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

Abstract

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 (GalcKO-Dbh) 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 GalcKO-Dbh 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.

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Fig. 1: Galanin mRNA levels in the LC are normal in mice lacking NE.
Fig. 2: NE, but not noradrenergic-derived galanin, is required for anxiety-like behavior immediately following foot shock stress.
Fig. 3: NE, but not noradrenergic-derived galanin, is required for anxiety-like behavior immediately following optogenetic LC stimulation.
Fig. 4: Both NE and noradrenergic-derived galanin are required for anxiety-like behavior 24 h following foot shock stress.
Fig. 5: Restoration of galanin, but not NE, signaling during stress exposure rescues normal stress-induced anxiety-like behavior 24 h later.

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Acknowledgements

We thank C. Strauss for helpful editing of this manuscript.

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RPT and DW conceived, designed, and supervised the project. RNAscope in situ hybridization was performed by SF. Immunohistochemistry experiments were performed by RPT and DL. All behavioral experiments were performed and analyzed by RPT with assistance from KEM. Pharmacological experiments were performed by RPT with assistance from DW. Mouse husbandry and genotyping were performed by LCL. RPT and DW wrote the manuscript with input from co-authors.

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Correspondence to David Weinshenker.

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Tillage, R.P., Foster, S.L., Lustberg, D. et al. Co-released norepinephrine and galanin act on different timescales to promote stress-induced anxiety-like behavior. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01011-8

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