The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells (“layer 6b cells”) taking advantage of the transgenic mouse Tg(Drd1a-cre)FK164Gsat/Mmucd (Drd1a-Cre), that selectively expresses Cre-recombinase in a subpopulation of layer 6b neurons across the entire cortical mantle. At P8, 18% of layer 6b neurons are labeled with Drd1a-Cre::tdTomato in somatosensory cortex (SS), and some co-express known layer 6b markers. Using Cre-dependent viral tracing, we identified topographical projections to higher order thalamic nuclei. VGluT1+ synapses formed by labeled layer 6b projections were found in posterior thalamic nucleus (Po) but not in the (pre)thalamic reticular nucleus (TRN). The lack of TRN collaterals was confirmed with single-cell tracing from SS. Transmission electron microscopy comparison of terminal varicosities from layer 5 and layer 6b axons in Po showed that L6b varicosities are markedly smaller and simpler than the majority from L5. Our results suggest that L6b projections to the thalamus are distinct from both L5 and L6a projections.

The mechanisms responsible for the generation of LGI1- or CASPR2-antibodies are unknown. Binks et al. describe two strikingly dichotomous HLA-associations, most significantly in HLA-DRB1*07:01 for LGI1, and HLA-DRB1*11:01 for CASPR2. Prediction of antigen-specific HLA-binding peptides generates testable hypotheses for T cell identification.

Corticothalamic projection systems arise from 2 main cortical layers. Layer V neurons project exclusively to higher-order thalamic nuclei, while layer VIa fibers project to both first-order and higher-order thalamic nuclei. During early postnatal development, layer VIa and VIb fibers accumulate at the borders of the dorsal lateral geniculate nucleus (dLGN) before they innervate it. After neonatal monocular enucleation or silencing of the early retinal activity, there is premature entry of layer VIa and VIb fibers into the dLGN contralateral to the manipulation. Layer V fibers do not innervate the superficial gray layer of the superior colliculus during the first postnatal week, but also demonstrate premature entry to the contralateral superficial gray layer following neonatal enucleation. Normally, layer V driver projections to the thalamus only innervate higher-order nuclei. Our results demonstrate that removal of retinal input from the dLGN induces cortical layer V projections to aberrantly enter, arborize, and synapse within the first-order dLGN. These results suggest that there is cross-hierarchical corticothalamic plasticity after monocular enucleation. Cross-hierarchical rewiring has been previously demonstrated in the thalamocortical system (Pouchelon et al. 2014), and now we provide evidence for cross-hierarchical corticothalamic rewiring after loss of the peripheral sensory input.

In this review we discuss recent advances in the understanding of corticothalamic axon guidance; patterning of the early telencephalon, the sequence and choreography of the development of projections from subplate, layers 5 and 6. These cortical subpopulations display different axonal outgrowth kinetics and innervate distinct thalamic nuclei in a temporal pattern determined by cortical layer identity and subclass specificity. Guidance by molecular cues, structural cues, and activity-dependent mechanisms contribute to this development. There is a substantial rearrangement of the corticofugal connectivity outside the thalamus at the border of and within the reticular thalamic nucleus, a region that shares some of the characteristics of the cortical subplate during development. The early transient circuits are not well understood, nor the extent to which this developmental pattern may be driven by peripheral sensory activity. We hypothesize that transient circuits during embryonic and early postnatal development are critical in the matching of the cortical and thalamic representations and forming the cortical circuits in the mature brain.