TY - JOUR
T1 - Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system
AU - Xiao, Tong
AU - Ackerman, Cheri M.
AU - Carroll, Elizabeth C.
AU - Jia, Shang
AU - Hoagland, Adam
AU - Chan, Jefferson
AU - Thai, Bao
AU - Liu, Christine S.
AU - Isacoff, Ehud Y.
AU - Chang, Christopher J.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048019562&partnerID=8YFLogxK
U2 - 10.1038/s41589-018-0062-z
DO - 10.1038/s41589-018-0062-z
M3 - Article
AN - SCOPUS:85048019562
SN - 1552-4450
SP - 1
EP - 9
JO - Nature Chemical Biology
JF - Nature Chemical Biology
ER -