Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term “chemo-connectomics.” We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection. [Display omitted] •Chemo-connectomics combines chemogenetics (DREADDs) with resting-state fMRI•Locus coeruleus (LC) activation rapidly increases brain-wide functional connectivity•Connectivity changes correlate positively with adrenergic receptor distribution•LC activation shifts large-scale network connectivity toward salience processing Zerbi et al. selectively activate the mouse locus coeruleus, which provides norepinephrine to the brain. This induces anxiety and rapidly shifts network connectivity toward salience and fear processing. This appears to be mediated by the spatial distribution of adrenergic receptors.