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. 2020 Jun 3;106(5):830-841.e3.
doi: 10.1016/j.neuron.2020.02.035. Epub 2020 Mar 23.

The Sensory Coding of Warm Perception

Ricardo Paricio-Montesinos  1 , Frederick Schwaller  2 , Annapoorani Udhayachandran  1 , Florian Rau  1 , Jan Walcher  2 , Roberta Evangelista  2 , Joris Vriens  3 , Thomas Voets  4 , James F A Poulet  5 , Gary R Lewin  6
Affiliations

The Sensory Coding of Warm Perception

Ricardo Paricio-Montesinos et al. Neuron. .

Abstract

Humans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3-/- triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates.

Keywords: C-fiber; Trp channels; nociception; perception; polymodal; sensory coding; thermal transduction; warm.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Mice Learn to Report Non-noxious Warm Stimuli Delivered to the Forepaw (A) Cartoon showing behavioral setup with right forepaw tethered to an 8 × 8 mm Peltier. (B) Warm-detection task. Temperature baseline was 32°C and reached 42°C for 4 s. Licks within the warming or warm plateau phase (gray area) were water rewarded (hit). Catch trials were introduced with no warm stimulus and used to measure spontaneous licking (false alarms). Right: thermal images of mice with their forepaw resting on the Peltier element. (C) Example learning curve (top) and PSTH of lick timing at training day 10 (bottom) from one warm-trained mouse. (D) Mice learned to report warm stimuli of 32°C–42°C after the fourth training session (n = 12; two-way repeated-measures ANOVA with Bonferroni post hoc tests). (E) Decreasing stimulus amplitude revealed a perceptual threshold of 1°C (n = 11; two-way repeated-measures ANOVA with Bonferroni post hoc tests). ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. Data are presented as mean ± SEM.
Figure 2
Figure 2
Forepaw Warming Evokes Spiking Responses in Polymodal C-Fibers (A) Example of two C-MH fibers firing during a 1°C/s heat ramp (one low and one high threshold). (B) Firing rates of all heat-responsive fibers during 1°C/s heat ramp (gray lines). Example traces from (A) are shown in red. (C) Proportions of thermosensory C-fibers and A-fibers. C-MH, C-mechanoheat; C-MHC, C-mechanoheatcold; C-MC, C-mechanocold; C-C, C-cold; A-MH, A-mechanoheat; A-MC, A-mechanoheatcold. (D) Percentage of fibers-in-class responsive to non-noxious warming (<42°C) and/or cooling (>22°C). (E) PSTH of mean spike rate of all heat-responsive fibers during 42°C heat ramps. (F) Mean number of action potentials per warm step of C-MH and C-MHC fibers did not differ (repeated-measures two-way ANOVA with Bonferroni post hoc analysis). Data are presented as mean ± SEM.
Figure 3
Figure 3
Warm-Inhibited C-Fibers with Ongoing Activity at Physiological Skin Temperatures (A) Top: thermal image of the mouse forepaw at room temperature, with a paw temperature of 26°C–28°C. Bottom: schematic of forepaw afferent recordings using the ex vivo skin-nerve preparation bath temperature set to 27°C. (B) Example of a C-MC fiber with ongoing activity. Cool ramps increased spike rate and warm ramps silenced spike activity. (C) Proportion of C-fibers with ongoing activity found at 32°C and 27°C. (D) PSTH spike rate of warm-excited fibers and warm-inhibited fibers during 10°C warm ramp. (E) PSTH of spike rate of all warm-inhibited units during 10°C cool ramp. (F) Percentage firing rate change in C-fibers with ongoing activity (gray lines) and mean activity change (blue, from ongoing firing rate) to cool and warm. Data are presented as mean ± SEM.
Figure 4
Figure 4
Warm Perception from 22°C Baseline and Its Afferent Coding (A) Learning curve of mice trained to report a 22°C to 32°C warming step. Mice reliably report the stimulus from the second session on (n = 6 mice, two-way repeated-measures ANOVA with Bonferroni post hoc tests). (B) Mice detect a warming step of 0.5°C starting from a baseline of 22°C (n = 6 mice, two-way repeated-measures ANOVA with Bonferroni post hoc tests). (C) Left: the same mice reliably detect warm from 32°C or 22°C baseline; hit and false-alarm rate differences were statistically significant (n = 6 mice, two-way repeated-measures ANOVA with Bonferroni post hoc tests). Right: the sensitivity index (d′) was poorer for warming steps from a 32°C baseline compared to 22°C (n = 6 mice, p = 0.0014, paired t test). (D) The proportion of cool-fibers with ongoing activity (left) and mean their firing rates (right) recorded at 22°C. (E) PSTHs of warm-inhibited fibers and warm-excited fibers during 22°C–32°C stimuli. (F) Average spike count of all warm-excited fibers during 22°C–32°C and 32°C–42°C stimuli. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. Data are presented as mean ± SEM.
Figure 5
Figure 5
TRPV1, TRPM2, TRPA1, and TRPM3 Are Not Absolutely Required for Warm Perception (A) Lick PSTH warm-trained control WT mice at day 10 showing distribution of first licks to the warm stimulus (red) or during catch trials (gray). (B) Same as (A), but for trpv1−/−. (C) Same as (A), but for trpm2−/−; note the small difference between hit and false-alarm lick rates. (D) Same as (A), but for trpv1:trpa1:trpm3−/−. (E) Sensitivity (d′) analysis revealed all trp mutant mice detect warm better than chance (d′ = 0). However, all trp mouse mutants had partial perceptual deficits compared to WT mice (WT mean d′ = 2.45 ± 0.30, trpv1−/− d′ = 1.48 ± 0.19 versus WT, p < 0.05; trpm2−/− d′ = 1.03 ± 0.29 versus WT p < 0.01, trpv1:trpa1:trpm3−/− d′ = 1.28 ± 0.20 versus WT; p < 0.01 unpaired t tests). (F) Sensitivity (d′) values of WT mice and trpv1−/−, trpm2−/−, and trpv1:trpa1:trpm3−/− mice during warm threshold sessions. ∗p < 0.05 and ∗∗p < 0.01, Data are presented as mean ± SEM.
Figure 6
Figure 6
TRPM8 Is Required for Warm Perception For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.neuron.2020.02.035. (A) trpm8−/− mice showed no warm detection, as hit and false-alarm rates were the same throughout training (n = 10; two-way repeated-measures ANOVA with Bonferroni post hoc tests). (B) After 10 training days, trpm8−/− mice had d′ values ∼ 0 (chance performance), which was significantly different compared to WT (WT mean d′ = 2.45 ± 0.30 and n = 12, trpm8−/− d′ = 0.04 ± 0.09 and n = 10; p < 0.0001 versus WT, unpaired t test). (C) PSTH of the first licks of trpm8−/− mice at day 10. No difference between presence (red) and absence (gray) of stimulus. (D) Schematic representation of pharmacological experiment using the TRPM8 antagonist PBMC. (E) Raster plot (top) from a DMSO-vehicle-treated mouse and population mean first-lick latency PSTH (bottom). (F) Raster plot (top) from a PBMC-treated mouse and population mean first-lick latency PSTH (bottom) show much reduced warm detection. (G) Hit and false-alarm rate differences was reversibly reduced in PBMC-treated mice compared to vehicle, with recovery 24 h after treatment (n = 5, two-way ANOVA with Bonferroni post hoc analysis). (H) Sensitivity (d′) indices were reversibly impaired in PBMC-treated mice compared to vehicle controls (n = 5, paired t tests between PBMC and DMSO or recovery groups). (I) PBMC-treated mice report tactile stimuli normally (n = 6, two-way ANOVA with Bonferroni post hoc analysis). ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001. Data are presented as mean ± SEM.
Figure 7
Figure 7
trpm8−/− Mice Lack Warm-Evoked Silencing of C-Fibers (A) Proportions of thermosensitive forepaw C-fibers were not significantly different between WT and trpv1:trpa1:trpm3−/− mice, but there was dramatic reduction in cold-sensitive C-MC and C-MHC fibers in trpm8−/− mice compared to WT. (B) Proportions of warm-responsive fibers did not differ between control and trpv1:trpa1:trpm3−/− and trpm8−/− mice. (C) Absence of cool-driven C-fibers with ongoing activity in trpm8−/− mice. The incidence and firing rates of cool-driven C-fibers with ongoing activity was not different between trpv1:trpa1:trpm3−/− mice and WT controls. (D) Mean warm-evoked firing rates did not differ among control, trpv1:trpa1:trpm3−/−, and trpm8−/− mice (repeated-measures two-way ANOVA with Bonferroni post hoc analysis). (E) PSTHs of mean spike rates to a warm ramp recorded from warm-activated C-fibers showed comparable responses between genotypes. (F) PSTHs from warm-inhibited, cool-driven fibers (not present in trpm8−/− mice). Data are presented as mean ± SEM.
Figure 8
Figure 8
Model of Afferent Encoding of Perceived Warmth Forepaw warming recruits two populations of sensory afferents: (1) activation of warm-sensitive C-fibers that are silent at rest (red) and (2) decreased spiking in a subset of cool-sensitive C-fibers that are active at rest (blue). A warm step from 32°C to 42°C elicits both types of responses, and a warm step of 22°C to 32°C evokes mainly warming-evoked inhibition. In the absence warm-evoked inhibition of C-fibers with cool-driven ongoing activity, warm detection fails (trpm8−/− mice), even in the presence of warm-evoked firing (red).
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Comment in

  • Feeling the warmth.
    Whalley K. Whalley K. Nat Rev Neurosci. 2020 Jun;21(6):299. doi: 10.1038/s41583-020-0302-6. Nat Rev Neurosci. 2020. PMID: 32246102 No abstract available.
  • Detecting Warm Temperatures Is a Cool Kind of Thing.
    Gómez Del Campo A, Viana F. Gómez Del Campo A, et al. Neuron. 2020 Jun 3;106(5):712-714. doi: 10.1016/j.neuron.2020.05.009. Neuron. 2020. PMID: 32497507

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