Norepinephrine-mediated arousal fluctuations drive inverted U-shaped functional connectivity dynamics

Arousal states dynamically shape brain function and behavioral performance, as posited by the Yerkes-Dodson law. Yet, functional network substrates underlying this inverted U-shaped pattern remain unknown. Here, by integrating functional magnetic resonance imaging (fMRI) with simultaneous electroencephalography (EEG) across humans and awake mice, we found arousal modulated inverted U-shaped global functional connectivity (FC) dynamics, peaking at middle arousal level. Such inverted U-shaped FC exhibited significant correlation with arousal modulated behavioral performance, recapitulating the Yerkes-Dodson framework at the functional network level. Further combining invasive multimodal neural recording and manipulations of locus coeruleus-norepinephrine (LC-NE) neurons with awake mouse EEG-fMRI, we revealed the causal contribution of LC-NE system to arousal modulated FC dynamics, in which the inverted U-shaped pattern was dependent on the baseline arousal level. To summarize, we uncovered the functional network basis of the Yerkes-Dodson law, which was causally driven by the NE-mediated arousal fluctuations. Tong and colleagues reveal a cross-species conserved mechanism where locus coeruleus-norepinephrine mediated arousal fluctuations drive an inverted U-shaped pattern of global functional connectivity, uncovering a network basis of the Yerkes-Dodson law.