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.

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SUMMARY Excitation and inhibition are highly specific in the cortex, with distinct synaptic connections made onto subtypes of projection neurons. The functional consequences of this selective connectivity depend on both synaptic strength and the intrinsic properties of targeted neurons but remain poorly understood. Here, we examine responses to callosal inputs at cortico-cortical (CC) and cortico-thalamic (CT) neurons in layer 5 of mouse prelimbic prefrontal cortex (PFC). We find callosally evoked excitation and feedforward inhibition are much stronger at CT neurons compared to neighboring CC neurons. Elevated inhibition at CT neurons reflects biased synaptic inputs from parvalbumin and somatostatin positive interneurons. The intrinsic properties of postsynaptic targets equalize excitatory and inhibitory response amplitudes but selectively accelerate decays at CT neurons. Feedforward inhibition further reduces response amplitude and balances action potential firing across these projection neurons. Our findings highlight the synaptic and cellular mechanisms regulating callosal recruitment of layer 5 microcircuits in PFC.

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GABAergic interneurons play key roles in cortical circuits, yet little is known about their early connectivity. Here we use glutamate uncaging and a novel optogenetic strategy to track changes in the afferent and efferent synaptic connections of developing neocortical interneuron subtypes. We find that Nkx2-1-derived interneurons possess functional synaptic connections before emerging pyramidal cell networks. Subsequent interneuron circuit maturation is both subtype and layer dependent. Glutamatergic input onto fast spiking (FS), but not somatostatin-positive, non-FS interneurons increases over development. Interneurons of both subtype located in layers (L) 4 and 5b engage in transient circuits that disappear after the somatosensory critical period. These include a pathway mediated by L5b somatostatin-positive interneurons that specifically targets L4 during the first postnatal week. The innervation patterns of immature cortical interneuron circuits are thus neither static nor progressively strengthened but follow a layer-specific choreography of transient connections that differ from those of the adult brain.