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Cortical responses to touch reflect subcortical integration of LTMR signals

Nature volume 600, pages 680–685 (2021)Cite this article

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Abstract

Current models to explain how signals emanating from cutaneous mechanoreceptors generate representations of touch are based on comparisons of the tactile responses of mechanoreceptor subtypes and neurons in somatosensory cortex1,2,3,4,5,6,7,8. Here we used mouse genetic manipulations to investigate the contributions of peripheral mechanoreceptor subtypes to cortical responses to touch. Cortical neurons exhibited remarkably homogeneous and transient responses to skin indentation that resembled rapidly adapting (RA) low-threshold mechanoreceptor (LTMR) responses. Concurrent disruption of signals from both Aβ RA-LTMRs and Aβ slowly adapting (SA)-LTMRs eliminated cortical responses to light indentation forces. However, disruption of either LTMR subtype alone caused opposite shifts in cortical sensitivity but otherwise largely unaltered tactile responses, indicating that both subtypes contribute to normal cortical responses. Selective optogenetic activation of single action potentials in Aβ RA-LTMRs or Aβ SA-LTMRs drove low-latency responses in most mechanically sensitive cortical neurons. Similarly, most somatosensory thalamic neurons were also driven by activation of Aβ RA-LTMRs or Aβ SA-LTMRs. These findings support a model in which signals from physiologically distinct mechanoreceptor subtypes are extensively integrated and transformed within the subcortical somatosensory system to generate cortical representations of touch.

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Fig. 1: Hindpaw S1 responses to step indentations.
Fig. 2: S1 in mice lacking Meissner corpuscles and/or Merkel cells exhibits shifted sensitivity.
Fig. 3: Selective activation of Aβ LTMR subtypes drives the majority of mechanically sensitive S1 neurons.
Fig. 4: Most VPL neurons receive convergent input from Aβ RA-LTMRs and Aβ SA-LTMRs.

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Data availability

Data are available upon request to the corresponding authors. Source data are provided with this paper.

Code Availability

Code is available upon request to the corresponding authors. Analysis scripts are available at https://github.com/ajemanuel/analyzeMEA. Source data are provided with this paper.

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Acknowledgements

We thank J. Hua, T. Monteiro, and S. Shea for assistance with mouse husbandry and histology, and J. Assad, S. Choi, M. Do, G. Fishell, S. Meltzer, L. Orefice, G. Rankin, C. Santiago and M. Springel for comments on the manuscript. This work was supported by NIH grants F32NS105324 (A.J.E.), K99NS119739 (A.J.E.), R01NS089521 (C.D.H.), DP1MH125776 (C.D.H.), R01NS108410 (C.D.H. and S.P.), NS097344 (D.D.G.), the Fondation Bertarelli (S.P. and D.D.G.) and a Harvard Medical School Dean’s Initiative Award (C.D.H. and D.D.G.). D.D.G. is an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Alan J. Emanuel, Brendan P. Lehnert, Christopher D. Harvey & David D. Ginty

  2. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    Alan J. Emanuel, Brendan P. Lehnert & David D. Ginty

  3. Department of Excellence for Neural Information Processing, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany

    Stefano Panzeri

  4. Neural Computation Laboratory, Istituto Italiano di Tecnologia, Genova, Italy

    Stefano Panzeri

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Contributions

A.J.E., C.D.H. and D.D.G. conceptualized experiments. A.J.E. performed experiments. A.J.E. analysed data with assistance from S.P. B.P.L. (Waabishkigidagaamigizi in ojibwemowin) developed methods for activation of skin sensory neurons. A.J.E., C.D.H. and D.D.G. wrote the manuscript and all authors contributed to review and editing.

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Correspondence to Christopher D. Harvey or David D. Ginty.

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Extended data figures and tables

Extended Data Fig. 1 Aβ LTMR Responses to Force-Controlled Step Indentations.

a, Raster plot showing cutaneous Aβ RA-LTMR and Aβ SA-LTMR responses to a series of step indentations ranging from 1 to 75 mN applied to the most responsive skin region for each neuron. Markers are colored according to how the neurons were labeled (Blue, unlabeled; Orange, Ret+; Green, TrkB+; Red, TrkC+). A subset of these recordings (unlabeled neurons that were recorded in littermate controls for TrkBcKO mice, Ret+ neurons, and TrkB+ neurons) were previously published14. b, Example RFs of an Aβ RA-LTMR (top) and an Aβ SA-LTMR (bottom) to 10-mN step indentations superimposed on a schematic of the hindpaw. Dashed lines outline pedal pads. Unfilled markers represent stimulus locations that did not evoke a response. Color represents the total number of action potentials evoked during the step indentation. c, RF sizes for Aβ RA-LTMRs (n = 17) and Aβ SA-LTMRs (n = 14) that were responsive to 10-mN step indentations. Markers are colored according to how the neurons were labeled. Mean ± s.e.m. areas of 2.3 ± 0.5 and 0.9 ± 0.2 mm2 for Aβ RA-LTMRs and Aβ SA-LTMRs, respectively and median ± i.q.r. of 1.3 ± 3.4 and 0.8 ± 0.9 for Aβ RA-LTMRs and Aβ SA-LTMRs, respectively (Two-sided Mann-Whitney U= 81.0, p=0.07). d, Force threshold for step indentation response for Aβ RA-LTMRs (n = 25) and Aβ SA-LTMRs (n = 20). Markers are colored according to how the neurons were labeled. Mean ± s.e.m. thresholds of 9.0 ± 2.1 and 9.2 ± 2.1 mN for Aβ RA-LTMRs and Aβ SA-LTMRs, respectively and median ± i.q.r. of 5.0 ± 8.0 and 5.0 ± 11.5 for Aβ RA-LTMRs and Aβ SA-LTMRs, respectively (Two-sided Mann-Whitney U=253.5, p=0.45). e, Individual (gray) and mean (black) waveforms recorded from a Pacinian corpuscle-innervating Aβ LTMR labeled with a RetCreER;PVFlpO intersectional strategy (3 mg tamoxifen administered at embryonic day 11.5). These neurons were not labeled with dye-conjugated CTB, which was injected into the pedal and digit pads 48 h prior to recording. f, A 100-Hz sine ramp stimulus was applied to multiple locations across the glabrous hindpaw to assess the responsive region for the Pacinian corpuscle-innervating Aβ LTMR. Top left: Response of neuron to most sensitive region. Top right: sine stimulus response threshold for each probed location. This Aβ LTMR likely innervated a Pacinian corpuscle in the ankle joint. Bottom left: Response to step indentations at most sensitive location. Bottom right: Response to step indentations at all locations overlaid. In some locations action potentials are generated as the probe initially comes into contact with the skin but are never generated in response to the step indentations (which were low-pass filtered at 33 Hz). g, Frequency-response relationships for sine stimuli delivered in a ramp (top) or in a 1-s step (bottom). All Pacinian corpuscle-innervating Aβ LTMRs were most sensitive to high frequency stimulation. Ankle and digit terminal locations were inferred based on the regions of the paw that responded to a handheld vibrating metal probe. Ankle neurons (n = 3) responded when the probe was applied to most regions of the paw, including digits and pedal pads. Digit neurons (n = 3) only responded when the probe was applied to a single digit.

Extended Data Fig. 2 Depth Calibration and Validation for S1 Recordings.

a, Current source density (CSD) plots of an exemplar hindpaw wild-type S1 recording. Sources (red) and sinks (blue) are apparent soon after the onset of the step indentation. The depth of an early, prolonged sink (marked by an asterisk) was used to rigidly adjust the depth of the probe so that this sink was at the center of layer IV. b, Optotagging protocol (top) and corresponding action potential timing of an example optotagged unit (bottom) from an Scnn1a-tg3-Cre;R26LSL-ChR2 mouse. NBQX (5 mM) was applied to the surface of the brain to block excitatory synaptic transmission starting on trial 16. c, Probability distributions of the latency to the first spike after LED pulses for two optotagged units. Shaded region represents 95% confidence interval of shuffled distribution. d, Probability distributions of the latency to the first spike after LED pulses for two non-optotagged units. Shaded region represents 95% confidence interval of shuffled distribution. e, Mechanical responses to 75-mN step indentations for each unit in a recording from a Scnn1a-tg3-Cre;R26LSL-ChR2 mouse before (left) and after (right) application of NBQX. Optotagged units (blue) had similar mechanical response profiles to non-optotagged units (gray). f, Depth distribution (after CSD calibration) of all units (gray, n = 866) recorded from wild-type hindpaw S1 compared with the depth of all optotagged units (blue, n = 24 from 5 recordings from 3 mice). The majority of optotagged units were within layer IV (416.5 – 535.5 μm deep). g, Typical location of an electrode array in hindpaw S1 superimposed upon post hoc histology of a mouse expressing ChR2-EYFP in layer IV neurons (Scnn1a-tg3-Cre;R26LSL-ChR2-EYFP). The probe was coated in DiI prior to recording. Scale bar, 500 μm.

Extended Data Fig. 3 Movement Subtraction.

a, Frame of video (taken at 10 Hz) of paw during stimulation. Dashed box outlines region of interest (ROI) used for movement analysis. The ROI was binarized using Otsu thresholding and the difference from frame to frame was calculated. b, The first derivative of the frame to frame difference for an example recording. When this derivative exceeded three standard deviations from 0.25 s before the step to 0.25 s after the step, the entire step was excluded from subsequent analyses. c, Firing rate histograms in response to 75-mN step indentations (from 0 to 0.5 s) without (left) and with (middle) subtraction from the recording in b. The difference is shown on the right.

Extended Data Fig. 4 Receptive Fields and Spatial Information of Units in Hindpaw S1 and Forepaw S1.

a, Left: stimulus locations used to probe receptive fields with 10-mN step indentations for hindpaw S1. The grid size is 5 × 5 mm. Right: Mean (± s.e.m.) spatial information for all hindpaw S1 units during the course of the 10-mN step indentation. b, Distribution of spatial information across all hindpaw S1 units at the onset (ON; 20-70 ms after step onset), sustained (SUS; 250-500 ms after step onset), and offset (OFF; 20-70 ms after step offset) portions of the 10-mN step indentation. c, A correlation (Pearson r = 0.79, p = 1.4 × 10−179) was apparent between the amount of spatial information at the onset and offset of the step indentation, but the amount of spatial information at the onset was reliably greater than that at the offset. Colors represent units from different recordings. Gray dashed line is the unity line. d, RF sizes of FS hindpaw S1 units (n = 201 units) were larger than those of RS hindpaw S1 units (n = 649 units). Two-sided Mann-Whitney U = 56,703, p = 1.6 × 10−10. Box plot element definitions: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers. e, Example RFs for units with varying degrees of spatial information at the onset. The mean spatial information over the 20-70 ms after the onset of the step indentation is displayed above the heatmap for each unit. The magnitude of the response (rather than the size of the RF) appeared to account for most of the differences in spatial information. f, Top: Mean (± s.e.m.) spatial information for all units in a recording from an Scnn1a-tg3-Cre;R26LSL-ChR2 mouse. The spatial information for two optotagged layer IV units (cyan and magenta) are overlaid. Bottom: Example RFs for these two optotagged units are qualitatively similar to those displayed in e. g, As in a, for forepaw S1. Stimuli were applied to 16 locations in a 4 × 4 mm grid. Thus, the spatial information calculated from forepaw S1 recordings is not directly comparable to that calculated from hindpaw S1 recordings. h, As in b, for forepaw S1. i, As in c, for forepaw S1. (Pearson r = 0.71, p = 1.2 × 10−99). j, As in d, for forepaw S1 (n = 435 RS and FS units, respectively; Two-sided Mann-Whitney U = 31,348). k, As in e, for forepaw S1. l, Receptive field sizes for hindpaw (n = 850 units from 12 recordings in 8 mice) and forepaw S1 (n = 677 units from 9 recordings in 4 mice) units. Two-sided Mann-Whitney U = 266932. Box plot element definitions as in d.

Extended Data Fig. 5 Hindpaw S1 FS Responses and Sensitivity Measurements using Fits to Saturating Exponential.

a, The hindpaw was tethered over a 7.6-mm diameter circular aperture through which step indentations were applied to the glabrous skin of the forepaw. b, Distribution of trough-to-peak times of action potential waveforms for hindpaw S1 units. The dashed red line demarcates the threshold (0.55 ms) used for classifying RS from FS units. c, Baseline firing rate for hindpaw S1 RS (n = 658 units from 12 recordings in 7 mice) and FS units (n = 181 units) from layers II/III, IV and V. Box plot element definitions: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers. d, Top: Heatmaps of the Z-scored firing rate for 181 FS units. Bottom: Grand mean firing rate (± s.e.m) for hindpaw S1 FS units from each layer. Shaded region indicates timing of step indentation. e, Left: Peak-normalized, baseline-subtracted firing rate at the onset of the step indentation for each force for an example hindpaw S1 RS unit. The step indentation begins at 0 s. Right: Fit of the intensity-response relation for this unit to a saturating exponential (\(R=1\mbox{--}{e}^{-I/{I}_{0}}\)). f, As in e for another example hindpaw S1 RS unit. g, Sensitivity as measured by the mean (± 95% confidence interval) I0 fit parameter for Aβ RA-LTMRs and Aβ SA-LTMRs (left) and well-fit (∑|residuals| < 1.2) RS and FS units in each layer of hindpaw (middle) and forepaw (right) S1. DRG n= 24 and 19 neurons for Aβ RA-LTMRs and Aβ SA-LTMRs, respectively. Hindpaw S1 n = 75 and 74 RS and FS units for layer II/III, respectively; n = 74 and 20 RS and FS units for layer IV, respectively; n = 224 and 62 RS and FS units for layer V, respectively. Forepaw S1 n = 24 and 35 RS and FS units for layer II/III, respectively; n = 27 and 13 RS and FS units for layer IV, respectively; n = 149 and 78 for layer V, respectively. No significant differences apparent within areas (DRG: Two-sided Mann-Whitney U = 183, p = 0.14; hindpaw S1: Kruskal-Wallis H = 7.04, p = 0.22; forepaw S1: Kruskal-Wallis H = 10.67, p = 0.06) but I0 differs between all DRG neurons and hindpaw S1 units (Two-sided Mann-Whitney U = 7594, p = 0.0004) and between all hindpaw S1 units and all forepaw S1 units (Two-sided Mann-Whitney U = 52,285, p = 9.6 × 10−18).

Extended Data Fig. 6 Forepaw S1 Responses to Step Indentation.

a, The forepaw was tethered over a 6.4-mm diameter circular aperture through which step indentations were applied to the glabrous skin of the forepaw. b, Distribution of trough-to-peak times of action potential waveforms for forepaw S1 units. The dashed red line demarcates the threshold (0.55 ms) used for classifying RS from FS units. c, Baseline firing rate for forepaw RS (n = 576 units from 12 recordings in 6 mice) and FS units (n = 258 units) from layers II/III, IV and V. Box plot element definitions: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers. d, Grand mean (± s.e.m.) baseline-subtracted firing rate for all forepaw S1 units (cyan; n = 834) and all hindpaw S1 units (gray; n = 866) in response to step indentations. The shaded regions represent the timing of step indentations and the numbers at the stop signify the intensity of the indentation (in mN). While a sustained response is generated within forepaw S1 to high forces, this response is dwarfed by the transients at the onset and offset of the step indentations. e, Top: Heatmaps of the Z-scored firing rate for forepaw S1 RS (left) and FS (right) units. Bottom: Grand mean firing rate (± s.e.m) for RS (left) and FS (right) units from each layer. Shaded region indicates timing of step indentation. f, Cumulative distributions of baseline-subtracted firing rate for all forepaw S1 units at each step intensity for the onset (ON; 10-50 ms after step onset), offset (OFF; 10-50 ms after step offset), sustained (SUS; 250-500 ms after step onset) periods. g, Sensitivity as measured by the I0 parameter for RS and FS units in each layer of forepaw S1 fit well (∑|residuals| < 1.2) with a saturating exponential. Number of units indicated on each bar. h, Density histograms of the β coefficients for the Aβ RA-LTMR and Aβ SA-LTMR profiles that best fit hindpaw S1 units at forces designated above each plot. Heatmap colors represent number of units per bin. Only units with significant R2 values, as determined by permutation of the LTMR response profiles, were included. i, As in h, for forepaw S1 units.

Extended Data Fig. 7 DKO Histology and S1 Receptive Fields and Response Durations in Knockout Mice.

a, Example pedal pad glabrous skin section in a littermate control (AET10) immunostained for NFH (magenta) to identify axons, Troma1 (yellow) to identify Merkel cells (indicated by arrowheads), and S100 (cyan) to identify Meissner corpuscles (indicated by arrows). Scale bar: 50 μm. Similar pattern observed in four littermate controls. b, Pedal pad glabrous skin section in a DKO (AEV5) immunostained for NFH (magenta), Troma1 (yellow), and S100 (cyan). No Merkel cells or Meissner corpuscles were apparent in this section. Scale bar: 50 μm. Similar pattern observed in four DKOs. c, Quantification of the density of Merkel cells within pedal pads for littermate controls (gray markers) and DKOs (purple markers). d, Quantification of the density of Meissner corpuscles within pedal pads for littermate controls (gray markers) and DKOs (purple markers). e, Durations of responses (violin plot shows kernel destiny estimate of underlying distribution) at the onset of step indentations (calculated by multiplying the number of consecutive bins with a Z score > 2 by the bin size [20 ms]) for hindpaw S1 units sensitive to each force in control TrkBfl/fl and TrkBcKO mice (top), in control Atoh1fl/fl and Atoh1cKO mice (middle), and in littermate controls and DKO mice (bottom). Plots shown only for forces to which at least 20 units responded at the indentation onset. *p < 0.05, Two-sided Mann-Whitney U test. f, As in e, for responses at the offset of step indentations. g, Schematic of RF measurements. 10-mN indentations were delivered to 36 locations in a 5 × 5 mm grid for wild-type animals, TrkBfl/fl controls, TrkBcKO mice, Atoh1fl/fl controls, and Atoh1cKO mice. 40-mN indentations were delivered at each location for DKOs and their littermate controls. h, Mean (± s.e.m.) spatial information (left; blue: TrkBcKO, gray: TrkBfl/fl) and mean (± s.e.m.) RF areas (right) for S1 units from wild-type (n = 649 units), TrkBfl/fl (230 units), and TrkBcKO (182 units) animals. *p < 0.05, ****p < 0.0001, Two-sided Mann-Whitney U test, Bonferroni corrections for multiple comparisons applied. i, As in h, for RF measurements in Atoh1fl/fl (gray; n = 48 units) and Atoh1cKO (red; 128 units) animals. j, As in h, for RF measurements (made at 40 mN) in DKOs (purple; n = 369 units) and their littermate controls (gray; 217 units). Two-sided Mann-Whitney U = 5,412. Box plot element definitions (h–j): center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers.

Extended Data Fig. 8 Optical Responses in Aβ LTMRs and Controls for Optogenetic Gain-of-Function Experiments.

a, Aβ LTMR subtypes selectively labeled in a TrkBCreER;R26LSL-ReaChR-mCitrine (TrkB::ReaChR) mouse (left), a RetCreER;AdvillinFlpO;R26LSL-FSF-ReaChR-mCitrine (Ret::ReaChR) mouse (middle), and a TrkCCreER;R26LSL-ReaChR-mCitrine (TrkC::ReaChR) mouse (right). Arrows indicate mCitrine+ fibers within S100+ Meissner corpuscles (left and middle) or abutting Troma1+ Merkel cells (right). Similar patterns observed in all 7 TrkB::ReaChR, 8 Ret::ReaChR, and 12 TrkC::ReaChR mice. Scale bars: 40 μm. b, Top: 33 μJ light pulses were directed to the skin at each location indicated by a marker. A ReaChR-expressing TrkB+ Aβ RA-LTMR responded with, in most cases, a single action potential when the pulses were directed onto the mechanical RF of the neuron. Bottom: Histogram showing the distribution of latencies to the first spike for all locations in which an action potential was evoked by optical stimulation. Scale bar: 1 mm. c, As in a, for a ReaChR-expressing Ret+ Aβ LTMR. Scale bar: 1 mm. d, As in a, for a ReaChR-expressing TrkC+ Aβ SA-LTMR. Scale bar: 1 mm. e, As in a, for a ReaChR-expressing TrkC+ proprioceptor. This proprioceptor responded to movement of a digit. Light did not evoke action potentials, even during ongoing activity. Similar results obtained in 4 additional proprioceptors from 3 mice. Scale bar: 1 mm. f, Hindpaw S1 recordings from mice (n = 3) in which proprioceptors expressed ReaChR, driven intersectionally using the CuxCreER and PVFlpO driver lines. No responses to optical stimulation were observed in S1 despite responsivity to mechanical stimulation. Dashed lines demarcate cortical layers. g, Native mCitrine fluorescence in Clark’s column and the dorsal column of the cervical spinal cord of a Cux2CreER;PVFlpO;R26LSL-FSF-ReaChR-mCitrine animal. Similar pattern observed in 2 additional mice. Scale bar: 500 μm. h, No optical responses were observed in hindpaw S1 of an R26LSL-FSF-ReaChR animal lacking Cre recombinase. Dashed lines demarcate cortical layers.

Extended Data Fig. 9 Response Profiles of S1 Units Sensitive to Selective Optogenetic Stimulation and Receptive Fields and Intensity-Response Relationships in VPL.

a, Grand mean (± s.e.m.) firing rate responses to step indentations for forepaw S1 (left) and hindpaw S1 (right) wild-type (cyan) units compared to that of units in each driver line that were responsive to optical stimulation. The response profiles are similar across all driver lines and wild-type units. Shaded regions indicate the timing of step indentations. b, Top: Schematic of probe position within VPL. Bottom: Post-hoc histology showing the location of the electrode tract (DiI, red) in relation to thalamic structures. Hoechst 33258 nuclear stain shown in blue. Scale bar: 500 μm. Similar histology observed in 3 mice. VPL: ventroposterolateral nucleus of the thalamus, VPM: ventroposteromedial nucleus of the thalamus, dLGN: dorsal lateral geniculate nucleus, vLGN: ventral lateral geniculate nucleus. c, Mean (± s.e.m.) spatial information of mechanically sensitive VPL units (n=56) in relation to 500-ms, 10-mN step indentations applied to 25 locations in a 4 × 4 mm grid. d, Left: Cumulative distribution of mean spatial information of VPL units at the onset (ON; 20-70 ms after step onset), sustained (SUS; 250-500 ms after step onset), and offset (OFF; 20-70 ms after step offset) portions of the 10-mN step indentation. Right: The amount of information at the onset and offset is correlated (Pearson r = 0.70, p = 1.3 × 10−9). e, Spatial information in VPL units (n = 56) and forepaw S1 units (n = 306) differs at the onset (left) but is indistinguishable at the offset (right) of the step indentation. Two-sided Mann-Whitney U = 6,520 and 8,071 for onset and offset comparisons, respectively. f, RFs of example VPL units with varying amounts of mean spatial information at the onset of the step indentation, noted above each heat map. g, RF area for S1 and VPL units (n = 850, 644, and 56 units for hindpaw S1, forepaw S1, and VPL, respectively). Kruskal-Wallis H = 3.12. Box plot element definitions: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers. h, Distribution of action potential waveform trough to peak times for mechanically sensitive VPL units. i, Sensitivity of VPL units compared to forepaw S1 units at the onset of the step indentation as assessed by I0 fits to saturating exponentials (left; n = 80 and 342 units for VPL and S1, respectively; U = 9,026) and maximum response firing rate (right; n = 174 and 599 units for VPL and S1, respectively; U = 51,650). Mann-Whitney U test. j, Sensitivity of VPL units at the offset of the step indentation as assessed by I0 values (left; n = 64 and 316 units for VPL and S1, respectively; U = 9,502) and maximum response firing rate (right; n = 174 and 599 units for VPL and S1, respectively; U = 40,986). Mann-Whitney U test.

Extended Data Fig. 10 Optogenetic Activation of Aβ RA-LTMRs and Aβ SA-LTMRs Modulate Firing Rates in VPL Units with Heterogeneous Response Profiles to Mechanical Indentations.

a, Mean (± s.e.m.) firing rate of two example VPL units that respond to 75-mN step indentations by transiently increasing their firing rate at the onset and offset of the step indentation, much like typical S1 units. The unit on the left can be driven by selective optical activation of Aβ RA-LTMRs and the unit on the right can be driven by selective optical activation of Aβ SA-LTMRs. b, Mean (± s.e.m.) of two VPL units with prominent sustained responses to 75-mN step indentations. The unit on the left can be driven by optical activation of Aβ RA-LTMRs and the unit on the right can be driven by optical activation of Aβ SA-LTMRs. c, Mean (± s.e.m.) firing rate of two VPL units that respond to the 75-mN step indentation with decreases in their firing rates. The firing rate of both units can be modulated by optical activation of Aβ SA-LTMRs but the unit on the left increases its firing rate while the unit on the right decreases its firing rate. d, Time of peak |firing rate| relative to the laser pulse for optically sensitive units in VPL and each layer of forepaw S1 TrkB::ReaChR (left; U = 9,038, p = 2.6 × 10−6 for all VPL units compared to all forepaw S1 units, Mann-Whitney U test; n = 119, 34, 21, 152, and 10 units in VPL, layers II/III, IV, V, and VI, respectively) and TrkC::ReaChR (right; U = 4,828, p = 2.8 × 10−9 for all VPL units compared to all forepaw S1 units, Mann-Whitney U test; n = 84, 34, 39, 120, and 11 units in VPL, layers II/III, IV, V, and VI, respectively) mice. Box plot element definitions: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers. e, Each panel shows mechanical (75 mN step indentation from 0 to 0.5 s) and optical (0.3 ms pulse at 0 ms) responses of one of four clusters determined by K-means clustering of the first three principal components of the Z-scored response to 75-mN step indentations. Individual (thin lines) and mean (thick lines) Z-scored responses from units from TrkC::ReaChR (red) and TrkB::ReaChR (black) mice. Both the mechanical and optical responses generated by stimulation of mice from either genotype are similar within clusters. f, The majority of units from each cluster respond to selective optical activation of Aβ SA-LTMRs (TrkC::ReaChR, red) or Aβ RA-LTMRs (TrkB::ReaChR, black). Total number of units indicated on each bar.

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Emanuel, A.J., Lehnert, B.P., Panzeri, S. et al. Cortical responses to touch reflect subcortical integration of LTMR signals. Nature 600, 680–685 (2021). https://doi.org/10.1038/s41586-021-04094-x

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