Functional imaging evidence for task-induced deactivation and disconnection of a major default mode network hub in the mouse brain

Abstract

Significance Our report first validates an imaging technique, functional ultrasound, an experimental approach providing significantly higher sensitivity and spatiotemporal resolution than fMRI, for the study of sensory stimulation-induced changes in activation and connectivity patterns in the awake mouse brain. Next, by using this approach in lightly sedated conscious mice, we provide functional evidence supporting an evolutionary preserved function of the default mode network, a set of highly connected brain areas, which is characteristically impaired in major neuropsychiatric diseases in humans. Uncovering the existence and function of the default mode network in mice, the main preclinical model organism for neuropsychiatric diseases, opens new avenues of high translational relevance for brain research and drug development. The default mode network (DMN) has been defined in functional brain imaging studies as a set of highly connected brain areas, which are active during wakeful rest and inactivated during task-based stimulation. DMN function is characteristically impaired in major neuropsychiatric diseases, emphasizing its interest for translational research. However, in the mouse, a major preclinical rodent model, there is still no functional imaging evidence supporting DMN deactivation and deconnection during high-demanding cognitive/sensory tasks. Here we have developed functional ultrasound (fUS) imaging to properly visualize both activation levels and functional connectivity patterns, in head-restrained awake and behaving mice, and investigated their modulation during a sensory-task, whisker stimulation. We identified reproducible and highly symmetric resting-state networks, with overall connectivity strength directly proportional to the wakefulness level of the animal. We show that unilateral whisker stimulation leads to the expected activation of the contralateral barrel cortex in lightly sedated mice, while interhemispheric inhibition reduces activity in the ipsilateral barrel cortex. Whisker stimulation also leads to elevated bilateral connectivity in the hippocampus. Importantly, in addition to functional changes in these major hubs of tactile information processing, whisker stimulation during genuine awake resting-state periods leads to highly specific reductions both in activation and interhemispheric correlation within the restrosplenial cortex, a major hub of the DMN. These results validate an imaging technique for the study of activation and connectivity in the lightly sedated awake mouse brain and provide evidence supporting an evolutionary preserved function of the DMN, putatively improving translational relevance of preclinical models of neuropsychiatric diseases.