Complementary Organization of Driver and Modulator Cortico-Thalamo-Cortical Circuits

Abstract Corticocortical (CC) projections in the visual system facilitate the hierarchical processing of sensory information. In addition to direct CC connections, indirect cortico-thalamo-cortical (CTC) pathways through the pulvinar nucleus of the thalamus can relay sensory signals and mediate interactions between areas according to behavioral demands. While the pulvinar is extensively connected to the entire visual cortex, it is unknown whether transthalamic pathways link all cortical areas or whether they follow systematic organizational rules. Because pulvinar neurons projecting to different cortical areas are spatially intermingled, their input/output relationships have been difficult to characterize using traditional anatomical methods. To determine the organization of CTC circuits, we mapped the higher visual areas (HVAs) of mice with intrinsic signal imaging and targeted five pulvinar→HVA pathways for projection-specific rabies tracing. We aligned post- mortem cortical tissue to in vivo maps for precise quantification of the areas and cell types projecting to each pulvinar→HVA population. Layer 5 corticothalamic (L5CT) “driver” inputs to the pulvinar originate predominantly from primary visual cortex (V1), consistent with the CC hierarchy. L5CT inputs from lateral HVAs specifically avoid driving reciprocal connections, consistent with the “no-strong-loops” hypothesis. Conversely, layer 6 corticothalamic (L6CT) “modulator” inputs are distributed across areas and are biased toward reciprocal connections. Unlike previous studies in primates, we find that every HVA receives disynaptic input from the superior colliculus. CTC circuits in the pulvinar thus depend on both target HVA and input cell type, such that driving and modulating higher-order pathways follow complementary connection rules similar to those governing first-order CT circuits. Significance Statement Understanding the functional role of the visual pulvinar will require knowledge of its anatomical connections. Using state-of-the-art rabies tracing, we establish a comprehensive map of brain-wide and CTC pulvinar connections. While the tectopulvinar pathway in primates selectively targets dorsal visual areas, we find SC input to every projection population in the mouse. This extrageniculate projection can support unconscious visually-guided behavior, suggesting that in mice all visual cortical areas contribute to such functions. Our results also unify several longstanding theories of thalamocortical anatomy. Namely, “driver” CTC inputs are feedforward relays that mirror the CC hierarchy and adhere to the “no-strong-loops” hypothesis. “Modulator” L6CT inputs to pulvinar→HVA projections are overrepresented in the target HVA, reflecting the reciprocal connectivity described in previous bulk tracing studies. Together, these findings constitute a definitive and comprehensive map which can inform future physiological experiments and theoretical models of pulvinar function.