Chemogenetic activation of Locus Coeruleus Noradrenergic Neurons Modulates the Default Mode Network

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. Dysregulation of DMN has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on DMN in mice. Chemogenetic-induced LC-NE activation decreased cerebral blood volume (CBV) and glucose uptake, while increasing synchronous low frequency power within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing LC-NE activation induces NE release, enhances calcium-weighted neuronal spiking, and reduces CBV in the anterior cingulate cortex. These data suggest the lack of conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthen functional connectivity within the frontal DMN, and this effect is causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.