The neural circuits of thermal perception

Abstract

Thermal information about skin surface temperature is a key sense for the perception of object identity and valence. The identification of ion channels involved in the transduction of thermal changes has provided a genetic access point to the thermal system. However, from sensory specific 'labeled-lines' to multimodal interactive pathways, the functional organization and identity of the neural circuits mediating innocuous thermal perception have been debated for over 100 years. Here we highlight points in the system that require further attention and review recent advances using in vivo electrophysiology, cellular resolution calcium imaging, optogenetics and thermal perceptual tasks in behaving mice that have begun to uncover the anatomical principles and neural processing mechanisms underlying innocuous thermal perception.

Figure 1

Thermal behavioral tasks for rodents. (a) A 2-plate thermal avoidance task. Floor plates have different temperatures and experimenters monitor the time spent on either plate. (b) Similar task as in (a) but animals walk around within a ring-shaped disk (white circle on infrared image) with a gradient of floor temperatures. (c) A thermal discrimination task where freely moving mice are trained to discriminate between two temperatures of water droplets delivered to the central spout, mice report the temperature by moving to one of two reporting nose-poke ports. (d) Cartoon schematic showing different stages of thermal perception task in head-fixed paw-tethered mice based on task in [14^•]. Mice are trained to report a thermal stimulus delivered to the glabrous skin of the right forepaw by licking a reward port. Following correct licking, mice are rewarded with water. Figure panels adapted with permission, from (a) [22], (b) [26], (c) [31^••].

Figure 2

Putative thermal pathways from paw to cortex in mice. (a) Cartoon mouse showing putative thermal pathways from skin to cortex via spinal cord and thalamus, primary somatosensory cortex (S1), secondary somatosensory cortex (S2), and insular cortex (IC). The thermal pathway via lateral parabrachial nucleus to hypothalamus is not included. (b) Schematic cross-sections of mouse nervous system taken at different levels with numbers corresponding to locations in (a). Thermal thalamic input to S1 is provided by ventral posterolateral (VPL) and posterior medial (POm), to S2 by POm and the posterior triangular nucleus (PoT), and IC by PoT.

Figure 3

Imaging thermal processing in LI/II of the spinal cord. (a) Cartoon schematic of preparation for two-photon calcium imaging of the dorsal spinal cord during thermal stimulation of the hindpaw in anaesthetized mice. (b) Top: example in vivo images of LI/II with superimposed thermally responsive neurons (filled color) during either cooling (left) or warming (right) thermal stimulation. Bottom: calcium response dynamics from single neurons sorted by their maximum response amplitudes (n = 138 and 276 cold and warm responsive cells). (c) Example calcium responses (ΔF/F) from a single LI/II neuron to (left) 10 °C cooling (32–22 °C) and (right) 13 °C warming (32–45 °C) show different response dynamics, note the warming stimulus goes over thermal pain threshold (42 °C) while cooling does not. (d) Graphs showing the numbers of responding cells and the calcium responses (ΔF/F) in LI/II neurons in response to stimuli with a fixed peak temperature (left, cool to 19 °C, right, warming to 43 °C) and different baseline temperatures. LI/II neurons show a graded recruitment for different amplitude cooling stimuli but similar recruitment for different amplitude warming, implying that warming-responsive neurons code for absolute warming temperatures while the relative change in temperature is coded in cooling responsive neurons. Figure panels were adapted with permission from [44^••].

Figure 4

Innocuous cooling processing and perception in mice. (a) Cartoon schematic of head-fixed, paw-tethered preparation for sensory cortex recordings and thermo-tactile stimulation. (b) Intrinsic optical imaging shows overlapping response in primary somatosensory cortex (S1) to cooling and touch of the forepaw glabrous skin. (c) Example in vivo whole-cell membrane potential recording from the same layer 2/3 neuron in an awake mouse showing responses to thermal and tactile stimulation of the right forepaw. Forepaw is tethered to the thermal stimulating surface of a Peltier element. From top: single trial responses, averaged membrane potential (V_m), stimulus, peri-stimulus time histogram (PSTH) of action potential firing (n = 13 thermal, 12 tactile stimuli). (d) Example single unit afferent recordings from an in vitro skin-nerve preparation showing a response to thermal stimulation of the glabrous skin in TRPM8+/+ (cyan) and a reduced response in TRPM8−/− (magenta) mice. Colored action potentials depict individual spikes selected for analysis. (e) Learning curve in TRPM8+/+ (cyan) and TRPM8−/− (magenta) mice shows that TRPM8 is required for mice to learn to report a 10 °C cooling of the paw. Figure panels taken with permission from [14^•].