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 beta-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.

Highlights

  • 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

  • To study how transition metals are used in the brain, we focused on the copper-rich LC region, which has broad projections throughout the central nervous system

  • The LC is distinguished as the principal source of NE synthesis in the central nervous system (CNS), mediated exclusively by the copper-dependent enzyme DBH

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Summary

Introduction

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. For reasons that remain insufficiently understood, the unique biology of the brain as the center of consciousness is underpinned by its unique chemistry involving accumulating select elements at higher concentrations than anywhere else in the body[1,2] These include redox-active transition metals such as copper and iron[2], in part because the brain is the body’s most oxidatively active organ, comprising just 2% of body weight but requiring 20% of oxygen consumption. Copper pools are regulated by several copper transporters[14,15], including the high affinity copper transporter, CTR1 ( known as SLC31A1), as well as metallochaperones that deliver copper to various destinations within the cytosol and organelles[16,17,18] In this context, the copper-dependent ATPases ATP7A and ATP7B serve the dual purpose of metalating proteins and/or controlling copper efflux from the cell[4,19]. The data identify an essential role for copper in the evolution and function of the LC-NE through a molecular CTR1–ATP7A–DBH–NE axis, including a role for copper in the regulation of sleep-related and arousal behaviors

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