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

Tong Xiao, Cheri M. Ackerman, Elizabeth C. Carroll, Shang Jia, Adam Hoagland, Jefferson Chan, Bao Thai, Christine S. Liu, Ehud Y. Isacoff, Christopher J. Chang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)655-663
Number of pages9
JournalNature chemical biology
Volume14
Issue number7
DOIs
StatePublished - Jul 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Xiao, T., Ackerman, C. M., Carroll, E. C., Jia, S., Hoagland, A., Chan, J., Thai, B., Liu, C. S., Isacoff, E. Y., & Chang, C. J. (2018). Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system. Nature chemical biology, 14(7), 655-663. https://doi.org/10.1038/s41589-018-0062-z