Cyclosporine A Decreases Dryness-Induced Hyperexcitability of Corneal Cold-Sensitive Nerve Terminals.

Cyclosporine A (CsA) is used for the treatment of dry eye (DE) with good clinical results, improving tear secretion and decreasing subjective symptoms. These effects are attributed to the improved tear film dynamics, but there are no data on the effect of CsA on the abnormal sensory nerve activity characteristic in DE. Our purpose was to evaluate the CsA effect on the enhanced activity of corneal cold thermoreceptors in a tear-deficient DE animal model using in vitro extracellular recording of cold thermoreceptors nerve terminal impulses (NTIs) before and in the presence of CsA. NTI shape was also analyzed. Blinking frequency and tearing rate were also measured in awake animals before and after topical CsA. CsA increased the tearing and blinking of treated animals. CsA significantly decreased the peak response to cold of cold thermoreceptors. Neither their spontaneous NTIs discharge rate nor their cooling threshold were modified. CsA also seemed to reverse some of the changes in NTI shape induced by tear deficiency. These data suggest that, at least in part, the beneficial clinical effects of CsA in DE can be attributed to a direct effect on sensory nerve endings, although the precise mechanisms underlying this effect need further studies to be fully clarified.

Trigger hair thermoreceptors provide for heat-induced calcium-electrical excitability in Venus flytrap.

Most plants suffer greatly from heat in general and fire in particular, but some can profit from what is called fire ecology.1Dionaea muscipula, the Venus flytrap, is one such plant. In its natural habitat in the Green Swamps, Dionaea often faces challenges from excessive growth of grass and evergreen shrubs that overshadow the plant.2 Without natural fire, the Dionaea populations would decline.3 How does Dionaea survive and even thrive after swamp fires? Here, we ask whether flytraps recognize heat waves at the forefront of swamp fires and demonstrate that a heat-sensor-based alarm may provide a fire survival strategy for them. In this study, we show that flytraps become electrically excited and close in response to a heat wave. Over a critical temperature of 38°C, traps fire action potentials (APs), which are interconnected with cytosolic Ca2+ transients. The heat-induced Ca2+-AP has a 3-min refractory period, yet traps still respond to cold, voltage, and glutamate. The heat responses were trap specific, emerging only when the trap became excitable. Upon heat stimulation, the Ca2+ wave originates in the trigger hair podium, indicating that the mechanosensory zone serves as a heat receptor organ. In contrast to the human heat receptor, the flytrap sensor detects temperature change rather than the absolute body temperature. We propose that by sensing the temperature differential, flytraps can recognize the heat of an approaching fire, thus closing before the trigger hairs are burned, while they can continue to catch prey throughout hot summers.

Exploiting the PIR Sensor Analog Behavior as Thermoreceptor: Movement Direction Classification Based on Spiking Neurons.

Pyroelectric infrared sensors (PIR) are widely used as infrared (IR) detectors due to their basic implementation, low cost, low power, and performance. Combined with a Fresnel lens, they can be used as a binary detector in applications of presence and motion control. Furthermore, due to their features, they can be used in autonomous intelligent devices or included in robotics applications or sensor networks. In this work, two neural processing architectures are presented: (1) an analog processing approach to achieve the behavior of a presynaptic neuron from a PIR sensor. An analog circuit similar to the leaky integrate and fire model is implemented to be able to generate spiking rates proportional to the IR stimuli received at a PIR sensor. (2) An embedded postsynaptic neuron where a spiking neural network matrix together with an algorithm based on digital processing techniques is introduced. This structure allows connecting a set of sensors to the post-synaptic circuit emulating an optic nerve. As a case study, the entire neural processing approach presented in this paper is applied to optical flow detection considering a four-PIR array as input. The results validate both the spiking approach for an analog sensor presented and the ability to retrieve the analog information sent as spike trains in a simulated optic nerve.

Blood-seeking horseflies prefer vessel-imitating temperature gradients on host-mimicking targets: Experimental corroboration of a new explanation of the visual unattractiveness of zebras to tabanids.

Several hypotheses tried to explain the advantages of zebra stripes. According to the most recent explanation, since the borderlines of sunlit white and black stripes can hamper thermal vessel detection by blood-seeking female horseflies, striped host animals are unattractive to these parasites which prefer hosts with a homogeneous coat, on which the temperature gradients above blood vessels can be detected more easily. This hypothesis has been tested in a field experiment with horseflies walking on a grey barrel with thin black stripes which were slightly warmer than their grey surroundings in sunshine, while in shade both areas had practically the same temperature. To eliminate the multiple (optical and thermal) cues of this test target, we repeated this experiment with improved test surfaces: we attracted horseflies by water- or host-imitating homogeneous black test surfaces, beneath which a heatable wire ran. When heated, this invisible and mechanically impalpable wire imitated thermally the slightly warmer subsurface blood vessels, otherwise it was thermally imperceptible. We measured the times spent by landed and walking horseflies on the test surface parts with and without underlying heated or unheated wire. We found that walking female and male horseflies had no preference for any (wired or wireless) area of the water-imitating horizontal plane test surface on the ground, independent of the temperature (heated or unheated) of the underlying wire. These horseflies looked for water, rather than a host. On the other hand, in the case of host-imitating test surfaces, female horseflies preferred the thin surface regions above the wire only if it was heated and thus warmer than its surroundings. This behaviour can be explained exclusively with the higher temperature of the wire given the lack of other sensorial cues. Our results prove the thermal vessel recognition of female horseflies and support the idea that sunlit zebra stripes impede the thermal detection of a host's vessels by blood-seeking horseflies, the consequence of which is the visual (non-thermal) unattractiveness of zebras to horseflies.

ThermoTRP channels in pain sexual dimorphism: new insights for drug intervention.

Chronic pain is a major burden for the society and remains more prevalent and severe in females. The presence of chronic pain is linked to persistent alterations in the peripheral and the central nervous system. One of the main types of peripheral pain transducers are the transient receptor potential channels (TRP), also known as thermoTRP channels, which intervene in the perception of hot and cold external stimuli. These channels, and especially TRPV1, TRPA1 and TRPM8, have been subjected to profound investigation because of their role as thermosensors and also because of their implication in acute and chronic pain. Surprisingly, their sensitivity to endogenous signaling has been far less studied. Cumulative evidence suggests that the function of these channels may be differently modulated in males and females, in part through sexual hormones, and this could constitute a significant contributor to the sex differences in chronic pain. Here, we review the exciting advances in thermoTRP pharmacology for males and females in two paradigmatic types of chronic pain with a strong peripheral component: chronic migraine and chemotherapy-induced peripheral neuropathy (CIPN). The possibilities of peripheral druggability offered by these channels and the differential exploitation for men and women represent a development opportunity that will lead to a significant increment of the armamentarium of analgesic medicines for personalized chronic pain treatment.

Skin-Inspired Thermoreceptors-Based Electronic Skin for Biomimicking Thermal Pain Reflexes.

Electronic systems possessing skin-like morphology and functionalities (electronic skins [e-skins]) have attracted considerable attention in recent years to provide sensory or haptic feedback in growing areas such as robotics, prosthetics, and interactive systems. However, the main focus thus far has been on the distributed pressure or force sensors. Herein a thermoreceptive e-skin with biological systems like functionality is presented. The soft, distributed, and highly sensitive miniaturized (≈700 µm2 ) artificial thermoreceptors (ATRs) in the e-skin are developed using an innovative fabrication route that involves dielectrophoretic assembly of oriented vanadium pentoxide nanowires at defined locations and high-resolution electrohydrodynamic printing. Inspired from the skin morphology, the ATRs are embedded in a thermally insulating soft nanosilica/epoxy polymeric layer and yet they exhibit excellent thermal sensitivity (-1.1 ± 0.3% °C-1 ), fast response (≈1s), exceptional stability (negligible hysteresis for >5 h operation), and mechanical durability (up to 10 000 bending and twisting loading cycles). Finally, the developed e-skin is integrated on the fingertip of a robotic hand and a biological system like reflex is demonstrated in response to temperature stimuli via localized learning at the hardware level.

The neural basis of heat seeking in a human-infective parasitic worm.

Soil-transmitted parasitic nematodes infect over one billion people and cause devastating morbidity worldwide. Many of these parasites have infective larvae that locate hosts using thermal cues. Here, we identify the thermosensory neurons of the human threadworm Strongyloides stercoralis and show that they display unique functional adaptations that enable the precise encoding of temperatures up to human body temperature. We demonstrate that experience-dependent thermal plasticity regulates the dynamic range of these neurons while preserving their ability to encode host-relevant temperatures. We describe a novel behavior in which infective larvae spontaneously reverse attraction to heat sources at sub-body temperatures and show that this behavior is mediated by rapid adaptation of the thermosensory neurons. Finally, we identify thermoreceptors that confer parasite-specific sensitivity to body heat. Our results pinpoint the parasite-specific neural adaptations that enable parasitic nematodes to target humans and provide the foundation for drug development to prevent human infection.

MnSOD functions as a thermoreceptor activated by low temperature.

A conservative characteristic of manganese superoxide dismutase is the rapid formation of product inhibition at high temperatures. At lower temperatures, the enzyme is less inhibited and undergoes more catalytic fast cycles before being product-inhibited. The temperature-dependent kinetics could be rationalized by the temperature-dependent coordination in the conserved center of manganese superoxide dismutase. As temperature decreases, a water molecule (WAT2) approaches or even coordinates Mn as the sixth ligand to interfere with O2•--Mn coordination and reduce product inhibition, so the dismutation should mainly proceed in the fast outer-sphere pathway at low temperatures. Cold-activation is an adaptive response to low temperature rather than a passive adaptation to excess superoxide levels since the cold-activated dismutase activity significantly exceeds the amount of superoxide in the cell or mitochondria. Physiologically speaking, cold activation of manganese superoxide dismutase mediates cold stress signaling and transduces temperature (physical signal) degree into H2O2 fluxes (chemical signal), which in turn may act as a second messenger to induce a series of physiological responses such as cold shock.

Differential Cutaneous Thermal Sensitivity in Humans: Method of Limit vs. Method of Sensation Magnitude.

INTRODUCTION: The method of limits (MLI) and method of level (MLE) are commonly employed for the quantitative assessment of cutaneous thermal sensitivity. Thermal sensation and thermal comfort are closely related and thermal sensations evoked from the peripheral thermoreceptors play an important role in thermoregulatory response to maintain normal body temperature. The purpose of this study was to compare the regional distribution of cutaneous warm and cold sensitivity between MLI and the method of sensation magnitude (MSM). METHOD: Twenty healthy men completed MLI and MSM to compare the regional distribution of cutaneous warm and cold sensitivity in the thermal neutral condition. The subjects rested on a bed in a supine position for 20 min. Next, the cutaneous thermal sensitivity of ten body sites was assessed by the means of MLI and MSM for both warmth and cold stimuli. RESULTS: The absolute mean heat flux in MLI and thermal sensation magnitude in MSM showed significantly greater sensitivity to cold than to warm stimulation (p < 0.01), together with a similar pattern of regional differences across ten body sites. Both sensory modalities indicated acceptable reliability (SRD%: 6.29-8.66) and excellent reproducibility (ICC: 0.826-0.906; p < 0.01). However, the Z-sore distribution in MSM was much narrower than in MLI, which may limit the test sensitivity for the detection of sensory disorders and/or comparison between individuals. CONCLUSION: The present results showed that both MLI and MSM are effective means for evaluating regional cutaneous thermal sensitivity to innocuous warm and cold stimulations to a strong degree of reliability and reproducibility.

Revisiting the evaluation of central versus peripheral thermoregulatory control in humans.

Human thermoregulatory control is often evaluated through the relationship between thermoeffector output and core or mean body temperature. In addition to providing a general indication of whether a variable of interest alters thermoregulatory control, this relationship is often used to determine how this alteration may occur. This latter interpretation relies upon two parameters of the thermoeffector output-body temperature relationship: the onset threshold and thermosensitivity. Traditionally, changes in the onset threshold and thermosensitivity are interpreted as "central" or "peripheral" modulation of thermoregulatory control, respectively. This mini-review revisits the origins of the thermoeffector output-body temperature relationship and its use to interpret "central" or "peripheral" modulation of thermoregulatory control. Against this background, we discuss the strengths and weaknesses of this approach and highlight that "central" thermoregulatory control reflects the neural control of body temperature whereas "peripheral" thermoregulatory control reflects properties specific to the thermoeffector organs. We highlight studies that employed more direct approaches to investigate the neural control of body temperature and peripheral properties of thermoeffector organs. We conclude by encouraging future investigations interested in studying thermoregulatory control to more directly investigate the component of the thermoeffector loop under investigation.heat; human; skin blood flow; sweat; thermoregulatory.

Predicting thermal pleasure experienced in dynamic environments from simulated cutaneous thermoreceptor activity.

Research into human thermal perception indoors has focused on "neutrality" under steady-state conditions. Recent interest in thermal alliesthesia has highlighted the hedonic dimension of our thermal world that has been largely overlooked by science. Here, we show the activity of sensory neurons can predict thermal pleasure under dynamic exposures. A numerical model of cutaneous thermoreceptors was applied to skin temperature measurements from 12 human subjects. A random forest model trained on simulated thermoreceptor impulses could classify pleasure responses (F1 score of 67%) with low false positives/negatives (4%). Accuracy increased (83%) when excluding the few extreme (dis)pleasure responses. Validation on an independent dataset confirmed model reliability. This is the first empirical demonstration of the relationship between thermoreceptors and pleasure arising from thermal stimuli. Insights into the neurophysiology of thermal perception can enhance the experience of built environments through designs that promote sensory excitation instead of neutrality.

The Behavioral Response to Heat in the Common Bed Bug, Cimex lectularius (Hemiptera: Cimicidae).

The bed bug, Cimex lectularius L., is a common ectoparasite found to live among its vertebrate hosts. Antennal segments in bugs are critical for sensing multiple cues in the environment for survival. To determine whether the thermo receptors of bed bugs are located on their antennae; innovative bioassays were created to observe the choice between heated and unheated stimuli and to characterize the response of bugs to a heat source. Additionally, the effect of complete antenectomized segments on heat detection were evaluated. Heat, carbon dioxide, and moisture are cues that are found to activate bed bug behavior; a temperature at 38°C was used to assess the direction/degree at which the insect reacts to the change in distance from said stimulus. Using a lightweight spherical ball suspended by air through a vacuum tube, bed bugs and other insects are able to move in 360° while on a stationary point. Noldus EthoVision XT was used to capture video images and to track the bed bugs during 5-min bioassays. A bioassay was created using four Petri dish arenas to observe bed bug attraction to heat based on antennae segments at 40°C. The purpose of this study was to evaluate the effects of heat on complete antenectomized segments of the antennae. The results in this experiment suggest that bed bugs detect and are attracted to heat modulated by nutritional status. Learning the involvement of antennae segments in heat detection will help identify the location and role of thermoreceptors for bed bug host interaction.

Correlation between nasal mucosal temperature change and the perception of nasal patency: a literature review.

BACKGROUND: The mechanism of nasal airflow sensation is poorly understood. This study aimed to examine the role of nasal mucosal temperature change in the subjective perception of nasal patency and the methods by which it can be quantified. METHOD: Medline and PubMed database searches were performed to retrieve literature relevant to the topic. RESULTS: The primary mechanism producing the sensation of nasal patency is thought to be the activation of transient receptor potential melastatin family member 8 ('TRPM8'), a thermoreceptor that is activated by nasal mucosal cooling. Computational fluid dynamics studies have demonstrated that increased airflow and heat flux are correlated with better patient-reported outcome measure scores. Similarly, physical measurements of the nasal cavity using temperature probes have shown a correlation between lower nasal mucosal temperatures and better patient-reported outcome measure scores. CONCLUSION: Nasal mucosal temperature change may be correlated with the perception of improved nasal patency. Future research should quantify the impact of mucosal cooling on the perception of nasal airway obstruction.

The Role of Thermosensitive Ion Channels in Mammalian Thermoregulation.

Ambient temperature detection and core body temperature maintenance are critical for the environment adaptability of mammals, requiring an elaborate neural network that converts the temperature information sensed by thermoreceptors into physiological and behavioral thermoregulatory responses. The molecular basis of thermosensation lies in the activation of various thermosensitive ion channels with distinct temperature thresholds expressed on the cell membrane of sensory neurons. These channels are able to convert thermal stimuli into electrical activities by gating ions into and out of the cell. In this chapter, we briefly introduce the physiological functions of the main thermosensitive ion channels involved in the core body temperature homeostasis orchestrated by the neural circuits in the peripheral and central nerve systems.

A mathematical model analyzing temperature threshold dependence in cold sensitive neurons.

Here we examine a class of neurons that have been recently explored, the somatosensory neuronal subclass of cold thermosensors. We create a mathematical model of a cold sensing neuron that has been formulated to understand the variety of ionic channels involved. In particular this model showcases the role of TRPM8 and voltage gated potassium channels in setting the temperature dependent activation and inactivation threshold level. Bifurcation analysis of the model demonstrates that a Hodgkin-Huxley type model with additional TRPM8 channels is sufficient to replicate observable experimental features of when different threshold level cold thermosensors turn on. Additionally, our analysis gives insight into what is happening at the temperature levels at which these neurons shut off and the role sodium and leak currents may have in this. This type of model construction and analysis provides a framework moving forward that will help tackle less well understood neuronal classes and their important ionic channels.

Thermoregulation in fish.

Thermoregulation is critical for survival and animals therefore employ strategies to keep their body temperature within a physiological range. As ectotherms, fish exclusively rely on behavioral strategies for thermoregulation. Different species of fish seek out their specific optimal temperatures through thermal navigation by biasing behavioral output based on experienced environmental temperatures. Like other vertebrates, fish sense water temperature using thermoreceptors in trigeminal and dorsal root ganglia neurons that innervate the skin. Recent research in larval zebrafish has revealed how neural circuits subsequently transform this sensation of temperature into thermoregulatory behaviors. Across fish species, thermoregulatory strategies rely on a modulation of swim vigor based on current temperature and a modulation of turning based on temperature change. Interestingly, temperature preferences are not fixed but depend on other environmental cues and internal states. The following review is intended as an overview on the current knowledge as well as open questions in fish thermoregulation.

New neurophysiological human thermal model based on thermoreceptor responses.

A new neurophysiological human thermal model based on thermoreceptor responses, the NHTM model, has been developed to predict regulatory responses and physiological variables in asymmetric transient environments. The passive system is based on Wissler's model, which is more complex and refined. Wissler's model segments the human body into 21 cylindrical parts. Each part is divided into 21 layers, 15 for the tissues and 6 for clothes, and each layer is divided into 12 angular sectors. Thus, we have 3780 nodes for the tissues and 1512 for clothes. The passive system simulates heat exchange within the body and between the body and the surroundings. The active system is composed of the thermoregulatory mechanisms, i.e., skin blood flow, shivering thermogenesis, and sweating. The skin blood flow model and the shivering model are based on thermoreceptor responses. The sweating model is that of Fiala et al. and is based on error signals. The NHTM model was compared with Wissler's model, and the results showed that a calculation based on neurophysiology can improve the performance of the thermoregulation model. The NHTM model was more accurate in the prediction of mean skin temperature, with a mean absolute error of 0.27 °C versus 0.80 °C for the original Wissler model. The prediction accuracy of the NHTM model for local skin temperatures and core temperature could be improved via an optimization method to prove the ability of the new thermoregulation model to fit with the physiological characteristics of different populations.

Connectomics Analysis Reveals First-, Second-, and Third-Order Thermosensory and Hygrosensory Neurons in the Adult Drosophila Brain.

Animals exhibit innate and learned preferences for temperature and humidity-conditions critical for their survival and reproduction. Leveraging a whole-brain electron microscopy volume, we studied the adult Drosophila melanogaster circuitry associated with antennal thermo- and hygrosensory neurons. We have identified two new target glomeruli in the antennal lobe, in addition to the five known ones, and the ventroposterior projection neurons (VP PNs) that relay thermo- and hygrosensory information to higher brain centers, including the mushroom body and lateral horn, seats of learned and innate behavior. We present the first connectome of a thermo- and hygrosensory neuropil, the lateral accessory calyx (lACA), by reconstructing neurons downstream of heating- and cooling-responsive VP PNs. A few mushroom body-intrinsic neurons solely receive thermosensory input from the lACA, while most receive additional olfactory and thermo- and/or hygrosensory PN inputs. Furthermore, several classes of lACA-associated neurons form a local network with outputs to other brain neuropils, suggesting that the lACA serves as a hub for thermo- and hygrosensory circuitry. For example, DN1a neurons link thermosensory PNs in the lACA to the circadian clock via the accessory medulla. Finally, we survey strongly connected downstream partners of VP PNs across the protocerebrum; these include a descending neuron targeted by dry-responsive VP PNs, meaning that just two synapses might separate hygrosensory inputs from motor circuits. These data provide a comprehensive first- and second-order layer analysis of Drosophila thermo- and hygrosensory systems and an initial survey of third-order neurons that could directly modulate behavior.

Negative Modulation of TRPM8 Channel Function by Protein Kinase C in Trigeminal Cold Thermoreceptor Neurons.

TRPM8 is the main molecular entity responsible for cold sensing. This polymodal ion channel is activated by cold, cooling compounds such as menthol, voltage, and rises in osmolality. In corneal cold thermoreceptor neurons (CTNs), TRPM8 expression determines not only their sensitivity to cold, but also their role as neural detectors of ocular surface wetness. Several reports suggest that Protein Kinase C (PKC) activation impacts on TRPM8 function; however, the molecular bases of this functional modulation are still poorly understood. We explored PKC-dependent regulation of TRPM8 using Phorbol 12-Myristate 13-Acetate to activate this kinase. Consistently, recombinant TRPM8 channels, cultured trigeminal neurons, and free nerve endings of corneal CTNs revealed a robust reduction of TRPM8-dependent responses under PKC activation. In corneal CTNs, PKC activation decreased ongoing activity, a key parameter in the role of TRPM8-expressing neurons as humidity detectors, and also the maximal cold-evoked response, which were validated by mathematical modeling. Biophysical analysis indicated that PKC-dependent downregulation of TRPM8 is mainly due to a decreased maximal conductance value, and complementary noise analysis revealed a reduced number of functional channels at the cell surface, providing important clues to understanding the molecular mechanisms of how PKC activity modulates TRPM8 channels in CTNs.