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Touch and tactile neuropathic pain sensitivity are set by corticospinal projections

Abstract

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain1,2,3,4. Mental influence on perception is largely assumed to occur locally within the brain. Here we investigate whether sensory inflow through the spinal cord undergoes direct top-down control by the cortex. Although the corticospinal tract (CST) is traditionally viewed as a primary motor pathway5, a subset of corticospinal neurons (CSNs) originating in the primary and secondary somatosensory cortex directly innervate the spinal dorsal horn via CST axons. Either reduction in somatosensory CSN activity or transection of the CST in mice selectively impairs behavioural responses to light touch without altering responses to noxious stimuli. Moreover, such CSN manipulation greatly attenuates tactile allodynia in a model of peripheral neuropathic pain. Tactile stimulation activates somatosensory CSNs, and their corticospinal projections facilitate light-touch-evoked activity of cholecystokinin interneurons in the deep dorsal horn. This touch-driven feed-forward spinal–cortical–spinal sensitization loop is important for the recruitment of spinal nociceptive neurons under tactile allodynia. These results reveal direct cortical modulation of normal and pathological tactile sensory processing in the spinal cord and open up opportunities for new treatments for neuropathic pain.

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Fig. 1: Adult CST ablation impairs light touch but not nociceptive behavioural responses.
Fig. 2: Hindlimb somatosensory CSN ablation causes specific loss of light touch response and mechanical allodynia.
Fig. 3: Light-touch-elicited activation of somatosensory CSNs and spinal dorsal horn neurons.
Fig. 4: Lumbar CCK+ neurons receive convergent Aβ fibre and CST inputs and are required for mechanical allodynia.

Data availability.

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank T. Huang, Y. Zhang and Q. Ma for advice and D. Ginty, S. Hegarty, Q. Ma, F. Wang and P. Williams for critical reading. This study was supported by grants from the Craig Neilsen Foundation (Y.L. and X.W.), Paralyzed Veterans of America Foundation (Y.L.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and NINDS (C.J.W. and Z.H.) and NIMH intramural research program ZIA MH002897 (K.H.W. and X.L.). IDDRC and viral cores supported by the grants NIH P30 HD018655 and P30EY012196 were used for this study.

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Nature thanks R. Ji and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors

Contributions

Y.L., A.L., X.L., Z.Z., K.H.W., C.J.W. and Z.H. conceived the experiments. Y.L., A.L., X.L., Z.Z., M.C., X.W., C.F., C.A., J.Z., Z.G., B.C., X.D., J.-Y.Z. and Y.Z. performed the experiments. Y.L., A.L., X.L., C.C., K.H.W., C.J.W. and Z.H. prepared the manuscript with input from all authors. K.H.W., C.J.W. and Z.H. co-supervised the project.

Corresponding authors

Correspondence to Kuan Hong Wang or Clifford J. Woolf or Zhigang He.

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The authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Effects of pyramidotomy on tactile behaviour and gross locomotion in mice.

a, Correlation between CST ablation and tactile behaviours in mice with pyramidotomy. For individual animals that received pyramidotomy, tag number, image and quantification of L3 spinal cord sections stained with anti-PKCγ antibodies showing remaining CST axons, percentage of withdrawal response to low-threshold von Frey filament (0.16g) and light brush, and sense time to the tape are shown. b, c, Performance on ground walking (b, P = 0.14, hindlimb weight support; P = 0.81, hindlimb retraction; P = 0.41, hindlimb protraction; P = 0.81, inter-limb coordination; P = 0.20, fore–hindlimb coordination), and rotarod test (c, P = 0.87) in mice with sham surgery (n = 8) or pyramidotomy (n = 12). n.s., no statistical significance. Two-sided student’s t-test. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 2 CST axon termination in the lumbar spinal cord.

a, Representative transverse spinal section (L3) from an Emx1-tdTomato (red) reporter line. b, Sections were co-stained with IB4 (green), a lamina IIi marker, and anti-PKCγ, a laminae IIi/III marker, in the spinal dorsal horn. Scale bar, 500 μm. For a and b, three and four mice, respectively, showed similar results.

Extended Data Fig. 3 Efficiency of somatosensory CSN ablation by P14 intraspinal injection.

a, Left, schematic of regional CSN ablation by P14 lumbar (T13–L6) intraspinal injection. Right, representative image (n = 8 animals with similar results) of the cortex with GFP+ areas covering hindlimb S1/S2. b, Representative images (n = 6 animals with similar results) of cortical sections showing hindlimb CSNs retrogradely labelled by lumbar (T13–L6) intraspinal injection of HiRet-GFP at P14. Scale bar, 100 μm. c, To assess ablation efficiency, at the end point, retrograde-targeting rAAV-mCherry was injected into the lumbar spinal cord in some animals. Representative images of cortical sections showing retrogradely labelled mCherry+ CSNs (left) within the GFP+ cortical areas (right) (S1/S2) in control or AAV-FLEX-DTR injected animals with quantification (normalized to those in controls as 100). **P < 0.01 (P < 0.0001), two-sided Student’s t-test. n = 5 and 5 for control and AAV-FLEX-DTR injected mice, respectively. Scale bar, 100 μm. d, Representative images of transverse lumbar spinal cord sections showing residual CST axons labelled by GFP (from mice co-injected with AAV-GFP to S1/S2 and AAV-FLEX-DTR) in control or S1/S2 CSN ablated animals with quantification. **P < 0.01 (P < 0.0001), two-sided Student’s t-test. n =  7 or 8 for control or AAV-FLEX-DTR-injected mice, respectively. Scale bar, 500 μm. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 4 Mechanical allodynia induced by SNI or CFA injection is compromised in mice with pyramidotomy, but cold allodynia and mechanical hyperalgesia induced by SNI are not.

a, Schematic drawing of experimental paradigm. be, Measurement of punctate (b) and dynamic (c) mechanical allodynia, cold allodynia (d) and mechanical hyperalgesia (e) after SNI in mice that underwent sham surgery (n = 8) or pyramidotomy (n = 9) 1–21 days after SNI. b, P < 0.0001, P < 0.0001, P = 0.0012, P = 0.0004 and P = 0.041; c, P < 0.0001, P < 0.0001, P = 0.0004, P = 0.001 and P = 0.0045; d, P = 0.26, P = 0.33, P = 0.29, P > 0.99 and P > 0.99; e, P > 0.99, P = 0.15, P = 0.56, P > 0.99 and P = 0.74 for 1, 3, 7, 14 and 21 d post SNI, respectively. f, g, Measurement of punctate (f) and dynamic (g) mechanical allodynia in mice that underwent sham surgery (n = 6) or pyramidotomy (n = 6) 1–7 days after hindpaw CFA injection. f, P = 0.01, P = 0.01, P = 0.01, P < 0.0001 and P < 0.0001; g, P < 0.0001 for 1, 2, 3, 5 and 7d post CFA injection, respectively. Two-way repeated measures ANOVA followed by Bonferroni correction. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 5 Calcium imaging of CSN activity in intact and SNI mice.

a, Schematic of experimental procedures. b, Confocal fluorescence images of coronal brain sections showing specific expression of GCaMP6s in CSNs. Left, a 10× image showing labelled CSN soma and dendrites; right, a 25× image showing the magnified view of apical dendritic trunks. Dotted line, expected focal plane of head-mounted microscope. Scale bars, 100 μm. c, Procedures for identifying the active events of CSN dendrites. Left, example of dendrites identified from a calcium movie by ICA analysis. The brightest spot in a dendritic tree, corresponding to the trunk (red circle), is used as a region of interest for temporal signal analysis. Top trace, temporal signal of the dendrite. Bottom trace, magnified calcium events. Horizontal bars indicate rising phases of calcium events, which are associated with neuronal activation and used in subsequent analysis. Scale bar, 100 µm. d, Example calcium movie frames showing dendritic activities of hindlimb S1 CSNs upon different sensory stimuli in intact mice. In these examples, brush stimuli activated CSNs, whereas von Frey (0.04 g) and laser heat stimuli did not. Calcium signals are expressed as ∆F/F0 (F0 is the time-average fluorescence of the whole movie). Scale bar, 200 µm. For b, d, the experiments were repeated independently four times with similar results. e, Pie charts showing the proportions of neurons that responded to brushes, von Frey filaments or both brush and von Frey stimulation before and after SNI. Few neurons responded to both stimuli before SNI, but this overlapping proportion increased after SNI.

Extended Data Fig. 6 Mechanical allodynia induced by spinal disinhibition (treatment with bicuculline and strychnine) is compromised in mice with pyramidotomy.

a, Drawing of experimental paradigm. b, c, Measurement of punctate (b) and dynamic (c) mechanical allodynia after intrathecal injection of bicuculline and strychnine in mice that had undergone sham surgery (n = 6) or pyramidotomy (n = 7). **P < 0.01 (P < 0.0001 for b and c at 10, 30, and 90 min post drug), two-way repeated measures ANOVA followed by Bonferroni correction. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 7 Neuronal activity in cortical and subcortical areas upon light touch after SNI.

ac, Drawings of c-Fos immunostaining in intact mice (a), mice with SNI only (b) and mice with SNI after light brush stimulation (c) from control mice and mice with pyramidotomy. mPFC, medial prefrontal cortex; ACC, anterior cingulate cortex; S1HL, hindlimb primary somatosensory cortex; S2, secondary somatosensory cortex; Pir, piriform cortex; PV, periventricular nucleus of the thalamus; VM, ventromedial nucleus of the hypothalamus; Amyg, amygdala. d, Quantification of c-Fos+ cells in multiple cortical areas in intact mice (with CSN, n = 3; with pyramidotomy, n = 3), mice with SNI only (with CSN, n = 3; with pyramidotomy, n = 3), and mice with SNI after light brush stimulation (with CSN, n = 4; with pyramidotomy, n = 3). **P < 0.01; n.s., no statistical significance. PFC SNI only with or without Py: P > 0.99; PFC SNI + brush with or without Py: P < 0.0001; ACC SNI only with or without Py: P > 0.99; ACC SNI + brush with or without Py: P = 0.0002; M1 SNI only with or without Py: P > 0.99; M1 SNI + brush with or without Py: P > 0.99; S1 SNI only with or without Py: P > 0.99; S1 SNI + brush with or without Py: P < 0.0001; insula SNI only with or without Py: P > 0.99; insula SNI + brush with or without Py: P < 0.0001; S2 SNI + brush with or without Py: P = 0.0075; Pir all conditions (ANOVA): P = 0.82. One-way ANOVA followed by Bonferroni correction. e, Representative images of multiple cortical areas stained with c-Fos (red) and GFP (green, HiRet-GFP injection) in mice with SNI after light brush stimulation. Arrowheads mark the co-localization of c-Fos+ and GFP+ CSNs. Scale bars, 20 μm. f, Quantification of c-Fos+ and GFP+ CSN co-localization in multiple cortical areas in animals with SNI after light brush stimulation without (n = 4) or with pyramidotomy (Py, n = 3). *P < 0.05; **P < 0.01, P = 0.03, 0.04, 0.0009, and 0.02 for mPFC, ACC, S1, and S2, respectively. Two-sided Student’s t-test. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 8 Ablation of lumbar CCK+ interneurons reduces tactile sensitivity and dorsal horn neuronal activation after SNI, but not nociceptive response or gross locomotion.

ad, Measurements of sensitivity to laser heat (a, P = 0.76), acetone (b, P = 0.86), von Frey filaments (c, P = 0.03 for 0.016 g) and brush (d, P = 0.002) stimuli in control mice (n = 8) or mice in which CCK–tdTomato interneurons had been ablated (n = 7). a, b, d, Two-sided Student’s t-test; c, two-way repeated measures ANOVA followed by Bonferroni correction. e, f, Performance on open field (e, P = 0.54) and ground walking (f, P = 0.68, 0.72, and 0.50 for hindlimb weight support, protraction, and retraction, respectively) in control mice (n = 8) or mice in which CCK–tdTomato interneurons had been ablated (n = 7). n.s., no statistical significance, two-sided Student’s t-test. gi, Representative images of c-Fos (green) activity (g) and quantification of CCK+/c-Fos+ cells (h) and c-Fos+ neurons in different laminae of the dorsal horn of the spinal cord (L3–4) of CCK–tdTomato (red) mice after SNI and brush stimulation in mice that had undergone sham surgery (n = 4), pyramidotomy (n = 5) or lumbar CCK–tdTomato ablation (n = 3) (i). Scale bars, 500 μm (g, right, middle, and left columns) and 50 μm (g, zoom in panels). **P < 0.01, two-sided Student’s t-test. h, P < 0.0001; i, P = 0.0045 and 0.0028 for laminae I–II and laminae III–V, respectively. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 9 Characterization of Aβ fibre and CST inputs onto CCK–tdTomato neurons.

a, Schematic of the stimulation and whole-cell patch recording set-up for tdTomato-labelled CCK+ interneurons. CST axons labelled by AAV-ChR2-YFP were stimulated with a 473-nm laser. A single dorsal root (L4–L6) was stimulated with a glass suction electrode. b, c, Representative consecutive traces (n = 3) of Aβ fibre (left) and opto-CST (right) stimulation-evoked responses (b) and summarization (c) of whole cell patch-clamp recordings on CCK–tdTomato interneurons. Three recording conditions were used: first, to detect evoked EPSCs (eEPSCs), we held the membrane potential at −70 mV, which is the equilibrium potential of Cl and therefore minimizes the flow of eIPSCs. Second, by holding the membrane potential at 0 mV, we examined the polysynaptic, inhibitory inputs (eIPSCs) onto CCK–tdTomato interneurons. Third, we used current clamp mode to examine whether the stimulation drove action potential firing at the resting membrane potential. Type 1: CCK–tdTomato neurons receive only excitatory inputs, and few of them generated AP outputs when Aβ or CST inputs were stimulated. Type 2: CCK–tdTomato neurons receive both excitatory inputs and feed-forward inhibitory inputs, with no AP output. Type 3: CCK–tdTomato neurons receive predominant feed-forward inhibition, with no AP output. Type 4: CCK–tdTomato neurons show no response at either voltage or current clamp recording. d, Left, representative recording of an Aβ (25 μA) dorsal root evoked EPSC at −70 mV. Latency and jitter properties (magnified in inset) with quantifications (n = 8 neurons) are consistent with monosynaptic sensory connectivity. Right, opto-stimulation evoked EPSCs (averaged traces) at −70 mV in the same cell as shown on the left. The evoked EPSC was blocked by AMPA and NMDA antagonists (NBQX (5 μM)/CPP (20 μM)). In addition, opto-stimulation evoked EPSCs were eliminated by TTX (0.5 μM), and reinstated by 4-AP (2 mM), indicating a monosynaptic connection between the CST and CCK–tdTomato interneurons. Bar graph, quantification of eEPSC amplitudes after administration of drugs as shown. **P < 0.0001; one-way ANOVA followed by Bonferroni correction. n = 8 neurons. Data shown as mean ± s.e.m.

Source data

Extended Data Fig. 10 Reinforcement of tactile allodynia in mice with SNI by optogenetic stimulation of somatosensory CSNs.

a, Drawing of experimental paradigm. b, c, Measurement of punctate (b, von Frey filaments) and dynamic (c, brush) mechanical allodynia upon opto-stimulation in control mice (n = 6) and mice expressing ChR2-YFP in CSNs (n = 6) after SNI. n.s., no statistical significance; *P < 0.05. b, c, P = 0.18, 0.08 and 0.41, 0.02 for PLAP and Cre, without or with laser, respectively; two-sided Student’s t-test. d, Representative images and quantification of pERK (red) and NK1R (green) immunostaining in the superficial dorsal horn (laminae I–II) of the spinal cord (L3–4) in control mice (n = 3) or mice expressing ChR2-YFP in hindlimb CSNs (n = 3) with SNI and brush stimulation coupled with opto-stimulation. Scale bar, 100 μm. *P < 0.05; P = 0.02 and 0.01 for pERK and pERK/NK1R ratio, respectively; two-sided Student’s t-test. Six sections crossing the lumbar spinal cord (L3–4) were quantified for individual animals. Data shown as mean ± s.e.m.

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Liu, Y., Latremoliere, A., Li, X. et al. Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561, 547–550 (2018). https://doi.org/10.1038/s41586-018-0515-2

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Keywords

  • Corticospinal Neurons (CSNs)
  • Tactile Sensory Processing
  • Dorsal Horn
  • Pyramidotomy
  • Brush Stimulation

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