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The location of a sensory cortex for temperature perception remains a topic of substantial debate. Both the parietal-opercular (SII) and posterior insula have been consistently implicated in thermosensory processing, but neither region has yet been identified as the locus of fine temperature discrimination. Using a perceptual learning paradigm in male and female humans, we show improvement in discrimination accuracy for subdegree changes in both warmth and cool detection over 5 d of repetitive training. We found that increases in discriminative accuracy were specific to the temperature (cold or warm) being trained. Using structural imaging to look for plastic changes associated with perceptual learning, we identified symmetrical increases in gray matter volume in the SII cortex. Furthermore, we observed distinct, adjacent regions for cold and warm discrimination, with cold discrimination having a more anterior locus than warm. The results suggest that thermosensory discrimination is supported by functionally and anatomically distinct temperature-specific modules in the SII cortex. SIGNIFICANCE STATEMENT We provide behavioral and neuroanatomical evidence that perceptual learning is possible within the temperature system. We show that structural plasticity localizes to parietal-opercular (SII), and not posterior insula, providing the best evidence to date resolving a longstanding debate about the location of putative "temperature cortex." Furthermore, we show that cold and warm pathways are behaviorally and anatomically dissociable, suggesting that the temperature system has distinct temperature-dependent processing modules., (Copyright © 2017 Mano et al.)

Predictions about sensory input exert a dominant effect on what we perceive, and this is particularly true for the experience of pain. However, it remains unclear what component of prediction, from an information-theoretic perspective, controls this effect. We used a vicarious pain observation paradigm to study how the underlying statistics of predictive information modulate experience. Subjects observed judgments that a group of people made to a painful thermal stimulus, before receiving the same stimulus themselves. We show that the mean observed rating exerted a strong assimilative effect on subjective pain. In addition, we show that observed uncertainty had a specific and potent hyperalgesic effect. Using computational functional magnetic resonance imaging, we found that this effect correlated with activity in the periaqueductal gray. Our results provide evidence for a novel form of cognitive hyperalgesia relating to perceptual uncertainty, induced here by vicarious observation, with control mediated by the brainstem pain modulatory system.

TRP vanilloid 2 (TRPV2) is a nonselective cation channel expressed prominently in medium- to large-diameter sensory neurons that can be activated by extreme heat (>52°C). These features suggest that TRPV2 might be a transducer of noxious heat in vivo. TRPV2 can also be activated by hypoosmolarity or cell stretch, suggesting potential roles in mechanotransduction. To address the physiological functions of TRPV2 in somatosensation, we generated TRPV2 knock-out mice and examined their behavioral and electrophysiological responses to heat and mechanical stimuli. TRPV2 knock-out mice showed reduced embryonic weight and perinatal viability. As adults, surviving knock-out mice also exhibited a slightly reduced body weight. TRPV2 knock-out mice showed normal behavioral responses to noxious heat over a broad range of temperatures and normal responses to punctate mechanical stimuli, both in the basal state and under hyperalgesic conditions such as peripheral inflammation and L5 spinal nerve ligation. Moreover, behavioral assays of TRPV1/TRPV2 double knock-out mice or of TRPV2 knock-out mice treated with resiniferatoxin to desensitize TRPV1-expressing afferents revealed no thermosensory consequences of TRPV2 absence. In line with behavioral findings, electrophysiological recordings from skin afferents showed that C-fiber responses to heat and C- and Aδ-fiber responses to noxious mechanical stimuli were unimpaired in the absence of TRPV2. The prevalence of thermosensitive Aδ-fibers was too low to permit comparison between genotypes. Thus, TRPV2 is important for perinatal viability but is not essential for heat or mechanical nociception or hypersensitivity in the adult mouse.

The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system.

The existence of heterogeneous populations of dorsal root ganglion (DRG) neurons conveying different somatosensory information is the basis for the perception of touch, temperature, and pain. A differential expression of transient receptor potential (TRP) cation channels contributes to this functional heterogeneity. However, little is known about the development of functionally diverse neuronal subpopulations. Here, we use calcium imaging of acutely dissociated mouse sensory neurons and quantitative reverse transcription PCR to show that TRP cation channels emerge in waves, with the diversification of functional groups starting at embryonic day 12.5 (E12.5) and extending well into the postnatal life. Functional responses of voltage-gated calcium channels were present in DRG neurons at E11.5 and reached adult levels by E14.5. Responses to capsaicin, menthol, and cinnamaldehyde were first seen at E12.5, E16.5, and postnatal day 0 (P0), when the mRNA for TRP cation channel, subfamily V, member 1 (TRPV1), TRP cation channel, subfamily M, member 8 (TRPM8), and TRP cation channel, subfamily A, member 1 (TRPA1), respectively, was first detected. Cold-sensitive neurons were present before the expression or functional responses of TRPM8 or TRPA1. Our data support a lineage relationship in which TRPM8- and TRPA1-expressing sensory neurons derive from the population of TRPV1-expressing neurons. The TRPA1 subpopulation of neurons emerges independently in two distinct classes of nociceptors: around birth in the peptidergic population and after P14 in the nonpeptidergic class. This indicates that neurons with similar receptive properties can be generated in different sublineages at different developmental stages. This study describes for the first time the emergence of functional subtypes of sensory neurons, providing new insight into the development of nociception and thermoreception.

Vanilloid receptor 1 (TRPV1) has been proposed to be the principal heat-responsive channel for nociceptive neurons. The skin of both rat and mouse receives major projections from primary sensory afferents that bind the plant lectin isolectin B4 (IB4). The majority of IB4-positive neurons are known to be heat-responsive nociceptors. Previous studies suggested that, unlike rat, mouse IB4-positive cutaneous afferents did not express TRPV1 immunoreactivity. Here, multiple antisera were used to confirm that mouse and rat have different distributions of TRPV1 and that TRPV1 immunoreactivity is absent in heat-sensitive nociceptors. Intracellular recording in TRPV1(-/-) mice was then used to confirm that TRPV1 was not required for detecting noxious heat. TRPV1(-/-) mice had more heat-sensitive neurons, and these neurons had normal temperature thresholds and response properties. Moreover, in TRPV1(-/-) mice, 82% of heat-responsive neurons did not express immunoreactivity for TRPV2, another putative noxious heat channel.

Mice that overexpress nerve growth factor (NGF-OE) in the skin have double the normal number of cutaneous sensory neurons, have increased innervation of the skin and spinal cord, and are hyperalgesic. Here, we have asked whether the increased cutaneous NGF level results in a selective survival of only certain functional types of neurons and whether it changes the properties of cutaneous neurons. Using electron microscopy, we show that the number of both myelinated and unmyelinated nociceptors increases substantially in NGF-OE mice by a factor of 3.3 and 1.5, respectively. Using extracellular recordings from single units, we demonstrate that large myelinated (Abeta) fibers are unchanged in prevalence and receptive properties. In contrast, among thin myelinated (Adelta) fibers, the percentage of nociceptors increased from a normal 65 to 97%, consistent with a selective survival of nociceptors during embryogenesis. These afferents showed a twofold increase in their mechanical responsiveness, but their heat responsiveness remained normal. Among unmyelinated (C) fibers, there was a profound increase in the percentage of heat responsive neurons from a normal 42 to 96%. This change cannot be accounted for by a selective survival of heat-sensitive neurons. Unmyelinated nociceptors increased fourfold in their thermal responsiveness but decreased in mechanical responsiveness. Therefore, target-derived NGF selectively rescues nociceptors during the period of programmed cell death with different efficacy for thin myelinated or unmyelinated fibers. NGF also affects the response to noxious heat or mechanical stimuli in each group differently, implying specific regulations of transduction processes rather than general changes of excitability.

Mice lacking the major Schwann cell myelin component P0 show a severe dysmyelination with pathological features reminiscent of the Déjérine-Sottas syndrome in humans. Previous morphological and electrophysiological studies on these mice did not only demonstrate a compromised myelination and myelin maintenance, but were suggestive of an impairment of axons as well. Here, we studied the axonal pathology in P0-deficient mice by quantitative electron microscopy. In addition, we investigated epidermal receptor end organs by immunocytochemistry and muscle pathology by histochemistry. In proximal sections of facial and femoral nerves, axon calibers were significantly reduced, whereas the number of myelin-competent axons was not diminished in 5- and 17-month-old P0-deficient mice. However, in distal branches of the femoral and sciatic nerve (digital nerves innervating the skin of the first toe) the numbers of myelin-competent axons were reduced by 70% in 6-month-old P0-deficient mice. Immunolabeling of foot pads revealed a corresponding loss of Merkel cells by 75%, suggesting that survival of these cells is dependent on the presence or maintenance of their innervating myelinated axons. In addition, quadriceps and gastrocnemius muscles showed pathological features indicative of denervation and axonal sprouting. These findings demonstrate that loss of an important myelin component can initiate degenerative mechanisms not only in the Schwann cell but also in the distal portions of myelinated axons, leading to the degeneration of specialized receptor end organs and impairment of muscle innervation.

Neurotrophin-4 (NT4) is the most recently discovered neurotrophic factor in mammals and, functionally, the least well understood. Here, we used mice that lack NT4 to determine whether NT4 is required for the survival of functionally identified subclasses of cutaneous sensory neurons. By using three independent methods of histological and electrophysiological analysis, we show that NT4 is specifically required for the survival of down hair (D-hair) receptors that innervate a subpopulation of hair follicles. All other functionally distinct types of afferents neurons innervating hairy skin were not affected in their survival or in their function. Previous studies have shown that BDNF is required for the mechanical sensitivity of slowly adapting (SA) mechanoreceptors but not for the postnatal survival of myelinated cutaneous afferent fibers. In contrast, the receptive properties of SA mechanoreceptors were not impaired in animals lacking NT4. Consequently, these data show that the two trkB ligands, NT4 and BDNF, have distinct and nonoverlapping roles in supporting cutaneous sensory neurons. Whereas NT4 is required for the survival of D-hair receptors, BDNF supports the mechanical function of SA fibers.

Mice with a targeted deletion of the low-affinity neurotrophin receptor p75 (p75-/-) exhibit a 50% loss of large- and small-diameter sensory neurons in the dorsal root ganglion. Using neurophysiological recording techniques, we now show that p75 is not required for the survival of specific, functionally defined subpopulations of sensory neurons. Rather, p75-/- mice exhibit losses of neurons that subserve nociceptive as well as non-nociceptive functions. The receptive properties of large myelinated afferent fibers were normal in p75-/- mice. However, the receptive properties of subpopulations of afferent fibers with thin myelinated or unmyelinated axons were strikingly impaired in mice lacking p75. Furthermore, the presence of p75 is required for normal mechanotransduction in C fibers and D-hair receptors and normal heat sensitivity in A-fiber nociceptors.

We investigated the ability of human nociceptive primary afferent neurons to encode mechanical pain and to produce vasodilatation. Pain was induced by shooting a light metal cylinder (0.3 g) at different velocities (6-18 m/sec) perpendicularly against the hairy skin of the hand. When single impact stimuli were applied, monotonically increasing stimulus-response functions were obtained in 10 psychophysical experiments using magnitude estimation techniques. In 35 microneurographic experiments nine unmyelinated afferents were recorded from the superficial radial nerve. All units responded readily to impact stimulation even at stimulus intensities that were not rated as painful. However, there was a close linear correlation between the number of action potentials evoked from the nociceptors and the psychophysical magnitude estimates of the perceived sensation or the stimulus intensity. This was also reflected by a corresponding increase of neurogenic vasodilatation. While two thin myelinated afferents displayed qualitatively similar responses 12 low-threshold mechanosensitive afferents (4 rapidly adapting, 5 slowly adapting type 1, 3 slowly adapting type II) failed to encode the intensity of the applied impact force and often became desensitized. This indicates that the total number of action potentials is the determinant of the magnitude of mechanical pain and the associated vasodilatation following single brief stimuli. By contrast, the close correlation between nociceptor activity and sensation changed when trains of mechanical impact stimuli (five stimuli of constant intensity, intratrain frequency of 1/32 to 2 Hz) were applied. Magnitude estimates of pain intensity were frequency dependent and stimuli with short interstimulus intervals were perceived as more painful than those delivered with long intervals. However, the total number of action potentials evoked from C-fibers was higher at longer interstimulus intervals than shorter intervals, thus yielding a negative correlation between the magnitude estimates of the perceived painful sensation and the number of action potentials elicited from nociceptive afferents. This suggests that temporal summation of the nociceptive discharge at central neurons becomes increasingly more important for the sensory discriminative experience of pain evoked by repetitive stimulation. We conclude that human nociceptive C-fibers signal brief noxious mechanical stimuli by the total number of action potentials evoked during a short period of time. However, with repetitive stimulation the total number of action potentials evoked from nociceptors is less important for evoking pain and temporal summation of the nociceptive primary afferent discharge becomes the crucial factor for signaling the magnitude of sensation.