The sensory coding of warm perception

Abstract

Humans easily discriminate tiny skin temperature changes that are perceived as warming or cooling. Dedicated thermoreceptors forming distinct thermosensory channels or "labelled lines" are thought to underlie thermal perception. We show that mice have similar perceptual thresholds for forepaw warming to humans (~1 o C change) and do not mistake warming for cooling. Mice perform warm discrimination tasks without dedicated thermoreceptors, but use information carried by unmyelinated polymodal C-fibers. Deletion of the heat-sensitive transduction channels TRPM2 and TRPV1 did not impact warming perception or afferent coding of warm. However, without the cold sensitive TRPM8 channel, afferent coding of cooling was impaired and these mice cannot perceive warming or cooling. Our data is incompatible with the existence of thermospecific labelled lines, but can be reconciled by the existence of central circuits that compare and integrate the input from at least two types of polymodal afferents, hitherto thought to exclusively signal pain.

Sensory stimulus evoked responses in layer 2/3 pyramidal neurons of the hind paw-related mouse primary somatosensory cortex

“…Somewhat surprisingly, this increased excitability is not correlated with any differences in spontaneous firing rate, or up-/down state properties (Table 2, Supple Figure 1 A-C). Taken together, the lack of contralateral hind paw stimulus evoked responses together with a lower intrinsic excitability suggests that these L2/3 PNs that might require other forms of tactile stimuli or sub-serve other physiological roles related to perception of temperature or pain (Cain et al, 2001;Milenkovic et al, 2014;Paricio-Montesinos et al, 2020;Walcher et al, 2018). Since the goal of our study was to describe the physiological properties of L2/3 PNs responding to paw stimulus, we did not further investigate these possibilities.…”

USH2A is a skin end-organ protein necessary for vibration sensing in mice and humans

“…We found the same proportion of Cmechanoheat, C-mechanocold, C-mechanoheatcold and C-cold primary afferents in Ush2a -/mice compared to their littermate controls (Extended data Fig 7a). Moreover, we used slow warming and cooling ramps 11 (1°C/sec) to quantify thermosensitivity and found no deficits in cool or warm driven activity in mice lacking USH2A (Extended data Fig 7b,c). These data suggest that deficits in thermal perception associated with loss of function mutations in the USH2A gene are not due to functional changes in thermosensory afferents.…”

“…We next asked whether genetic ablation of Ush2a in mice impairs forepaw vibration detection in behaving animals. We adapted a goal-directed sensory perception task 10,11 and trained waterrestricted and head restrained Ush2a +/+ and Ush2a -/mice 12 to report a 5Hz forepaw vibration stimulus for a water reward 13 (Fig 1e). Mice learned to report a 60mN 5Hz forepaw vibration over a 1d), indicating that Ush2a -/mice had significantly higher 5Hz vibration perceptual thresholds than control mice.…”

“…We thus asked if the sensory coding of thermal stimuli was altered in the absence of USH2A. In mice, skin warming and cooling are signalled by polymodal C-fibers that respond to small increases or decreases in temperature 10,11 . We recorded from polymodal C-fibers and classified them according to their response to mechanical, warm and cooling stimuli.…”

“…Catch trials, where no stimulus was presented and licks were counted as false alarms, were interleaved as 50% of the total trials.Trials were not cued by any external event or stimulus as previously described 11 and were delivered at randomized time intervals between 3 and 30 s. If mice licked during a 2s window before the stimulus onset, a 3-30s delay was imposed to promote stimulus-water reward association. One training session consisted of around 60 trials (30x stimulus + 30x catch).…”