Mapping the mouse connectome with voxel resolution

Fine-grained descriptions of brain connectivity are required to understand how neural information is processed and relayed across spatial scales. Prior investigations of the mouse brain connectome have employed discrete anatomical parcellations, limiting spatial resolution and potentially concealing network attributes critical to connectome organization. In this work, we provide a voxel-level description of the network and hierarchical structure of the directed mouse connectome, unconstrained by regional partitioning. We found that hub regions and core network components of the voxel-wise mouse connectome exhibit a rich topography encompassing key cortical and subcortical relay regions. We also typified regional substrates based on their directional topology into sink or source regions, and reported a previously unappreciated role of modulatory nuclei as critical effectors of inter-modular and network communicability. Finally, we demonstrated a close spatial correspondence between the mesoscale topography of the mouse connectome and its functional macroscale organization, showing that, like in primates and humans, the mouse cortical connectome is organized along two major topographical axes that can be linked to hierarchical patterns of laminar connectivity, and shape the topography of fMRI dynamic states, respectively. This investigation was paralleled by further studies aimed to more closely relate structural connectome features to the corresponding large scale functional networks of the mouse brain. We first focused on the mouse default mode network (DMN), describing its axonal substrates with sublaminar precision and cell-type specificity. We found that regions of the mouse DMN are predominantly located within the isocortex and exhibit preferential connectivity. Dedicated tract tracing experiments carried out by the Allen Brain Institute revealed that layer 2/3 DMN neurons projected mostly in the DMN, whereas layer 5 neurons project both in and out. Further analyses revealed the presence of separate in-DMN and out-DMN-projecting cell types with distinct genetic profiles. Lastly, we carried out a fine-grained comparison of functional topography and dynamic organization of large-scale fMRI networks in wakeful and anesthetized mice, relating the corresponding functional networks to the underlying architecture of structural connectivity. Recapitulating prior observations in conscious primates, we found that the awake mouse brain is subjected to a profound topological reconfiguration such to maximize cross-talk between cortical and subcortical neural systems, departing from the underlying structure of the axonal connectome. Taken together, these results advance our understanding of the foundational wiring principles of the mammalian connectome, and create opportunities for identifying targets of interventions to modulate brain function and its network structure in a physiologically-accessible species.