Corticothalamic pathways, responsible for the top-down control of the thalamus display a classical, canonical organization in that every cortical region sends dual, layer 6 (L6) and layer 5 (L5) output to the thalamus. Here we demonstrate a qualitative, region-specific difference in the organization of corticothalamic pathways. We show that L5 pyramidal cells of the frontal, but not other cortical regions establish monosynaptic connection with the inhibitory thalamic reticular nucleus (TRN). The frontal L5-TRN pathway paralleled the L6-TRN projection but displayed distinct morphological and physiological features. The exact spike output of the L5 contacted TRN cells correlated with the level of cortical synchrony. Optogenetic perturbation of the L5-TRN connection disrupted the tight link between cortical and TRN activity. L5-driven TRN cells innervated all thalamic nuclei involved in the control of frontal cortical activity. Our data show that frontal cortical functions require a highly specialized cortical control over intrathalamic inhibitory processes.

Corticothalamic pathways, responsible for the top-down control of the thalamus, have a canonical organization such that every cortical region sends output from both layer 6 (L6) and layer 5 (L5) to the thalamus. Here we demonstrate a qualitative, region-specific difference in the organization of mouse corticothalamic pathways. Specifically, L5 pyramidal cells of the frontal cortex, but not other cortical regions, establish monosynaptic connections with the inhibitory thalamic reticular nucleus (TRN). The frontal L5–TRN pathway parallels the L6–TRN projection but has distinct morphological and physiological features. The exact spike output of the L5-contacted TRN cells correlated with the level of cortical synchrony. Optogenetic perturbation of the L5–TRN connection disrupted the tight link between cortical and TRN activity. L5-driven TRN cells innervated thalamic nuclei involved in the control of frontal cortex activity. Our data show that frontal cortex functions require a highly specialized cortical control over intrathalamic inhibitory processes.