Co-released norepinephrine and galanin act on different timescales to promote stress-induced anxiety-like behavior

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2021-07, Vol.46 (8), p.1535-1543
• Main Authors: Tillage, Rachel P, Foster, Stephanie L, Lustberg, Daniel, Liles, L Cameron, McCann, Katharine E, Weinshenker, David
• Format: Article
• Language: English
• Subjects: Adrenergic Neurons - metabolism; Animals; Anxiety; Behavior; Catecholamines; Feet; Footshock; Galanin; Galanin - genetics; Galanin - metabolism; Genetics; Information processing; Locus coeruleus; Locus Coeruleus - metabolism; Mental disorders; Mice; Neuromodulation; Norepinephrine; Optics; Stress response
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-021-01011-8

Both the noradrenergic and galaninergic systems have been implicated in stress-related neuropsychiatric disorders, and these two neuromodulators are co-released from the stress-responsive locus coeruleus (LC); however, the individual contributions of LC-derived norepinephrine (NE) and galanin to behavioral stress responses are unclear. Here we aimed to disentangle the functional roles of co-released NE and galanin in stress-induced behavior. We used foot shock, optogenetics, and behavioral pharmacology in wild-type (WT) mice and mice lacking either NE (Dbh ) or galanin (Gal ) specifically in noradrenergic neurons to isolate the roles of these co-transmitters in regulating anxiety-like behavior in the elevated zero maze (EZM) either immediately or 24 h following stress. Foot shock and optogenetic LC stimulation produced immediate anxiety-like behavior in WT mice, and the effects of foot shock persisted for 24 h. NE-deficient mice were resistant to the anxiogenic effects of acute stress and optogenetic LC stimulation, while mice lacking noradrenergic-derived galanin displayed typical increases in anxiety-like behavior. However, when tested 24 h after foot shock, both Dbh and Gal mice lacked normal expression of anxiety-like behavior. Pharmacological rescue of NE, but not galanin, in knockout mice during EZM testing was anxiogenic. In contrast, restoring galanin, but not NE, signaling during foot shock normalized stress-induced anxiety-like behavior 24 h later. These results indicate that NE and noradrenergic-derived galanin play complementary, but distinguishable roles in behavioral responses to stress. NE is required for the expression of acute stress-induced anxiety, while noradrenergic-derived galanin mediates the development of more persistent responses following a stressor.