Reciprocal interactions between the prefrontal cortex (PFC) and thalamus play a critical role in cognition, but the underlying circuits remain poorly understood. Here we use optogenetics to dissect the specificity and dynamics of cortico-thalamo-cortical networks in the mouse brain. We find that cortico-thalamic (CT) neurons in prelimbic PFC project to both mediodorsal (MD) and ventromedial (VM) thalamus, where layer 5 and 6 inputs activate thalamo-cortical (TC) neurons with distinct temporal profiles. We show that TC neurons in MD and VM in turn make distinct connections in PFC, with MD preferentially and strongly activating layer 2/3 cortico-cortical (CC) neurons. Finally, we assess local connections from superficial CC to deep CT neurons, which link thalamo-cortical and cortico-thalamic networks within the PFC. Together our findings indicate that PFC strongly drives neurons in the thalamus, whereas MD and VM indirectly influence reciprocally connected neurons in the PFC, providing a mechanistic understanding of these circuits. Collins, Anastasiades et al. show that prefrontal cortex (PFC) engages multiple thalamic nuclei. Dorsal and ventral thalamus in turn target distinct networks within the PFC. Finally, local connectivity in the PFC completes a loop connecting thalamic input with cortico-thalamic output.
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