Logic of brain-wide connections with the cerebellar cortex

The cerebellum governs movement and cognition through multiple lobules that carry distinct signals and connect to distinct long-range brain networks. How these specialized computations are reconciled with the brain-wide convergence required for coherent behaviour is unknown, in part because the input-output connectivity of functionally distinct lobules has not been mapped. We combined anterograde and retrograde transsynaptic viral tracing with whole-brain two-photon tomography to map the monosynaptic and disynaptic inputs and outputs of Lobule V (LV) and Simplex (LS), two lobules preferentially involved in movement and reward, respectively. Monosynaptic connectivity was strongly segregated: LV and LS received climbing fiber and mossy fiber inputs from largely non-overlapping source regions and projected to distinct targets within the cerebellar nuclei. In contrast, disynaptic inputs to LV- and LS-projecting olivary neurons arose from a shared set of forebrain, midbrain, and hindbrain regions, with the segregation re-emerging at the level of fine-scale spatial topography within these regions. Disynaptic outputs through the cerebellar nuclei likewise overlapped more than the monosynaptic projections to the nuclei themselves. These findings reveal that overlapping brain-wide pathways interface with locally specialized monosynaptic cerebellar pathways. This organizational logic could support distinct movement- and reward-related computations in the cerebellum while distributing outputs to shared downstream networks, providing an architectural substrate for both segregating and integrating cerebellar motor and cognitive functions.