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.

大脑对金属的异常高需求，以及对它们的失调如何导致神经系统疾病的认识不足，激发了对无机化学如何影响神经回路的研究。我们现在报告过渡金属铜对于调节休息活动周期和唤醒至关重要。斑马鱼的铜成像和基因表达分析确定了蓝斑-去甲肾上腺素 (LC-NE) 系统，这是一种脊椎动物特有的神经调节电路，对调节睡眠、唤醒、注意力、记忆和情绪至关重要，它是一种富含铜的单元，具有高水平的铜转运蛋白 CTR1 和 ATP7A 以及产生 NE 的铜酶多巴胺 β-羟化酶 (DBH)。ATP7A 基因破坏导致铜缺乏，ATP7A 将铜加载到 DBH 中，降低 NE 水平并阻碍 LC 功能，表现为休息活动调节的中断。此外，由 ATP7A 破坏引起的铜缺乏引起的 LC 功能障碍可以通过恢复 NE 的突触水平来挽救，为铜依赖性 LC 功能建立分子 CTR1-ATP7A-DBH-NE 轴。