Summary Perception of the thermal environment begins with the activation of peripheral thermosensory neurons innervating the body surface. To understand how temperature is represented in vivo, we used genetically-encoded calcium indicators to measure temperature-evoked responses in hundreds of neurons across the trigeminal ganglion. Our results show how warm, hot and cold stimuli are represented by distinct population responses, uncover unique functional classes of thermosensory neurons mediating warm and cold sensing, and reveal the molecular logic for peripheral warmth sensing. Next, we examined how the peripheral somatosensory system is functionally reorganized to produce altered perception of the thermal environment after injury. We identify fundamental transformations in sensory coding, including the silencing and recruitment of large ensembles of neurons, providing a cellular basis for perceptual changes in temperature sensing, including heat hypersensitivity, persistence of heat perception, cold hyperalgesia, and cold analgesia.

Mammalian somatosenory neurons respond to thermal stimuli allowing animals to reliably discriminate hot from cold and select their preferred environments. We previously generated mice that are completely insensitive to temperatures from noxious cold to painful heat (−5 to 55 °C) by ablating several different classes of nociceptor early in development. Here we have adopted a selective ablation strategy in adult mice to dissect this phenotype and thereby demonstrated that separate populations of molecularly defined neurons respond to hot and cold. TRPV1-expressing neurons are responsible for all behavioral responses to temperatures between 40 and 50°C, while TRPM8-neurons are required for cold aversion. We also show that more extreme cold and heat activate additional populations of nociceptors including cells expressing Mrgprd. Thus, although eliminating Mrgprd-neurons alone does not affect behavioral responses to temperature, when combined with ablation of TRPV1- or TRPM8-cells, it significantly decreases responses to extreme heat and cold respectively. Notably, ablation of TRPM8-neurons distorts responses to preferred temperatures suggesting that the pleasant thermal sensation of warmth may in fact just reflect reduced aversive-input form TRPM8 and TRPV1-neurons. As predicted by this hypothesis, mice lacking both these classes of thermosensor exhibited neither aversive nor attractive responses to temperatures between 10 and 50 °C. Taken together these results provide a simple cellular basis for mammalian thermosensation whereby two molecularly defined classes of sensory neurons detect and encode both attractive and aversive cues.

Summary Piezo2 is a mechanically activated ion-channel required for touch discrimination, vibration detection and proprioception. Here we discovered that Piezo2 is extensively spliced, producing different Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, while non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell-type specific. Biophysical characterization revealed substantial differences in ion-permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants. Together our results describe, at the molecular level, a potential mechanism by which transduction is tuned permitting the detection of a variety of mechanosensory stimuli.

SummaryPiezo2 is a mechanically activated ion-channel required for touch discrimination, vibration detection and proprioception. Here we discovered that Piezo2 is extensively spliced, producing different Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, while non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell-type specific. Biophysical characterization revealed substantial differences in ionpermeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants. Together our results describe, at the molecular level, a potential mechanism by which transduction is tuned permitting the detection of a variety of mechanosensory stimuli. eTOC BlurbSzczot et al. find that the mechanoreceptor Piezo2 is extensively alternatively spliced generating multiple distinct isoforms. Their findings indicate that these splice products have specific tissue and cell-type expression patterns and exhibit differences in receptor properties.