CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety

Neuron. 2015 Aug 5;87(3):605-20. doi: 10.1016/j.neuron.2015.07.002. Epub 2015 Jul 23.


The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders.

Publication types

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

MeSH terms

  • Adrenergic Neurons / chemistry
  • Adrenergic Neurons / metabolism*
  • Animals
  • Anxiety / metabolism*
  • Anxiety / psychology
  • Corticotropin-Releasing Hormone / metabolism*
  • Locus Coeruleus / chemistry
  • Locus Coeruleus / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Norepinephrine / metabolism
  • Optogenetics / methods
  • Stress, Psychological / metabolism*
  • Stress, Psychological / psychology


  • Corticotropin-Releasing Hormone
  • Norepinephrine