Structural Basis of Large-Scale Functional Connectivity in the Mouse

Translational neuroimaging requires approaches and techniques that can bridge between multiple different species and disease states. One candidate method that offers insights into the brain's functional connectivity (FC) is resting-state fMRI (rs-fMRI). In both humans and nonhuman primates, patterns of FC (often referred to as the functional connectome) have been related to the underlying structural connectivity (SC; also called the structural connectome). Given the recent rise in preclinical neuroimaging of mouse models, it is an important question whether the mouse functional connectome conforms to the underlying SC. Here, we compared FC derived from rs-fMRI in female mice with the underlying monosynaptic structural connectome as provided by the Allen Brain Connectivity Atlas. We show that FC between interhemispheric homotopic cortical and hippocampal areas, as well as in cortico-striatal pathways, emerges primarily via monosynaptic structural connections. In particular, we demonstrate that the striatum (STR) can be segregated according to differential rs-fMRI connectivity patterns that mirror monosynaptic connectivity with isocortex. In contrast, for certain subcortical networks, FC emerges along polysynaptic pathways as shown for left and right STR, which do not share direct anatomical connections, but high FC is putatively driven by a top-down cortical control. Finally, we show that FC involving cortico-thalamic pathways is limited, possibly confounded by the effect of anesthesia, small regional size, and tracer injection volume. These findings provide a critical foundation for using rs-fMRI connectivity as a translational tool to study complex brain circuitry interactions and their pathology due to neurological or psychiatric diseases across species.SIGNIFICANCE STATEMENT A comprehensive understanding of how the anatomical architecture of the brain, often referred to as the "connectome," corresponds to its function is arguably one of the biggest challenges for understanding the brain and its pathologies. Here, we use the mouse as a model for comparing functional connectivity (FC) derived from resting-state fMRI with gold standard structural connectivity measures based on tracer injections. In particular, we demonstrate high correspondence between FC measurements of cortico-cortical and cortico-striatal regions and their anatomical underpinnings. This work provides a critical foundation for studying the pathology of these circuits across mouse models and human patients.