Many theories propose recurrent interactions across the cortical hierarchy, but it is unclear if cortical circuits are selectively wired to implement looped computations. Using subcellular channelrhodopsin-2-assisted circuit mapping in mouse visual cortex, we compared feedforward (FF) or feedback (FB) cortico-cortical synaptic input to cells projecting back to the input source (looped neurons) with cells projecting to a different cortical or subcortical area. FF and FB afferents showed similar cell-type selectivity, making stronger connections with looped neurons than with other projection types in layer (L) 5 and L6, but not in L2/3, resulting in selective modulation of activity in looped neurons. In most cases, stronger connections in looped L5 neurons were located on their apical tufts, but not on their perisomatic dendrites. Our results reveal that cortico-cortical connections are selectively wired to form monosynaptic excitatory loops and support a differential role of supragranular and infragranular neurons in hierarchical recurrent computations.

Many theories propose recurrent interactions across the cortical hierarchy, but it is unclear if cortical circuits are selectively wired to implement looped computations. Using subcellular channelrhodopsin-2-assisted circuit mapping in mouse visual cortex, we compared feedforward (FF) or feedback (FB) cortico-cortical input to cells projecting back to the input source (looped neurons) with cells projecting to a different cortical or subcortical area (non-looped neurons). Despite having different laminar innervation patterns, FF and FB afferents showed similar cell-type selectivity, making stronger connections with looped neurons versus nonlooped neurons in layer (L) 5 and L6, but not in L2/3. FB inputs preferentially innervated the apical tufts of looped L5 neurons, but not their perisomatic dendrites. Our results reveal that interareal cortical connections are selectively wired into monosynaptic excitatory loops involving L6 and the apical dendrites of L5 neurons, supporting a role of these circuit elements in hierarchical recurrent computations. Results Neurons with different projection patterns are intermingled in visual areasPrimary visual cortex (V1), the lowest-order area of mouse visual cortex, sends FF projections to the higher-order lateromedial (LM) and anteromedial (AM) visual areas, which in turn reciprocate with FB connections [17][18][19] . Using dual injections of retrograde tracers, we measured the laminar distribution of different projection neurons in V1 and in LM (Figure 1). In each experiment, we compared the laminar distribution of LM-or V1-projecting IT neurons with either IT neurons projecting to AM, PT neurons projecting to the superior colliculus (SC), or CT neurons projecting to the dorsal lateral geniculate nucleus (dLGN) or to the lateral posterior nucleus (LP) of the thalamus. In each case, the different projection neurons were closely intermingled ( Figure 1A,B). In both V1 and LM, IT neurons were distributed across all layers except L1, including L4 19,20 , indicating that FF and FB projections originate from neurons spanning most of the cortical depth. In contrast, PT and CT neurons were confined to L5 and L5/6, respectively, as previously described 4 (Figure 1A,B). In both V1 and LM, we found double-labeled IT neurons in L2-6 after injecting tracers in two different cortical areas, indicating that subpopulations of ascending and descending projection neurons have diverging axons innervating more

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