title: Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress.
abstract: Organismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1)-mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing single-minded 1, a transcription factor abundantly expressed in the paraventricular nucleus (PVN) of the hypothalamus. Mice with single-minded 1-mediated Glp1r knockdown had reduced hypothalamic-pituitary-adrenal axis responses to both acute and chronic stress and were protected against weight loss associated with chronic stress. In addition, regional Glp1r knockdown attenuated stress-induced cardiovascular responses accompanied by decreased sympathetic drive to the heart. Finally, Glp1r knockdown reduced anxiety-like behavior, implicating PVN GLP-1 signaling in behavioral stress reactivity. Collectively, these findings support a circuit whereby brainstem GLP-1 activates PVN signaling to mount an appropriate whole-organism response to stress. These results raise the possibility that dysfunction of this system may contribute to stress-related pathologies, and thereby provide a novel target for intervention.
  
  
  
  Dysfunctional stress responses are linked to a number of somatic and psychiatric diseases, emphasizing the importance of precise neuronal control of effector pathways. Pharmacological evidence suggests a role for glucagon-like peptide-1 (GLP-1) in modulating stress responses. Using a targeted knockdown of the GLP-1 receptor in the single-minded 1 neurons, we show dependence of paraventricular nucleus GLP-1 signaling in the coordination of neuroendocrine, autonomic, and behavioral responses to acute and chronic stress. To our knowledge, this is the first direct demonstration of an obligate brainstem-to-hypothalamus circuit orchestrating general stress excitation across multiple effector systems. These findings provide novel information regarding signaling pathways coordinating central control of whole-body stress reactivity.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.|Department of Psychiatry and Neurobiology, Yale School of Medicine, New Haven, Connecticut 06508.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Ghosal
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.
authors.forename: Amy E B
authors.identifier: 0000-0003-1057-8853
authors.initials: AEB
authors.lastname: Packard
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.
authors.forename: Parinaz
authors.initials: P
authors.lastname: Mahbod
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.|Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: McKlveen
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.
authors.forename: Brent
authors.initials: B
authors.lastname: Myers
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ulrich-Lai
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, and.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Smith
authors.affiliation: Duke Molecular Physiology Institute, Duke University, Durham, North Carolina 27701.
authors.forename: David A
authors.identifier: 0000-0003-4155-4870
authors.initials: DA
authors.lastname: D'Alessio
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio 45237, james.herman@uc.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
mesh_terms: D000208:Acute Disease; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000235:genetics / Q000523:psychology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001522:Behavior, Animal; D002908:Chronic Disease; D004435:Eating; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics; D006339:Heart Rate / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010286:Paraventricular Hypothalamic Nucleus; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013315:Stress, Psychological / Q000503:physiopathology* / Q000523:psychology; D013550:Swimming / Q000523:psychology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000067757:Glucagon-Like Peptide-1 Receptor; D011495:Histone-Lysine N-Methyltransferase; D012097:Repressor Proteins; C000593834:Glp1r protein, mouse; C101750:Sim1 protein, mouse; C513479:GLP protein, mouse
keywords: HPA axis; acute stress; blood pressure; chronic stress; elevated plus maze; heart rate