Disruption of Glucagon-Like Peptide 1 Signaling in Sim1 Neurons Reduces Physiological and Behavioral Reactivity to Acute and Chronic Stress

J Neurosci. 2017 Jan 4;37(1):184-193. doi: 10.1523/JNEUROSCI.1104-16.2016.

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.

Significance statement: 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.

Keywords: HPA axis; acute stress; blood pressure; chronic stress; elevated plus maze; heart rate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Anxiety / etiology
  • Anxiety / genetics
  • Anxiety / psychology
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Behavior, Animal
  • Chronic Disease
  • Eating
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Heart Rate / genetics
  • Histone-Lysine N-Methyltransferase / genetics*
  • Hypothalamo-Hypophyseal System / physiopathology
  • Male
  • Mice
  • Mice, Knockout
  • Paraventricular Hypothalamic Nucleus
  • Pituitary-Adrenal System / physiopathology
  • Repressor Proteins / genetics*
  • Signal Transduction / genetics*
  • Stress, Psychological / physiopathology*
  • Stress, Psychological / psychology
  • Swimming / psychology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Repressor Proteins
  • Sim1 protein, mouse
  • GLP protein, mouse
  • Histone-Lysine N-Methyltransferase