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Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons

Abstract

During development, thalamocortical (TC) input has a critical role in the spatial delineation and patterning of cortical areas1,2,3,4,5,6, yet the underlying cellular and molecular mechanisms that drive cortical neuron differentiation are poorly understood. In the primary (S1) and secondary (S2) somatosensory cortex, layer 4 (L4) neurons receive mutually exclusive input originating from two thalamic nuclei7,8: the ventrobasalis (VB), which conveys tactile input9,10, and the posterior nucleus (Po), which conveys modulatory and nociceptive input11,12,13,14. Recently, we have shown that L4 neuron identity is not fully committed postnatally15, implying a capacity for TC input to influence differentiation during cortical circuit assembly. Here we investigate whether the cell-type-specific molecular and functional identity of L4 neurons is instructed by the origin of their TC input. Genetic ablation of the VB at birth resulted in an anatomical and functional rewiring of Po projections onto L4 neurons in S1. This induced acquisition of Po input led to a respecification of postsynaptic L4 neurons, which developed functional molecular features of Po-target neurons while repressing VB-target traits. Respecified L4 neurons were able to respond both to touch and to noxious stimuli, in sharp contrast to the normal segregation of these sensory modalities in distinct cortical circuits. These findings reveal a behaviourally relevant TC-input-type-specific control over the molecular and functional differentiation of postsynaptic L4 neurons and cognate intracortical circuits, which instructs the development of modality-specific neuronal and circuit properties during corticogenesis.

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Figure 1: TC input to S1L4 is preserved in vb mice.
Figure 2: Po TC axons are rewired onto S1L4 neurons in vb mice.
Figure 3: VB→Po switch in input congruently respecifies S1L4vb neurons.
Figure 4: Functional convergence of normally segregated sensory modalities in vb mice.

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Acknowledgements

We thank S. Endo for the gift of the G-substrate antibody, N. Aagaard Jensen for the gift of the miR-Zbtb20 construct, F. Ango for the gift of the Sema3a-Tomato construct, and A. Goffinet for the gift of Dlx5/6::Cre/Celsr3flox tissue. We are thankful to A. Benoit and F. Smets for technical assistance, to B. Golding for help with the in situ hybridizations, to O. Schaad, C. Barraclough and M. Docquier of the Genomics Platform of the University of Geneva for help with the microarray experiments. We thank E. Azim and F. Rijli for their comments on the manuscript. Work in the Jabaudon laboratory is supported by the Swiss National Science Foundation (SNF) (PP00P3_123447), the Leenaards Foundation, the Synapsis Foundation and the NARSAD Foundation. C.B. was supported by an Ambizione grant from the SNF and by the Gertrude von Meissner Foundation, C.L. by the SNF and the Simons Foundation Autism Research Initiative (SFARI), and F.C. and A.H. by the SNF (grant 31003A-135631), EMBO, the International Foundation for Research in Paraplegia, and the Hans Wilsdorf Foundation.

Author information

Authors and Affiliations

Authors

Contributions

D.J. and G.P. conceived the project, D.J. and C.B. designed the electrophysiological experiments, and G.P., C.B., I.V., L.T., F.G. and D.J. performed the experiments. D.J. and G.P. wrote the manuscript with help from C.L. and A.H.

Corresponding author

Correspondence to Denis Jabaudon.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Early postnatal VB ablation in vb mice.

af, Coronal sections of the thalamus and S1 cortex at P0 (a, b), P4 (c, d) and P7 (e, f) in control (a, c, e) and vb (b, d, f) mice. Staining for Fluoro-Jade B (FJ) reveals a peak of VB-specific neuronal degeneration at P4 in vbmice, a time at which the VB-specific marker GSBS21 is already lacking. VGLUT2 immunostaining indicates that TC axons are present in deep cortical layers of vb mice at P0 (arrowhead) and reach L4 at P4, a time at which VB degeneration is at its peak. These axons are not clustered into whisker-related barrels and do not express the VB-specific marker GSBS, which is normally expressed at P4. DAPI (4′,6-diamidino-2-phenylindole) staining indicates that postsynaptic L4 neurons fail to assemble into barrels in vb cortex. At P7, immunostaining for the glial marker GFAP shows a secondary glial ‘scar’ (red arrowheads) at the ventral thalamic border in vb mice (e, f). g, Quantification of FJ+ neurons. h, i, Schematic representation of VB (blue) and Po (red) axonal development in control (h) and vb (i) S1 cortex. j, k, Nissl (j) and cytochrome oxidase (k) stainings reveal specific ablation of the VB in vb mice. l, In situ hybridization for the interneuron marker GAD67 shows preserved delineation of the dorsal and the ventral thalamus (red arrowheads). m, Schematic representation of vb thalamus. Scale bars, 200 μm (insets, 50 μm). CP, cerebral peduncle; CP, cortical plate; dLG, dorsolateral geniculate nucleus; LD, laterodorsal nucleus; LP, lateroposterior nucleus; PF, parafascicular nucleus; VM, ventromedial nucleus.

Extended Data Figure 2 Rewiring of input to S1L4 occurs in the absence of cortical neuron death.

a, Nissl-stained flattened preparation of the somatosensory cortex showing lack of barrel-like clusters in postsynaptic L4 cortical neurons in vb mice (empty red arrowhead). b, c, Presynaptic TC terminals are still present in L4 of vb cortex at P23 using the pan-TC presynaptic marker VGLUT2 (white arrowheads) (b) whereas cortical barrels are lacking (c). d, e, Fluoro-Jade B, cleaved caspase 3 (CASP3) (d) and GFAP (e) expression do not show evidence of cortical neuron degeneration in vb mice (inset shows non-cortical CASP3+ neurons in a non-cortical region of the same section). f, g, Staining and quantification using DAPI (f) and the L2/3-L4 marker CUX1 (g) show lack of barrels but preservation of S1L4 cell numbers in vb mice. Total quantification surface: 0.25 mm2. Scale bars, 400 μm (a), 200 μm (bd, f, g), inset 10 μm (d).

Extended Data Figure 3 Ectopic TC projections to S1 in vbmice originate from the Po.

ac, In control mice, retrograde labelling from S1 using FluoroGold (FG) labels both GSBS+ VB neurons and CALB2+ Po neurons (b, numbered blue arrowheads), whereas other thalamic nuclei are not detectably labelled (b, c). df’, In vb mice, retrograde labelling from S1 exclusively labels GSBS Po neurons (d, blue arrowhead). No additional labelling is found in other thalamic nuclei (d, e). FG+ Po neurons are CALB2+ and located outside of the glial scar (f, f’: high magnification from inset in f). g, Povb neurons were undistinguishable from control Po neurons by molecular and microarray comparative gene expression analysis between Povb, Po and VB neurons demonstrating that they are bona fide Po neurons. Heatmap representation of the expression intensity of the 100 most VB-specific genes in VB, Po and Povb neurons. None of these genes are statistically significantly upregulated in Povb neurons compared to Po. h, i, Po-S2L4 connectivity is normal in vb as assessed by anterograde labelling of Po projections in S2L4 v b - cortex (h) and S2L4 neuron responses to optogenetic stimulation of Po axons (i). Scale bars, 1 mm (low-magnification images) (af) and 100 μm elsewhere. AM, anteromedial; AV, anteroventral; Cx, cortex; dLG, dorsolateral geniculate; Hip, hippocampus; LD, laterodorsal; LP, lateroposterior; PF, parafascicular; VL, ventrolateral; VM, ventromedial.

Extended Data Figure 4 VB→Po switch in input leads to downregulation of S1L4 transcripts and upregulation of S2L4 transcripts in S1L4vb neurons.

a, In situ hybridizations (expression density map) from the Allen Brain Atlas (ABA) database showing expression of three sample genes specifically expressed in L2/3, L4 and L5 (Mdga1, Rorb, Fezf2, respectively). The heatmap on the right represents relative expression intensity in the microarray samples, which is concordant with the ABA data. Relative expression = (expression in the defined region – mean expression in all layers)/(mean expression in all layers) (see ref. 22). b, Heatmap representing sample-specific gene expression for the union of the top 100 most specifically expressed genes of L4vb, L2/3, L4 and L5/6 samples in S1 and S2. Note that S1L4vb gene expression is intermediate between S1L4 and S2L4 neurons. ce, In situ hybridization showing downregulation of the S1L4-enriched transcripts Pcdh20 (c) and Grm4 (d), and upregulation of S2L4-enriched transcripts NeuroD6 (e) in S1L4vb neurons. Scale bars, 1 mm (low magnifications), 100 μm (high magnifications), 30 μm (inset).

Extended Data Figure 5 S1L4vb developmental gene expression is S2L4-like.

a, Schematic representation of VB (blue) and Po (red) axonal development in control S1 (left), control S2 (middle) and S1vb (right) cortex. Boxed area indicates region shown in c. b, Summary of the findings: the time course of expression of L4 gene expression in S1L4vb neurons is similar to that of S2L4 control cortex. Values are colour-coded using S1L4 P0 control values as baseline. c, In situ hybridizations for Rorb and Grm4 (S1L4-type) and Cdh8 and NeuroD6 (S2-L4-type) transcripts at P0, P4 and P10 indicate that S1L4vb developmental gene expression is S2L4-like. Scale bars, 100 μm. CP, cortical plate. See also Supplementary Note 2.

Extended Data Figure 6 Loss of VB input and acquisition of Po input each define genetic changes in S1L4vb neurons.

a, Schematic representation of the phenotypes examined. Celsr3 conditional knockouts (cKO) S1L4 neurons lack both VB and Po inputs (see Supplementary Note 3) whereas S1L4vb receive Po but not VB input. b, Summary of the findings: expression of Rorb and Pcdh20 expression is decreased both in Celsr3 cKO and vb L4 neurons, but this decrease is mitigated by Po input in vb cortex. By contrast, Grm4 expression is not rescued by Po input and is thus VB-dependent. Cdh8 upregulation in vb L4 neurons depends on Po input as it does not occur in the absence of TC input (Celsr3 cKO). c, In situ hybridizations showing expression of the S1L4-type genes Rorb, Pcdh20 and Grm4, and the S2L4-type gene Cdh8. The two photomicrographs with an asterisk are also presented in Extended Data Fig. 4. Normalized intensity values were obtained by radial scanning of intensity using the gel tool of ImageJ software. Scale bars, 200 μm.

Extended Data Figure 7 VB input regulates expression of genes controlling neurite differentiation and polarity in S1L4 neurons.

a, Npas4 and Sema3a expression is increased in vb mice, whereas Zbtb20 is decreased. Open circles indicate values for individual replicates, value within bars indicate P value obtained with the microarray analysis. b, Overexpression of Npas4 and Sema3a or downregulation of Zbtb20 using a miR construct in S1L4 neurons collected 2 days after in utero electroporation at E14.5 led to changes in cell polarity. Dendrites are preferentially oriented away from the axon (yellow arrowhead, 0° in bulls eye plot), whereas they are evenly distributed when a controlGFP plasmid is used. n and P values are indicated in the figure, ANOVA. c, In vivo overexpression of Npas4, Sema3a or miR-Zbtb20 by in utero electroporation at E14.5, the time of birth of L4 neurons, impairs dendritic orientation towards VB axons located in barrel hollows at P7 (VGLUT2+ region within barrels, pink area in single-cell displays) and increases in the number of primary dendrites for Npas4 and miR-Zbtb20 (*P < 0.05, ANOVA, n values indicated within bars). Septae correspond to spaces between barrels (grey area in single cell displays). Scale bars, 10 μm (b), 20 μm (c). See also Supplementary Note 4. Values: mean ± s.e.m.

Extended Data Figure 8 S1L4vb E/I input balance is S2L4-like.

a, Schematic summary of the experiment: S1L4, S2L4 and S1L4vb neurons were recorded while optogenetically stimulating the VB (for S1L4 neurons) or the Po (for S2L4 and S1L4vb neurons). Feed-forward inhibitory input onto L4 neurons was determined by changing the holding potential as detailed in Methods. bd, Sample traces (b) normalized to the excitatory input amplitude (c) and average values (d) showing that E/I ratios are increased to S2L4 levels in S1L4vb neurons. Values: mean ± s.e.m. *P < 0.05, ANOVA; ns, not significant (P = 0.4).

Extended Data Figure 9 Pre-thalamic trigeminal input pathways are not rewired in vb mice.

a, Schematic representation of trigeminothalamic pathways and summary of the findings. Input to the VB, which conveys information on whisker contacts, originates from the PrV nucleus of the trigeminal complex, forming the lemniscal pathway, with a small contingent of fibres reaching the VB–Po border, see Supplementary Note 6 for details). Input to the Po, which forms the paralemniscal pathway, originates from the SpVi nucleus (interpolaris part of the spinal nucleus) of the trigeminal complex. In vb mice, the PrV nucleus is markedly atrophied, presumably owing to loss of VB targets, and only a few cells subside. The paralemniscal pathway is unaffected. Dashed lines indicate location of the sections shown in bd. b, Cytochrome oxidase staining showing markedly atrophied PrV in vb mice. c, The PrV is not detectably activated by whisker contacts during environmental exploration in vbmice, whereas the SpVi is unaffected. d, Retrograde labelling from the Po shows numerous labelled neurons in the SpVi and sparse labelled neurons in both control and vb mice (n = 5 Ctrl and n = 3 vb injections). Scale bars, 100 μm.

Extended Data Table 1 VB input regulates a core set of genes involved in neurite differentiation and polarization

Supplementary information

Supplementary Information

This file contains Supplementary Notes 1–6, a Supplementary Discussion and additional references. (PDF 227 kb)

Open field exploration is normal in vb–mice

Mice were placed in a 45 x 45 cm arena and locomotion in the dark was recorded during 15 minutes using an infrared camera coupled to a tracking software. Video speed is increased 3-fold. Distance travelled, % time spent in central, intermediate, or lateral sectors of the arena were similar between control and vb–mice. (MOV 8195 kb)

vb–mice show increased behavioral signs of pain following noxious stimulation

Injection of 50 µl of a capsaicin solution into the whisker pad was performed under isoflurane anesthesia and the mouse's behavior was recorded upon waking up and at distance from the injection. vb–mice displayed increased and prolonged (up to 20 minutes) behavioral signs of pain following administration of capsaicin in the whisker pad, including immobility, panting, hunched posture, rough hair coat and partially closed eyelids. In contrast, while some of these signs were transiently present in control mice for the first few minutes after injection, they always subsided within a few minutes. (MOV 27636 kb)

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Pouchelon, G., Gambino, F., Bellone, C. et al. Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons. Nature 511, 471–474 (2014). https://doi.org/10.1038/nature13390

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