Traditionally, the transfer of information between cortical areas has been attributed to direct monosynaptic projections. However, there is a growing recognition that communication between cortical areas is also accomplished through di-synaptic cortico-thalamo-cortical (transthalamic) pathways through higher-order (HO) thalamic nuclei. These circuits are driven by descending layer 5 (L5) corticothalamic projections that robustly activate HO thalamic nuclei.

This dissertation investigates the role of L5-initiated transthalamic pathways in sensory-guided decision-making across visual and somatosensory systems in mice. Using targeted optogenetic inhibition to selectively suppress L5 projections from primary sensory cortex to HO thalamus, we interrupt the first leg of these transthalamic pathways while leaving surrounding circuitry intact. Our findings demonstrate that L5-transthalamic pathways are essential for accurate perceptual discrimination.

In the visual system, inhibiting L5 projections from primary visual cortex (V1) to the HO thalamic nucleus pulvinar disrupted visual discrimination performance, even with direct corticocortical projections unaffected. Similarly, suppressing L5 corticothalamic input disrupted whisker-based texture discrimination in the somatosensory system. Two-photon imaging of neurons in primary (S1) and secondary (S2) somatosensory cortex further revealed a role for transthalamic circuits in establishing task-dependent salience signals in higher-order cortex. These results highlight the importance of including L5-initiated transthalamic circuits in cortical processing frameworks, especially when addressing how the hierarchical propagation of sensory signals supports perceptual decision-making.