BRAIN STATE SHAPES THE INTRINSIC SENDER-TO-RECEIVER ARCHITECTURE OF THE MOUSE BRAIN

Resting-state fMRI robustly captures intrinsic brain dynamics, however standard, undirected functional connectivity cannot distinguish regions that drive network-wide activity (“senders”) from those that follow it (“receivers”). This limitation matters, because brain-state transitions associated with cognition, arousal, or neuropsychiatric phenotypes can emerge without anatomical rewiring, and may reflect reconfigurations of communication routing beyond what undirected connectivity can capture. Here, we use Transfer Entropy (TE) and resting-state fMRI to characterize brain-wide directed information flow in the resting mouse brain. We optimized a TE framework for mouse fMRI, enabling the quantification of directed interactions both across brain states and under targeted manipulations. We find that brain communication is organized along a sender-to-receiver axis that robustly reconfigures across brain states. Under sedation-induced low arousal, regions of the default mode network (DMN) and primary somatosensory cortices act as information senders, whereas the motor cortex and insula serve as receivers. Notably, this functional sender-to-receiver organization diverges from the corresponding axis in the structural connectome. Consistent with this dissociation, a mouse model of autism shows altered information flow without detectable axonal remodelling. In awake mice, this axis largely reorganizes, with arousal- and interoceptive-related regions like the basal forebrain (BF), insula and hypothalamus becoming prominent senders, and peri-hippocampal cortices shifting to a receiving role. Supporting a key role of the BF in orchestrating cortical dynamics, targeted BF ablation in awake mice substantially reconfigures the directional architecture of the DMN. Together, these results demonstrate that the mammalian brain is intrinsically organized into a robust yet flexible, state-dependent sender-to-receiver architecture.