Disruption of Glucagon-Like Peptide 1 Signaling inSim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress

Journal Article

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-mediatedGlp1rknockdown 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, regionalGlp1rknockdown attenuated stress-induced cardiovascular responses accompanied by decreased sympathetic drive to the heart. Finally,Glp1rknockdown 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.SIGNIFICANCE STATEMENTDysfunctional 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.

Full Text

Duke Authors

Cited Authors

  • Ghosal, S; Packard, AEB; Mahbod, P; McKlveen, JM; Seeley, RJ; Myers, B; Ulrich-Lai, Y; Smith, EP; D'Alessio, DA; Herman, JP

Published Date

  • January 4, 2017

Published In

Volume / Issue

  • 37 / 1

Start / End Page

  • 184 - 193

Published By

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.1104-16.2016


  • en