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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Appropriate integration of GABAergic interneurons into nascent cortical circuits is critical for ensuring normal information processing within the brain. Network and cognitive deficits associated with neurological disorders, such as schizophrenia, that result from NMDA receptor-hypofunction have been mainly attributed to dysfunction of parvalbumin-expressing interneurons that paradoxically express low levels of synaptic NMDA receptors. Here, we reveal that throughout postnatal development, thalamic, and entorhinal cortical inputs onto hippocampal neurogliaform cells are characterized by a large NMDA receptor-mediated component. This NMDA receptor-signaling is prerequisite for developmental programs ultimately responsible for the appropriate long-range AMPAR-mediated recruitment of neurogliaform cells. In contrast, AMPAR-mediated input at local Schaffer-collateral synapses on neurogliaform cells remains normal following NMDA receptor-ablation. These afferent specific deficits potentially impact neurogliaform cell mediated inhibition within the hippocampus and our findings reveal circuit loci implicating this relatively understudied interneuron subtype in the etiology of neurodevelopmental disorders characterized by NMDA receptor-hypofunction.

Placental transfer of Δ9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid regulation of fetal nervous system development in utero. Here we examined the effect of maternal cannabinoid intake on mouse hippocampal interneurons largely focusing on cholecystokinin containing interneurons (CCK-INTs), a prominent cannabinoid subtype 1 receptor (CB1R) expressing neuronal population throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed decreased dendritic complexity. Consistent with these anatomical deficits, pups born to cannabinoid treated dams exhibited compromised CCK-INT mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R mediated suppression of inhibition from residual CCK-INTs, and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers that abuse marijuana during pregnancy.

150 Introduction: 630 Results: 3,236 Discussion: 1,357 Figures: 8 + 8 supplementary figures + 2 supplementary tables ACKNOWLEDGEMENTSWe thank the Carter lab for helpful discussions and comments on the manuscript. This work was supported by NIH T32 GM007308 (DPC) and NIH R01 MH085974 (AGC).

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Review of K. Guo et al.Ongoing communication between cortex and thalamus plays an important role in cognition, sensation, and motor function. The synaptic basis of cortico-thalamocortical interactions has been a field of intense study over many decades, often going hand-in-hand with studies of activity recorded in vivo. In the classical model of cortico-thalamo-cortical circuits, derived largely from studies of primary sensory cortices (e.g., S1, V1, A1), ascending input from sensory thalamus undergoes cortical processing, before being relayed back to thalamus via two distinct populations of deep-layer projection neurons (Guillery and Sherman, 2002). Layer (L)5 pyramidal tract (PT) neurons provide "driver" input to higher-order thalamic nuclei, which relay this information to the next region of the sensory hierarchy (e.g., S2, V2, A2) ( Fig. 1A) and provide feedback to primary sensory cortices. In contrast, L6 cortico-thalamic (CT) cells provide "modulator" feedback to the primary sensory thalamic nucleus and target the thalamic reticular nucleus (TRN) to drive thalamic feedforward inhibition ( Fig. 1A). This architecture facilitates information flow up the hierarchy of sensory processing, with thalamus functioning as a relay between cortical regions (Guillery and Sherman, 2002) ( Fig. 1A).The organization of cortico-thalamocortical circuits in higher-order cortices has been proposed to diverge from the classical sensory model, with connections instead organized in reciprocal "loops" (Svoboda and Li, 2018). Studying the synaptic organization of these circuits has been challenging due to the inability to produce ex vivo slices with intact connectivity between higher-order cortices, TRN, and thalamus, a preparation that has greatly facilitated study of thalamocortical circuits in sensory regions (Agmon and Connors, 1991). A recent study by K. Guo et al. (2018) harnessed the power of optogenetics to overcome these anatomical constraints.K. Guo et al. (2018) focused on interactions between ventromedial thalamus (VM), a higher-order thalamic nucleus that receives input from the basal ganglia and cerebellum, and anterolateral motor cortex (ALM), a region of frontal cortex involved in motor planning. Reciprocal connections between VM and ALM have recently been shown to play an important role in sustaining activity while mice plan to perform a movement in response to a tactile signal (Z. V. Guo et al., 2017). Therefore, understanding the organiza-tion of this circuit is important to determining neural mechanisms of motor planning and is of broad interest to deciphering how higher-order cortico-thalamocortical loops support cognitive processing. Because detailed understanding of the circuit between VM and ALM requires knowledge of input-, layer-, and cell typespecific connectivity, K. Guo et al. (2018) used retrograde tracers to define projection neuron populations in individual layers: CT neurons in L6 (labeled via injection in VM), PT neurons in L5B (labeled via injection in the pons), and unlabeled cells in L2/3. They ...

The innervation of taste buds is an excellent model system for studying the guidance of axons during targeting because of their discrete nature and the high fidelity of innervation. The pregustatory epithelium of fungiform papillae is known to secrete diffusible axon guidance cues such as BDNF and Sema3A that attract and repel, respectively, geniculate ganglion axons during targeting, but diffusible factors alone are unlikely to explain how taste axon terminals are restricted to their territories within the taste bud. Nondiffusible cell surface proteins such as Ephs and ephrins can act as receptors and/or ligands for one another and are known to control axon terminal positioning in several parts of the nervous system, but they have not been studied in the gustatory system. We report that ephrin-B2 linked β-galactosidase staining and immunostaining was present along the dorsal epithelium of the mouse tongue as early as embryonic day 15.5 (E15.5), but was not detected at E14.5, when axons first enter the epithelium. Ephrin-B1 immunolabeling was barely detected in the epithelium and found at a somewhat higher concentration in the mesenchyme subjacent to the epithelium. EphB1 and EphB2 were detected in lingual sensory afferents in vivo and geniculate neurites in vitro. Ephrin-B1 and ephrin-B2 were similarly effective in repelling or suppressing outgrowth by geniculate neurites in vitro. These in vitro effects were independent of the neurotrophin used to promote outgrowth, but were reduced by elevated levels of laminin. In vivo, mice null for EphB1 and EphB2 exhibited decreased gustatory innervation of fungiform papillae. These data provide evidence that ephrin-B forward signaling is necessary for normal gustatory innervation of the mammalian tongue.