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.

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.

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.

Temperature signaling underlying thermotaxis and cold tolerance in Caenorhabditis elegans.

Caenorhabditis elegans has a simple nervous system of 302 neurons. It however senses environmental cues incredibly precisely and produces various behaviors by processing information in the neural circuit. In addition to classical genetic analysis, fluorescent proteins and calcium indicators enable in vivo monitoring of protein dynamics and neural activity on either fixed or free-moving worms. These analyses have provided the detailed molecular mechanisms of neuronal and systemic signaling that regulate worm responses. Here, we focus on responses of C. elegans against temperature and review key findings that regulate thermotaxis and cold tolerance. Thermotaxis of C. elegans has been studied extensively for almost 50 years, and cold tolerance is a relatively recent concept in C. elegans. Although both thermotaxis and cold tolerance require temperature sensation, the responsible neurons and molecular pathways are different, and C. elegans uses the proper mechanisms depending on its situation. We summarize the molecular mechanisms of the major thermosensory circuit as well as the modulatory strategy through neural and tissue communication that enables fine tuning of thermotaxis and cold tolerance.

Context-dependent operation of neural circuits underlies a navigation behavior in Caenorhabditis elegans.

The nervous system evaluates environmental cues and adjusts motor output to ensure navigation toward a preferred environment. The nematode Caenorhabditis elegans navigates in the thermal environment and migrates toward its cultivation temperature by moving up or down thermal gradients depending not only on absolute temperature but on relative difference between current and previously experienced cultivation temperature. Although previous studies showed that such thermal context-dependent opposing migration is mediated by bias in frequency and direction of reorientation behavior, the complete neural pathways-from sensory to motor neurons-and their circuit logics underlying the opposing behavioral bias remain elusive. By conducting comprehensive cell ablation, high-resolution behavioral analyses, and computational modeling, we identified multiple neural pathways regulating behavioral components important for thermotaxis, and demonstrate that distinct sets of neurons are required for opposing bias of even single behavioral components. Furthermore, our imaging analyses show that the context-dependent operation is evident in sensory neurons, very early in the neural pathway, and manifested by bidirectional responses of a first-layer interneuron AIB under different thermal contexts. Our results suggest that the contextual differences are encoded among sensory neurons and a first-layer interneuron, processed among different downstream neurons, and lead to the flexible execution of context-dependent behavior.

Insect responses to heat: physiological mechanisms, evolution and ecological implications in a warming world.

Surviving changing climate conditions is particularly difficult for organisms such as insects that depend on environmental temperature to regulate their physiological functions. Insects are extremely threatened by global warming, since many do not have enough physiological tolerance even to survive continuous exposure to the current maximum temperatures experienced in their habitats. Here, we review literature on the physiological mechanisms that regulate responses to heat and provide heat tolerance in insects: (i) neuronal mechanisms to detect and respond to heat; (ii) metabolic responses to heat; (iii) thermoregulation; (iv) stress responses to tolerate heat; and (v) hormones that coordinate developmental and behavioural responses at warm temperatures. Our review shows that, apart from the stress response mediated by heat shock proteins, the physiological mechanisms of heat tolerance in insects remain poorly studied. Based on life-history theory, we discuss the costs of heat tolerance and the potential evolutionary mechanisms driving insect adaptations to high temperatures. Some insects may deal with ongoing global warming by the joint action of phenotypic plasticity and genetic adaptation. Plastic responses are limited and may not be by themselves enough to withstand ongoing warming trends. Although the evidence is still scarce and deserves further research in different insect taxa, genetic adaptation to high temperatures may result from rapid evolution. Finally, we emphasize the importance of incorporating physiological information for modelling species distributions and ecological interactions under global warming scenarios. This review identifies several open questions to improve our understanding of how insects respond physiologically to heat and the evolutionary and ecological consequences of those responses. Further lines of research are suggested at the species, order and class levels, with experimental and analytical approaches such as artificial selection, quantitative genetics and comparative analyses.

Mosquito heat seeking is driven by an ancestral cooling receptor.

Mosquitoes transmit pathogens that kill >700,000 people annually. These insects use body heat to locate and feed on warm-blooded hosts, but the molecular basis of such behavior is unknown. Here, we identify ionotropic receptor IR21a, a receptor conserved throughout insects, as a key mediator of heat seeking in the malaria vector Anopheles gambiae Although Ir21a mediates heat avoidance in Drosophila, we find it drives heat seeking and heat-stimulated blood feeding in Anopheles At a cellular level, Ir21a is essential for the detection of cooling, suggesting that during evolution mosquito heat seeking relied on cooling-mediated repulsion. Our data indicate that the evolution of blood feeding in Anopheles involves repurposing an ancestral thermoreceptor from non-blood-feeding Diptera.

Evidence for the involvement of peripheral cold-sensitive TRPM8 channels in human cutaneous hygrosensation.

In contrast to other species, humans are believed to lack hygroreceptors for sensing skin wetness. Yet, the molecular basis of human hygrosensation is currently unknown, and it remains unclear whether we possess a receptor-mediated sensing mechanism for skin wetness. The aim of this study was to assess the role of the cutaneous cold-sensitive transient receptor potential melastatin-8 (TRPM8) channel as a molecular mediator of human hygrosensation. To this end, we exploited both the thermal and chemical activation of TRPM8-expressing cutaneous Aδ cold thermoreceptors, and we assessed wetness sensing in healthy young men in response to 1) dry skin cooling in the TRPM8 range of thermosensitivity and 2) application of the TRPM8 agonist menthol. Our results indicate that 1) independently of contact with moisture, a cold-dry stimulus in the TRPM8 range of activation induced wetness perceptions across 12 different body regions and those wetness perceptions varied across the body following regional differences in cold sensitivity; and 2) independently of skin cooling, menthol-induced stimulation of TRPM8 triggered wetness perceptions that were greater than those induced by physical dry cooling and by contact with an aqueous cream containing actual moisture. For the first time, we show that the cutaneous cold-sensing TRPM8 channel plays the dual role of cold and wetness sensor in human skin and that this ion channel is a peripheral mediator of human skin wetness perception.

Feeling the heat at the millennium: Thermosensors playing with fire.

An outstanding question regards the ability of organisms to sense their environments and respond in a suitable way. Pathogenic bacteria in particular exploit host-temperature sensing as a cue for triggering virulence gene expression. This micro-review does not attempt to fully cover the field of bacterial thermosensors and in detail describe each identified case. Instead, the review focus on the time-period at the end of the 1990's and beginning of the 2000's when several key discoveries were made, identifying protein, DNA and RNA as potential thermosensors controlling gene expression in several different bacterial pathogens in general and on the prfA thermosensor of Listeria monocytogenes in particular.

Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage.

The cornea is extensively innervated by trigeminal ganglion cold thermoreceptor neurons expressing TRPM8 (transient receptor potential cation channel subfamily M member 8). These neurons respond to cooling, hyperosmolarity and wetness of the corneal surface. Surgical injury of corneal nerve fibers alters tear production and often causes dry eye sensation. The contribution of TRPM8-expressing corneal cold-sensitive neurons (CCSNs) to these symptoms is unclear. Using extracellular recording of CCSNs nerve terminals combined with in vivo confocal tracking of reinnervation, Ca2+ imaging and patch-clamp recordings of fluorescent retrogradely labeled corneal neurons in culture, we analyzed the functional modifications of CCSNs induced by peripheral axonal damage in male mice. After injury, the percentage of CCSNs, the cold- and menthol-evoked intracellular [Ca2+] rises and the TRPM8 current density in CCSNs were larger than in sham animals, with no differences in the brake K+ current IKD Active and passive membrane properties of CCSNs from both groups were alike and corresponded mainly to those of canonical low- and high-threshold cold thermoreceptor neurons. Ongoing firing activity and menthol sensitivity were higher in CCSN terminals of injured mice, an observation accounted for by mathematical modeling. These functional changes developed in parallel with a partial reinnervation of the cornea by TRPM8(+) fibers and with an increase in basal tearing in injured animals compared with sham mice. Our results unveil key TRPM8-dependent functional changes in CCSNs in response to injury, suggesting that increased tearing rate and ocular dryness sensation derived from deep surgical ablation of corneal nerves are due to enhanced functional expression of TRPM8 channels in these injured trigeminal primary sensory neurons.SIGNIFICANCE STATEMENT We unveil a key role of TRPM8 channels in the sensory and autonomic disturbances associated with surgical damage of eye surface nerves. We studied the damage-induced functional alterations of corneal cold-sensitive neurons using confocal tracking of reinnervation, extracellular corneal nerve terminal recordings, tearing measurements in vivo, Ca2+ imaging and patch-clamp recordings of cultured corneal neurons, and mathematical modeling. Corneal nerve ablation upregulates TRPM8 mainly in canonical cold thermoreceptors, enhancing their cold and menthol sensitivity, inducing a rise in the ongoing firing activity of TRPM8(+) nerve endings and an increase in basal tearing. Our results suggest that unpleasant dryness sensations, together with augmented tearing rate after corneal nerve injury, are largely due to upregulation of TRPM8 in cold thermoreceptor neurons.

Specialized cutaneous Schwann cells initiate pain sensation.

An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.

Assessment of overall body thermal sensation based on the thermal response of local cutaneous thermoreceptors.

In non-uniform environments, different body parts may experience different ranges of physical/environmental parameters. Therefore, to assess the overall thermal sensation in non-uniform environments, the local temperature/thermal sensation of various body parts should be calculated. The local temperature/thermal sensation based on cutaneous thermoreceptor (TRs) responses has been evaluated using MSTB (Multi-Segmental Thermoregulatory Bioheat) model and LTRESP (Local Thermal Response) index in our recent studies. In the present study, a new combined method was proposed to evaluate the overall thermal sensation considering the effects of local sensations of various body segments. In this new method, the local sensations predicted by LTRESP index were defined as the input data for UCB model to predict the overall thermal sensation. So, there was no need to feed it with experimental data to assess the whole-body thermal sensation. Meanwhile, in this method, the overall thermal sensation was predicted taking into account the cutaneous TRs thermal responses. The results indicated that the new combined method could evaluate the overall thermal sensation with a reasonable accuracy under different environmental conditions. Thus, the new method could be practical for predicting the overall thermal sensation in both uniform and non-uniform thermal environments.

Profiling of how nociceptor neurons detect danger - new and old foes.

The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro-immune interplay is still ill-defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH 1-mediated immunity but also as drivers of TH 2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide-ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

Thermosensory mapping of skin wetness sensitivity across the body of young males and females at rest and following maximal incremental running.

KEY POINTS: Humans lack skin receptors for wetness (i.e. hygroreceptors), yet we present a remarkable wetness sensitivity. Afferent inputs from skin cold-sensitive thermoreceptors are key for sensing wetness; yet, it is unknown whether males and females differ in their wetness sensitivity across their body and whether high intensity exercise modulates this sensitivity. We mapped sensitivity to cold, neutral and warm wetness across five body regions and show that females are more sensitive to skin wetness than males, and that this difference is greater for cold than warm wetness sensitivity. We also show that a single bout of maximal exercise reduced the sensitivity to skin wetness (i.e. hygro-hypoesthesia) of both sexes as a result of concurrent decreases in thermal sensitivity. These novel findings clarify the physiological mechanisms underpinning this fundamental human sensory experience. In addition, they indicate sex differences in thermoregulatory responses and will inform the design of more effective sport and protective clothing, as well as thermoregulatory models. ABSTRACT: Humans lack skin hygroreceptors and we rely on integrating cold and tactile inputs from A-type skin nerve fibres to sense wetness. Yet, it is unknown whether sex and exercise independently modulate skin wetness sensitivity across the body. We mapped local sensitivity to cold, neutral and warm wetness of the forehead, neck, underarm, lower back and dorsal foot in 10 males (27.8 ± 2.7 years; 1.92 ± 0.1 m2 body surface area) and 10 females (25.4 ± 3.9 years; 1.68 ± 0.1 m2 body surface area), at rest and post maximal incremental running. Participants underwent our quantitative sensory test where they reported the magnitude of thermal and wetness perceptions (visual analogue scale) resulting from the application of a cold (5°C below skin temperature) wet (0.8 mL of water), neutral wet and warm wet (5°C above skin temperature) thermal probe (1.32 cm2 ) to five skin sites. We found that: (i) females were ∼14% to ∼17% more sensitive to cold-wetness than males, yet both sexes were as sensitive to neutral- and warm-wetness; (ii) regional differences were present for cold-wetness only, and these followed a craniocaudal increase that was more pronounced in males (i.e. the foot was ∼31% more sensitive than the forehead); and (iii) maximal exercise reduced cold-wetness sensitivity over specific regions in males (i.e. ∼40% decrease in foot sensitivity), and also induced a generalized reduction in warm-wetness sensitivity in both sexes (i.e. ∼4% to ∼6%). For the first time, we show that females are more sensitive to cold wetness than males and that maximal exercise induce hygro-hypoesthesia. These novel findings expand our knowledge on sex differences in thermoregulatory physiology.

Patch-Clamp Combined with Fast Temperature Jumps to Study Thermal TRP Channels.

Patch-clamp recording combined with biophysical modeling and mutagenic perturbations provides an effective means to study structural functions of ion channels. The methodology has been successful for studying ligand- or voltage-gated channels and brought about much of the knowledge we know today on how ligand or voltage gates an ion channel. The approach, when applied to thermal channels, however, has faced unique challenges. For one problem, thermal channels can operate at high temperatures, and for these channels, prolonged temperature stimulation incurs excessive thermal stress to destabilize patches. For another problem, conventional temperature controls are slow and limit the attainment of high resolution data such as time-resolved activations of thermal channels. Due to these issues, thermal channels have been less accessible to biophysical studies at mechanistic levels. In this chapter we address the problems and demonstrate fast temperature controls enabling recording of time-resolved responses of thermal channels at high temperatures.

Probing the coding logic of thermosensation using spinal cord calcium imaging.

The spinal cord dorsal horn is the first relay station of the neural network for processing somatosensory information. High-throughput optical recording methods facilitate the study of sensory coding in the cortex but have not been successfully applied to study spinal cord circuitry until recently. Here, we review the development of an in vivo two-photon spinal calcium imaging preparation and biological findings from the first systematic characterization of the spinal response to cutaneous thermal stimuli, focusing on the difference between the coding of heat and cold, and the contribution of different peripheral inputs to thermosensory response in the spinal cord. Here we also report that knockout of TRPV1 channel impairs sensation of warmth, and somatostatin- and calbindin2-expressing neurons in the spinal dorsal horn preferentially respond to heat. Future work combining this technology with genetic tools and animal models of chronic pain will further elucidate the role of each neuronal type in the spinal thermosensory coding and their plasticity under pathological condition.

Thermonociceptive interaction: interchannel pain modulation occurs before intrachannel convergence of warmth.

Nonnoxious warmth reduces both perceived pain intensity and the amplitude of EEG markers of pain. However, the spatial properties of thermonociceptive interaction, and the level of sensory processing at which it occurs, remain unclear. We investigated whether interchannel warmth-pain interactions occur before or after intrachannel spatial summation of warmth. Warm stimuli were applied to the fingers of the right hand. Their number and location were manipulated in different conditions. A concomitant noxious test pulse was delivered to the middle finger using a CO2 laser. We replicated the classical suppressive effect of warmth on both perceived pain intensity and EEG markers. Importantly, inhibition of pain was not affected by the location and the number of thermal stimuli, even though they increased the perceived intensity of warmth. Our results therefore suggest that the inhibitory effect of warmth on pain is not somatotopically organized. The results also rule out the possibility that warmth affects nociceptive processing after intrachannel warmth summation. NEW & NOTEWORTHY We used spatial summation of warmth as a model to investigate thermonociceptive interactions. Painful CO2 laser pulses were delivered during different thermal conditions. We found that warmth inhibited pain regardless of its location. Crucially, spatial summation of multiple warm stimuli did not further inhibit pain. These findings suggest that warmth-pain interaction occurs independently of or after spatial summation of warmth.

Cells and circuits for thermosensation in mammals.

How is temperature detected and how is the resulting sensory information synthesized to produce appropriate thermosensory responses? Research in the last few years has gone a long way to answering the first part of this question. Excitingly, recent research has uncovered some of the ways sensory inputs are processed spinally, as well as identifying supra-spinal centers involved in processing responses to thermal stimuli. In this review, we explore the new areas of research that have contributed to our comprehension of the way the peripheral sensory neurons are tuned in addition to the receptors used to differentiate thermal stimuli. We also describe recent work which begins to illuminate the processing of primary sensory signals by the spinal cord and regions of the brain.

Temperature of water ingested before exercise alters the onset of physiological heat loss responses.

This study sought to determine whether the temperature of water ingested before exercise alters the onset threshold and subsequent thermosensitivity of local vasomotor and sudomotor responses after exercise begins. Twenty men [24 (SD 4) yr of age, 75.8 (SD 8.1) kg body mass, 52.3 (SD 7.7) ml·min-1·kg-1 peak O2 consumption (V̇o2peak)] ingested 1.5°C, 37°C, or 50°C water (3.2 ml/kg), rested for 5 min, and then cycled at 50% V̇o2peak for 15 min at 23.0 (SD 0.9) °C and 32 (SD 10) % relative humidity. Mean body temperature (Tb), local sweat rate (LSR), and skin blood flow (SBF) were measured. In a subset of eight men [25 (SD 5) yr of age, 78.6 (SD 8.3) kg body mass, 48.9 (SD 11.1) ml·min-1·kg-1 V̇o2peak], blood pressure was measured and cutaneous vascular conductance (CVC) was determined. The change in Tb was greater at the onset of LSR measurement with ingestion of 1.5°C than 50°C water [ΔTb = 0.19 (SD 0.15) vs. 0.11 (SD 0.12) °C, P = 0.04], but not 37°C water [ΔTb = 0.14 (SD 0.14) °C, P = 0.23], but did not differ between trials for SBF measurement [ΔTb = 0.18 (SD 0.15) °C, 0.11 (SD 0.13) °C, and 0.09 (SD 0.09) °C with 1.5°C, 37°C, and 50°C water, respectively, P = 0.07]. Conversely, the thermosensitivity of LSR and SBF was not different [LSR = 1.11 (SD 0.75), 1.11 (SD 0.75), and 1.34 (SD 1.11) mg·min-1·cm-2·°C-1 with 1.5°C, 37°C, and 50°C ingested water, respectively ( P = 0.46); SBF = 717 (SD 882), 517 (SD 606), and 857 (SD 904) %baseline arbitrary units (AU)/°C with 1.5°C, 37°C, and 50°C ingested water, respectively ( P = 0.95)]. After 15 min of exercise, LSR and SBF were greater with ingestion of 50°C than 1.5°C water [LSR = 0.40 (SD 0.17) vs. 0.31 (SD 0.19) mg·min-1·cm-2 ( P = 0.02); SBF = 407 (SD 149) vs. 279 (SD 117) %baseline AU ( P < 0.001)], but not 37°C water [LSR = 0.50 (SD 0.22) mg·min-1·cm-2; SBF = 324 (SD 169) %baseline AU]. CVC was statistically unaffected [275 (SD 81), 340 (SD 114), and 384 (SD 160) %baseline CVC with 1.5°C, 37°C, and 50°C ingested water, respectively, P = 0.30]. Collectively, these results support the concept that visceral thermoreceptors modify the central drive for thermoeffector responses.

A new local index for predicting local thermal response of individual body segments.

Physiologically, the thermal sensation/perception of human body is related to the response of cutaneous thermoreceptors (TRs) to the environment. However, the thermal response of skin warm and cold TRs is a function of two important factors: TRs temperatures and their time derivative at the subcutaneous locations of TRs. The available thermal models based on TRs response consider the same sensitivity for all thermal receptors of body. Thus, they estimate an average value of thermal response for whole body TRs. Therefore, considering the physiological thermal perception of humans, this study has presented a local thermal response index for estimating local sensation of different body segments based on local thermal response of individual TRs. Further, this index has used the ASHRAE thermal sensation scales to express the TRs thermal responses. Also, the new multi-segmental thermoregulatory bioheat model (MSTB) is utilized to calculate the individual TRs temperature. Finally, the predicted local thermal sensation by the new local index has been compared with published measured data under uniform/non-uniform thermal conditions. The results show that the local thermal sensation of individual body parts could be evaluated by the new local predictive index (LTRESP) with reasonable accuracy under various thermal conditions.