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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2015-08, Vol.87 (3), p.605-620
• Main Authors: McCall, Jordan G., Al-Hasani, Ream, Siuda, Edward R., Hong, Daniel Y., Norris, Aaron J., Ford, Christopher P., Bruchas, Michael R.
• Format: Article
• Language: English
• Subjects: Adrenergic Neurons - chemistry; Adrenergic Neurons - metabolism; Animals; Anxiety; Anxiety - metabolism; Anxiety - psychology; Behavior; Colleges & universities; Corticotropin-Releasing Hormone - metabolism; Laboratories; Locus Coeruleus - chemistry; Locus Coeruleus - metabolism; Male; Mice; Mice, Inbred C57BL; Neurons; Neurosciences; Norepinephrine - metabolism; Optogenetics - methods; Principal components analysis; Rodents; Stress; Stress, Psychological - metabolism; Stress, Psychological - psychology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.07.002

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. •Inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior•Increased tonic LC-NE neuronal activity promotes anxiety-like and aversive behavior•CRH+ CeA-LC projections increase LC-NE activity and promote anxiogenic responses•CRH+ CeA-LC-induced anxiety-like behavior is mediated by CRHR1 receptors McCall et al. identify locus coeruleus (LC) neuronal activity as a critical mediator of stress-induced anxiety. Selective modulation of LC activity bidirectionally controls anxiety-like and aversive behaviors. Anatomical studies identify amygdalar CRH+ inputs that modulate LC activity and drive anxiety-like behavior.