Abstract
Accumulating evidence indicates that disruption of galanin signaling is associated with neuropsychiatric disease, but the precise functions of this neuropeptide remain largely unresolved due to lack of tools for experimentally disrupting its transmission in a cell type-specific manner. To examine the function of galanin in the noradrenergic system, we generated and crossed two novel knock-in mouse lines to create animals lacking galanin specifically in noradrenergic neurons (GalcKO–Dbh). We observed reduced levels of galanin peptide in pons, hippocampus, and prefrontal cortex of GalcKO–Dbh mice, indicating that noradrenergic neurons are a significant source of galanin to those brain regions, while midbrain and hypothalamic galanin levels were comparable to littermate controls. In these same brain regions, we observed no change in levels of norepinephrine or its major metabolite at baseline or after an acute stressor, suggesting that loss of galanin does not affect noradrenergic synthesis or turnover. GalcKO–Dbh mice had normal performance in tests of depression, learning, and motor-related behavior, but had an altered response in some anxiety-related tasks. Specifically, GalcKO–Dbh mice showed increased marble and shock probe burying and had a reduced latency to eat in a novel environment, indicative of a more proactive coping strategy. Together, these findings indicate that noradrenergic neurons provide a significant source of galanin to discrete brain areas, and noradrenergic-specific galanin opposes adaptive coping responses.
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Acknowledgements
This study was supported in part by the Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine and the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. This work was supported by the Intramural Research Program of the NIH, NIEHS (ES102805 to PJ) and the Extramural Research Program of NIH (MH116622 to RPT, DA038453 and AG047667 to DW). The authors declare no conflict of interest. All procedures related to the use of animals were approved by the Animal Care and Use Committee of the NIEHS and Emory University and were in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals.
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We thank Philip V. Holmes, Jessica Hooversmith, Hannah Yoder, and Diane D’Agostin for their technical assistance. Valuable support was provided by the NIEHS Fluorescence Microscopy and Imaging and Transgenic Cores. RPT, NRS, PJ, and DW conceived, designed, and supervised the project. PJ and NWP created the Dbhcre and GalcKO mouse lines. Immunohistochemistry, in situ hybridization, and image acquisition was performed by RPT, NRS, KGS, MH, and JMP. Fiber quantification was performed by MH, JMP, and NRS. Behavioral and neurochemical experiments were performed by RPT under the guidance of DW. DL assisted with neurochemical experiments. Mouse husbandry and genotyping at Emory University were performed by CJ. RPT, NRS, PJ, and DW wrote the manuscript with input from co-authors.
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Tillage, R.P., Sciolino, N.R., Plummer, N.W. et al. Elimination of galanin synthesis in noradrenergic neurons reduces galanin in select brain areas and promotes active coping behaviors. Brain Struct Funct 225, 785–803 (2020). https://doi.org/10.1007/s00429-020-02035-4
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DOI: https://doi.org/10.1007/s00429-020-02035-4