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A somatosensory circuit for cooling perception in mice

Nature Neuroscience volume 17, pages 1560–1566 (2014)Cite this article

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Abstract

The temperature of an object provides important somatosensory information for animals performing tactile tasks. Humans can perceive skin cooling of less than one degree, but the sensory afferents and central circuits that they engage to enable the perception of surface temperature are poorly understood. To address these questions, we examined the perception of glabrous skin cooling in mice. We found that mice were also capable of perceiving small amplitude skin cooling and that primary somatosensory (S1) cortical neurons were required for cooling perception. Moreover, the absence of the menthol-gated transient receptor potential melastatin 8 ion channel in sensory afferent fibers eliminated the ability to perceive cold and the corresponding activation of S1 neurons. Our results identify parts of a neural circuit underlying cold perception in mice and provide a new model system for the analysis of thermal processing and perception and multimodal integration.

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Figure 1: Mice can perceive mild cooling of the forepaw.
Figure 2: Intrinsic optical imaging reveals overlapping cooling and touch responses in forepaw somatosensory cortex.
Figure 3: Whole-cell recordings from L2/3 neurons in forepaw S1 of awake mice reveal responses to cooling and tactile stimuli.
Figure 4: Whole-cell recordings from L2/3 forepaw S1 neurons during cooling and tactile stimulation in isoflurane anesthetized mice.
Figure 5: Pharmacological inactivation of forepaw primary somatosensory cortex prevents cooling perception.
Figure 6: Trpm8−/− mice are unable to report cooling of the forepaw and have reduced cortical responses to cooling.
Figure 7: Trpm8 expressing afferent neurons drive mild cold perception.

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Acknowledgements

We thank J. König for technical assistance, J.-S. Jouhanneau for help with cell reconstruction, L. Estebanez for programming advice, and L. Estebanez and E. Bobrov for constructive comments on a previous version of the manuscript. This work was funded by grants from the European Research Council (ERC-2010-StG-260590, J.F.A.P.; ERC-2011-StG-280565, J.S.) and the Deutsche Forschungs Gemeinschaft (Exc 257 NeuroCure and DFG-FOR-1341 BaCoFun, J.F.A.P.; Collaborative Research Center 665 Project B6, G.R.L.). Additional support was obtained from a Bernstein Center for Computational Neuroscience grant from the BMBF (01GQ1001E, G.R.L.).

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  1. Wen-Jie Zhao, Jan Walcher and Tobias Albert: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

    Nevena Milenkovic, Wen-Jie Zhao, Jan Walcher, Tobias Albert, Gary R Lewin & James F A Poulet

  2. Neuroscience Research Center and Cluster of Excellence NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Nevena Milenkovic, Wen-Jie Zhao, Jan Walcher, Tobias Albert, Gary R Lewin & James F A Poulet

  3. Institute of Pharmacology, Heidelberg University, Heidelberg, Germany

    Jan Siemens

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Contributions

N.M., J.F.A.P. and G.R.L. designed the project. N.M. performed and analyzed behavioral training, intrinsic optical imaging, whole-cell recordings and pharmacological inactivation. W.-J.Z. performed whole-cell recordings. J.W. performed and analyzed afferent recordings. T.A. wrote code and performed behavioral training. J.S. provided reagents and the Trpm8 mice. J.F.A.P. and G.R.L. supervised the project and wrote the manuscript.

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Correspondence to James F A Poulet.

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Integrated supplementary information

Supplementary Figure 1 Examples of learning curves and lick timing from individual mice during thermal detection task.

a, Examples of individual learning curves from 3 mice, bold cyan line showing the correct hit rate, light cyan the false licks. Mice were trained one session/day. b, Peri-stimulus time histograms (PSTHs) of licking during stimulus presentation from day 5 from the corresponding mice in a. Thermal stimulus onset is at time = 0s and lasted for 3 s. Top PSTHs shows the successful hits, bottom PSTHs in light cyan show the false licks.

Supplementary Figure 2 A cold responsive L2/3 excitatory cortical pyramidal neuron in mouse forepaw S1.

a, Anatomical reconstruction of a cortical pyramidal neuron in mouse forepaw somatosensory cortex. b, Single trial examples of the response of the same cell to cold stimulation of the paw under isoflurane anesthesia with averaged membrane potential response underneath and PSTH on bottom to 40 presentations of a cooling stimulus. Horizontal marks on Vm represent –60 mV for single trials and –74 mV for the averaged response.

Supplementary Figure 3 Mouse forepaw does not move during cooling thermal stimulation under isoflurane anesthesia.

a, b, c, Three example, averaged Layer 2/3 cortical whole-cell recordings (black traces) from different mice during cold-thermal (32-22°C) stimulation of the forepaw (blue trace). the distance of paw movement (orange) was monitored with a movement sensor arm resting on top of the forepaw digits while the force was kept constant (green). The movement sensor was sensitive enough to record a slow (about 3 s duration) movement of the peltier element during cooling that moved the paw by about 1 μm. This slight movement did not cause responses in cortex as (i) cortical control recordings showed no response, data not shown; (ii) the same stimulator was used for single nerve afferent fibers recordings and did not evoked tactile responses in low threshold mechanoreceptors; (iii) the cold response starts before movement onset in the middle cell, see vertical red dashed line in (b). Horizontal marks next to Vm represent, (a) –56 mV, (b) –64 mV, (c) –64 mV.

Supplementary Figure 4 Layer 2/3 cortical neurons in Trpm8–/– mice respond to tactile stimulation of the forepaw.

a, b, c, Three example cells from different mice showing significant averaged subthreshold responses (magenta) to 100 Hz vibrotactile stimulation (orange) of the forepaw digits.

Supplementary Figure 5 Trpm8–/– mice are able to learn an acoustic detection task.

a, cartoon schematic of head-restrained mouse undergoing acoustic training with water rewards. b, 2 Trpm8–/– mice were trained to lick in response to brief (5 ms) acoustic stimulus presentation at randomized times directly after cooling detection training. These Trpm8–/– mice were not able to learn to report mild cooling, they learned to lick after the acoustic stimulus already in the first trial. On the forth session, the mean hit rate was 86.1 ± 3.0% (mean in purple) compared to false licks 8.5 ± 3.5% (mean in black). Error bars show s.e.m.

Supplementary Figure 6 Primary sensory afferent recordings from Trpm8+/+ and Trpm8–/– mice during a 10 °C cooling stimulus

a, Example recordings from cutaneous C-fibers in WT (blue) and Trpm8–/– (magenta) mice during cold stimulation matching the stimulus used during behavioral training (32-22°C). Inset shows colored spikes that were selected for analysis, and in grey the discarded spikes. b, Temperature threshold for the first spike in all fibers responding to cold. In good agreement with the dataset in Figure 6, very few cold responsive A-β or A-δ fibers were identified with the 10°C cooling stimulus. In comparison, a large number of C-MHC (C-MechanoHeatCold) and C-MC (C-MechanoCold) fibers with low response threshold were identified. The C-fiber population showed a large reduction in Trpm8–/– mice. Grey dot shows a unimodal, cold specific C-fiber with similar threshold to other cold sensitive C-fibers. Horizontal bars represent mean with s.e.m..

Supplementary Figure 7 Population analysis of all fibers recorded in entire dataset from Trpm8–/– and Trpm8+/+ mice

a, From the entire surveyed population, 15.6% (24/154 single units) responded to cooling in Trpm8+/+ mice but only 5.7% (11/193 single units) in the Trpm8–/– mice (Chi-squared test P = 0.0024). There was no change in the proportion of heating sensitive afferents in the Trpm8–/– mouse. b From the four subtypes of C recorded (C-M, C-Mechano; C-MH, C-MechanoHeat; C-MC, C-MechanoCold, C-MHC, C-MechanoHeatCold), there was a significant reduction in the numbers of recorded C-MC (Chi-squared test P = 0.0025) and no C-MHCs were identified, but there was no change in the numbers of in C-M and C-MH in the Trpm8–/– mouse. c, We recorded 5 major types of A fiber (A-β; A-δ; A-βC; A-δC; A-δH) none of which showed significant changes in numbers in the Trpm8–/– mouse.

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Milenkovic, N., Zhao, WJ., Walcher, J. et al. A somatosensory circuit for cooling perception in mice. Nat Neurosci 17, 1560–1566 (2014). https://doi.org/10.1038/nn.3828

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