Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system

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Abstract

The unusually high demand for metals in the brain, along with insufficient understanding of how their dysregulation contributes to neurological diseases, motivates the study of how inorganic chemistry influences neural circuitry. We now report that the transition metal copper is essential for regulating rest–activity cycles and arousal. Copper imaging and gene expression analysis in zebrafish identifies the locus coeruleus–norepinephrine (LC-NE) system, a vertebrate-specific neuromodulatory circuit critical for regulating sleep, arousal, attention, memory and emotion, as a copper-enriched unit with high levels of copper transporters CTR1 and ATP7A and the copper enzyme dopamine β-hydroxylase (DBH) that produces NE. Copper deficiency induced by genetic disruption of ATP7A, which loads copper into DBH, lowers NE levels and hinders LC function as manifested by disruption in rest–activity modulation. Moreover, LC dysfunction caused by copper deficiency from ATP7A disruption can be rescued by restoring synaptic levels of NE, establishing a molecular CTR1–ATP7A–DBH–NE axis for copper-dependent LC function.

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Fig. 1: Molecular imaging reveals distributions of labile copper in the living brain.
Fig. 2: LA-ICP-MS imaging reveals heterogeneous copper distribution patterns in the brain during development.
Fig. 3: Dysregulation of brain copper homeostasis alters arousal and rest–activity behavior.
Fig. 4: Copper transporter gene expression is highly and specifically enriched in LC.
Fig. 5: LC-NE circuitry mediates copper-regulated behaviors.
Fig. 6: Copper transporter gene duplication coincides with the rise of brain NE levels and NE transport in Gnathostomata.

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Acknowledgements

We thank A. T. Look (Dana-Farber Cancer Institute) and J. Gitlin (Marine Biological Laboratory) for providing plasmids and transgenic fish lines, C. Miller (University of California, Berkeley) and R. Segev (Ben Gurion University of the Negev) for providing fish samples, and R. Feng and R. Fish for assistance with pilot experiments. We thank the NIH (GM79465 to C.J.C. and PN2EY018241 to E.Y.I.) for providing funding for this work. C.J.C. is an Investigator of the Howard Hughes Medical Institute and a CIFAR Senior Fellow. C.M.A. was partially supported by a Hertz Foundation Graduate Fellowship and a Chemical Biology Training Grant from the NIH (T32 GM066698). Experiments at the CRL Molecular Imaging Center were supported by the Helen Wills Neuroscience Institute.

Author information

T.X. and C.J.C. designed research; T.X., C.M.A., E.C.C. and A.H. performed imaging and behavioral assays; T.X., C.M.A. and B.T. performed copper imaging and analysis assays; S.J. and J.C. synthesized and characterized fluorescent copper probes; T.X. and C.S.L. conducted in situ hybridization and IHC assays; T.X., C.M.A., E.C.C. and C.J.C. wrote the manuscript; E.Y.I. provided valuable input on the manuscript.

Correspondence to Christopher J. Chang.

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Xiao, T., Ackerman, C.M., Carroll, E.C. et al. Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system. Nat Chem Biol 14, 655–663 (2018) doi:10.1038/s41589-018-0062-z

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