth
    ROBERT STANLEY SHERWIN; Fiscal Year: 2013
    ....
  7. Role of Vagal Afferents in Maintainence of Body Weight and Glucose Homeostasis
    Swalpa Udit; Fiscal Year: 2013
    ..abstract_text> ..
  8. Interstitial Cystitis/Painful Bladder Syndrome: Neurophysics/Autonomic Character
    Thomas Chelimsky; Fiscal Year: 2013
    ..This expanded view is designed to lead to a better understanding of causal factors that contribute to the disease process, and to suggest novel treatment or prevention strategies. ..
  9. Gastric dysreflexia after spinal cord injury
    Gregory M Holmes; Fiscal Year: 2013
    ..This proposal will provide the basis to refine a model of post-SCI alterations in gastrointestinal function that encompasses the entire length of the GI tract. Ultimately this will help alleviate GI dysfunctions in SCI patients. ..
  10. Arcuate nucleus glutamatergic neurons modulate energy homeostasis
    Anthony N van den Pol; Fiscal Year: 2013
    ..abstract_text> ..
  11. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  12. Neuronal Responses to Effective Weight Loss Maintenance Strategies
    Jason R Tregellas; Fiscal Year: 2013
    ..By understanding the complex interactions between the brain response to eating and food cues and physiologic changes with these interventions we hope to be able to develop new strategies and/or interventions for sustained weight loss. ..
  13. NEURAL HIERARCHY IN THE MODULATION OF INGESTIVE BEHAVIOR
    Harvey J Grill; Fiscal Year: 2013
    ..A variety of preliminary results support the hypotheses under investigation. ..
  14. Pharmacogenomics of Gastric Function &Weight in Obesity
    MICHAEL L CAMILLERI; Fiscal Year: 2013
    ....
  15. Responsiveness to nicotine of nucleus tractus solitarius neurons
    VICTOR V UTESHEV-GAARD; Fiscal Year: 2013
    ..The experiments here will point to new ways of using nicotinic mechanisms to modify functions of the gastrointestinal system associated with feeding. ..
  16. Peptidergic Control of Appetitive Ingestive Behaviors
    TIMOTHY JON BARTNESS; Fiscal Year: 2013
    ..This will greatly impact behavioral or drug therapies for obesity and for the genetic disorder Prader-Willi-Syndrome characterized by obesity and uncontrollable FH. ..
  17. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  18. Insulin effects in the vagal complex
    Camille Bond Blake; Fiscal Year: 2013
    ..The results of this study will provide a clearer understanding of how insulin regulates autonomic function, which could lead to new insights in designing treatments for diabetes. ..
  19. INNATE AND ADAPTIVE IMMUNITY IN IBD
    Charles O Elson; Fiscal Year: 2013
    ..The long-term goal is to increase our understanding of the fundamental mechanisms of IBD in order to develop better diagnostic and therapeutic strategies for patients...
  20. SLEEP, AGING AND CIRCADIAN RHYTHM DISORDERS
    Charles A Czeisler; Fiscal Year: 2013
    ..This research has important implications for the development of strategies to prevent, and therapies to treat, obesity and diabetes in older adults. ..
  21. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  22. Pre-Ingestive Influences on Solid and Fluid Food Intake in Lean and Obease Adults
    Richard D Mattes; Fiscal Year: 2013
    ..The findings should aid development of dietary recommendations and products to address the problems of overweight/obesity. ..
  23. FOREBRAIN PLASTICY IN HYPERTENSION
    Costantino Iadecola; Fiscal Year: 2013
    ..Thus, the collective scientific outcome of the Program is anticipated to be greater than the sum of its individual components. ..
  24. The Role Leptin on Arousal
    PAIGE B BECK; Fiscal Year: 2013
    ....
  25. Brainstem LepRb neurons in the control of metabolism
    JONATHAN NICHOLAS FLAK; Fiscal Year: 2013
    ..These studies will provide important insights into novel mechanisms of leptin action in the central nervous system and into the control of energy and glucose homeostasis. ..
  26. Neural mechanisms controlling food intake and body weight after bariatric surgery
    Hans Rudolf Berthoud; Fiscal Year: 2013
    ..This will result in more optimal surgical procedures, behavioral tips helping patients to cope with different eating habits, and development of new drugs. ..
  27. Translational Research in Cystic Fibrosis
    Mitchell L Drumm; Fiscal Year: 2013
    ..This goal is also a function of the Biomedical Research Cores. ..
  28. Neural mechanisms underlying abnormal food reward processing in depressed women
    LAURA MCGRATH HOLSEN; Fiscal Year: 2013
    ....
  29. Neuroendocrine Integration of Satiety and Food Reward
    Diana L Williams; Fiscal Year: 2013
    ....
  30. Weight Suppression, Dieting and Bulimia Nervosa: A Biobehavioral Study
    Michael R Lowe; Fiscal Year: 2013
    ....
  31. ROLE OF FORKHEAD PROTEINS IN INSULIN ACTION
    Domenico Accili; Fiscal Year: 2013
    ..Therefore, it is hoped that by parsing its modes of action and interacting partners, new ways to modulate its function can be found. ..
  32. Plasticity at the Excitatory Synapse
    Richard L Huganir; Fiscal Year: 2013
    ..Understanding these basic mechanisms of synaptic transmission and plasticity will provide insight into normal and abnormal brain function. ..
  33. Ginsenocide Rb1: A Novel Anti-Obesity and Anti-Hyperglycemic Compound
    Stephen C Woods; Fiscal Year: 2013
    ....
  34. The effects of glucose on central vagal brainstem circuits
    KIRSTEEN NAIRN BROWNING; Fiscal Year: 2013
    ..abstract_text> ..
  35. Penn TREC Survivor Center
    Kathryn H Schmitz; Fiscal Year: 2013
    ..abstract_text> ..
  36. Genetics of Parkonsonism
    Jeffery Marvin Vance; Fiscal Year: 2013
    ....
  37. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  38. Changes in neural response to eating after bariatric surgery: MRI results
    Thomas A Wadden; Fiscal Year: 2013
    ..In addition, we will serially measure postprandial changes in appetite-regulating hormones and examine the relationships between neural and endocrine response to food consumption. ..
  39. Center for Integrative Neuroscience
    Michael A Webster; Fiscal Year: 2013
    ..abstract_text> ..
  40. Modulation of Taste-Related Behavior by Molecular Mediators of Appetite &Satiety
    Cedrick D Dotson; Fiscal Year: 2013
    ..Using a combination of genetic and pharmacological models, the proposed studies focus on investigating the general hypothesis that taste-related behavior can be modulated by metabolic hormones such as PYY and/or NPY. ..
  41. Mechanisms underlying adverse health consequences of shift work
    Frank A Scheer; Fiscal Year: 2013
    ..We anticipate that this work will lay the groundwork for the development of targeted and timed therapies to counteract the public health burden of shift work. ..
  42. Neuroendocrinology of Energy Balance Control
    Matthew R Hayes; Fiscal Year: 2013
    ..In addition, results may help identify potential targets for combination drug therapy to enhance the food intake and body weight suppressive effects of GLP-1- based pharmaceuticals. ..
  43. NEW MODALITIES FOR TREATMENT OF PAIN AND DRUG ABUSE
    Victor J Hruby; Fiscal Year: 2013
    ....
  44. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  45. Cholecystokinin - Role in postprandial gastric motility
    Helen E Raybould; Fiscal Year: 2013
    ....
  46. Hypothalamic SIRT1 and Energy Balance
    Eduardo A Nillni; Fiscal Year: 2013
    ..2. Exposure to High Fat Diet (HFD) alters hypothalamic Sirt1 expression, signaling, and Sirt1 co- substrate/activator NAD+ levels. 3. The inhibitory effect of Sirt1 on mTOR signaling in the DIO condition is one of the causes of obesity. ..
  47. Asynchronous Glutamate Release in Vagal Afferent to NTS Neurotransmission
    JAMES HENRY PETERS; Fiscal Year: 2013
    ..The findings from this project will determine the role of asynchronous glutamate release from vagal afferents and its impact on food intake. ..
  48. Role of Oxytocin Signaling in the Pathogenesis of Diet-Induced Obesity
    JAMES ERNEST BLEVINS; Fiscal Year: 2013
    ....
  49. Functional Brain Imaging and Appetite-Related Hormones Pre and Post Obesity Surge
    Allan Geliebter; Fiscal Year: 2013
    ..The findings may also improve our understanding of the causes of obesity, which could lead to new less invasive treatments. ..
  50. Food intake control by leptin signaling in the hippocampus
    SCOTT EDWARD KANOSKI; Fiscal Year: 2013
    ..Results will contribute to the development of pharmacological obesity treatment by informing about the neuroendocrine and intracellular/molecular systems that control food intake and food-motivated behavior. ..
  51. Glucagon-like peptide-1 in brainstem integration of energy balance control
    ELIZABETH GENEVIEVE MIETLICKI-BAASE; Fiscal Year: 2013
    ..Experiments in this proposal use a unique combination of in vivo, in vitro, and ex vivo techniques to investigate the research questions described. ..
  52. Investigations of botanicals on food intake, satiety, weight loss, and oxidative
    Stephen D Anton; Fiscal Year: 2013
    ....