Neurons embedded in loop-like motifs act as central hubs for brain-wide integration.

Efficient cooperation between brain areas requires a dynamic balance between the segregation of region-specific functional roles and information broadcasting. Imaging studies of brain-wide co-ordination cannot reach the single-cell assembly level analysis. In this study, we explored co-ordinative relationships between single neurons across 71 mouse brain regions using the concept of cell assembly as an investigative tool. Cell assemblies can be considered the fundamental brain processing units, and identifying their aggregate structure can provide a high-resolution view of inter-regional co-ordinative relationships. We first examined pairwise co-ordination between areas, and then we investigated higher-order forms of inter-regional connectivity, searching for triplets of neurons. We mainly focused on one functionally relevant motif: the loop-like triplet, modelling a reentrant flow of information, which we hypothesised could represent a core mechanism for the integration of information. We found that this reentrant mode of communication was often asymmetrical between areas and largely unrelated to neuron pair co-ordination. We found that hub neurons, which have a higher-than-average number of co-ordinative relationships with external regions, are consistently and significantly embedded in loop-like assemblies. These findings suggest that this peculiar motif represents a core architectural feature supporting brain-wide integration. KEY POINTS: Cell assembly detection allows the identification of motifs of inter-regional co-ordination. Loop-like motifs of co-ordination are heterogeneously distributed across the brain. External hub neurons are consistently and brain-wide embedded in loop-like motifs. Loop-like motifs appear as an integration-oriented structure of co-ordination.