Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236-155.742 Mb) and chromosome 13 (72.969-89.423 Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome-wide significant cis-eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.

The ability to feel hot and cold is critical for animals and human beings to survive in the natural environment. Unlike other sensations, the physiology of cold sensation is mostly unknown. In the present study, we use genetically modified mice that do not express nerve growth factor-inducible B (NGFIB) to investigate the possible role of NGFIB in cold sensation. We found that genetic deletion of NGFIB selectively affected behavioral responses to cold stimuli while behavioral responses to noxious heat or mechanical stimuli were normal. Furthermore, behavioral responses remained reduced or blocked in NGFIB knockout mice even after repetitive application of cold stimuli. Our results provide strong evidence that the first transcription factor NGFIB determines the ability of animals to respond to cold stimulation.

Diabetic foot is a common severe complication of diabetes, and its main symptom is diabetic foot ulcer. The production of plantar diabetic foot ulcers is usually affected by two factors, namely neuropathy or vascular disease. While previous studies proved that stochastic resonance (SR) could effectively enhance the plantar touch of patients with diabetic feet, the potential impact of SR on neural circuit feedback, especially on the input of the tactile nerves of the lower limbs, is less clear. This study aims to explore the potential impact on the tactile threshold of the human foot when using vibrating insoles. We study a white noise vibration insole based on SR mechanism. We compare and analyze the tactile threshold voltage (TTV) triggered by an electrical stimulation device in three main plantar pressure-bearing areas (the second metatarsal (M2), the fourth metatarsal (M4), and the heel (H) area) of 8 participants using EEG and self-developed vibration insole. Significance found in M2 and M4 areas, white noise signal (WNS) lowered the tactile threshold in these areas, and had a potentially positive impact on patients with diabetic feet, especially in the M4 area. The influence of WNS on the plantar heel area was still controversial. This study showed that WNS applied to the sole could improve the plantar tactile sensing ability of patients with diabetic feet, but it did not cover all areas. The application of WNS showed better benefits for the forefoot area than for the hindfoot area, which was speculated that may be related to the difference in the distribution density of blood vessels in plantar areas. Due to the impaired natural touch in participants with diabetic foot, using artificial evoked sensation WNS intervention, would be a feasible approach to improve plantar sensation.

Intravital microscopy is a powerful tool in neuroscience but has not been adapted to the taste sensory organ due to anatomical constraint. Here we developed an imaging window to facilitate microscopic access to the murine tongue in vivo. Real-time two-photon microscopy allowed the visualization of three-dimensional microanatomy of the intact tongue mucosa and functional activity of taste cells in response to topically administered tastants in live mice. Video microscopy also showed the calcium activity of taste cells elicited by small-sized tastants in the blood circulation. Molecular kinetic analysis suggested that intravascular taste sensation takes place at the microvilli on the apical side of taste cells after diffusion of the molecules through the pericellular capillaries and tight junctions in the taste bud. Our results demonstrate the capabilities and utilities of the new tool for taste research in vivo.

Loss of tactile sensation is a common occurrence in patients with traumatic peripheral nerve injury or soft tissue loss, but as yet, solutions for restoring such sensation are limited. Implanted neuro-prosthetics are a promising direction for tactile sensory restoration, but available technologies have substantial shortcomings, including complexity of use and of production and the need for an external power supply. In this work, we propose, fabricate, and demonstrate the use of a triboelectric nanogenerator (TENG) as a relatively simple, self-powered, biocompatible, sensitive, and flexible device for restoring tactile sensation. This integrated tactile TENG (TENG-IT) device is implanted under the skin and translates tactile pressure into electrical potential, which it relays via cuff electrodes to healthy sensory nerves, thereby stimulating them, to mimic tactile sensation. We show that the device elicits electrical activity in sensory neurons in vitro, and that the extent of this activity is dependent on the level of tactile pressure applied to the device. We subsequently demonstrate the TENG-IT in vivo, showing that it provides tactile sensation capabilities (as measured by a von Frey test) to rats in which sensation in the hindfoot was blocked through transection of the distal tibial nerve. These findings point to the substantial potential of self-powered TENG-based implanted devices as a means of restoring tactile sensation.

STIM1 has been identified as a new warm sensor, but the exact molecular mechanism remains unclear. In this study, a variety of mutants of STIM1, Orai1 and Orai3 were generated. The single-cell calcium imaging and confocal analysis were used to evaluate the thermal sensitivity of the resulting STIM mutants and the interaction between STIM1 and Orai mutants in response to temperature. Our results suggested that the CC1-SOAR of STIM1 was a direct activation domain of temperature, leading to subsequent STIM1 activation, and the transmembrane (TM) region and K domain but not EF-SAM were needed for this process. Furthermore, both the TM and SOAR domains exhibited similarities and differences between STIM1-mediated thermal sensation and store-operated calcium entry (SOCE), and the key sites of Orai1 showed similar roles in these two responses. Additionally, the TM23 (comprising TM2, loop2, and TM3) region of Orai1 was identified as the key domain determining the STIM1/Orai1 thermal response pattern, while the temperature reactive mode of STIM1/Orai3 seemed to result from a combined effect of Orai3. These findings provide important support for the specific molecular mechanism of STIM1-induced thermal response, as well as the interaction mechanism of STIM1 with Orai1 and Orai3 after being activated by temperature.

Animals display wide-ranging evolutionary adaptations based on their ecological niche. Octopuses explore the seafloor with their flexible arms using a specialized "taste by touch" system to locally sense and respond to prey-derived chemicals and movement. How the peripherally distributed octopus nervous system mediates relatively autonomous arm behavior is unknown. Here, we report that octopus arms use a family of cephalopod-specific chemotactile receptors (CRs) to detect poorly soluble natural products, thereby defining a form of contact-dependent, aquatic chemosensation. CRs form discrete ion channel complexes that mediate the detection of diverse stimuli and transduction of specific ionic signals. Furthermore, distinct chemo- and mechanosensory cells exhibit specific receptor expression and electrical activities to support peripheral information coding and complex chemotactile behaviors. These findings demonstrate that the peripherally distributed octopus nervous system is a key site for signal processing and highlight how molecular and anatomical features synergistically evolve to suit an animal's environmental context.

The ion-channel TRPV1 is believed to be a major sensor of noxious heat, but surprisingly animals lacking TRPV1 still display marked responses to elevated temperature. In this study, we explored the role of TRPV1-expressing neurons in somatosensation by generating mice wherein this lineage of cells was selectively labelled or ablated. Our data show that TRPV1 is an embryonic marker of many nociceptors including all TRPV1- and TRPM8-neurons as well as many Mrg-expressing neurons. Mutant mice lacking these cells are completely insensitive to hot or cold but in marked contrast retain normal touch and mechanical pain sensation. These animals also exhibit defective body temperature control and lose both itch and pain reactions to potent chemical mediators. Together with previous cell ablation studies, our results define and delimit the roles of TRPV1- and TRPM8-neurons in thermosensation, thermoregulation and nociception, thus significantly extending the concept of labelled lines in somatosensory coding.

Observing someone else in pain produces a shared emotional experience that predominantly activates brain areas processing the emotional component of pain. Occasionally, however, sensory areas are also activated and there are anecdotal reports of people sharing both the somatic and emotional components of someone else's pain. Here we presented a series of images or short clips depicting noxious events to a large group of normal controls. Approximately one-third of this sample reported an actual noxious somatic experience in response to one or more of the images or clips. Ten of these pain responders were subsequently recruited and matched with 10 non-responders to take part in an fMRI study. The subjects were scanned while observing static images of noxious events. In contrast with emotional images not containing noxious events the responders activated emotional and sensory brain regions associated with pain while the non-responders activated very little. These findings provide convincing evidence that some people can readily experience both the emotional and sensory components of pain during observation of other's pain resulting in a shared physical pain experience.

Timing emerges from a hierarchy of computations ranging from early encoding of physical duration (time sensation) to abstract time representations (time perception) suitable for storage and decisional processes. However, the neural basis of the perceptual experience of time remains elusive. To address this, we dissociate brain activity uniquely related to lower-level sensory and higher-order perceptual timing operations, using event-related fMRI. Participants compared subsecond (500 msec) sinusoidal gratings drifting with constant velocity (standard) against two probe stimuli: (1) control gratings drifting at constant velocity or (2) accelerating gratings, which induced illusory shortening of time. We tested two probe intervals: a 500-msec duration (Short) and a longer duration required for an accelerating probe to be perceived as long as the standard (Long-individually determined). On each trial, participants classified the probe as shorter or longer than the standard. This allowed for comparison of trials with an "Objective" (physical) or "Subjective" (perceived) difference in duration, based on participant classifications. Objective duration revealed responses in bilateral early extrastriate areas, extending to higher visual areas in the fusiform gyrus (at more lenient thresholds). By contrast, Subjective duration was reflected by distributed responses in a cortical/subcortical areas. This comprised the left superior frontal gyrus and the left cerebellum, and a wider set of common timing areas including the BG, parietal cortex, and posterior cingulate cortex. These results suggest two functionally independent timing stages: early extraction of duration information in sensory cortices and Subjective experience of duration in a higher-order cortical-subcortical timing areas.

Keratinocytes are the most abundant cell type in the epidermis, the most superficial layer of skin. Historically, epidermal-innervating sensory neurons were thought to be the exclusive detectors and transmitters of environmental stimuli. However, recent work from our lab (Moehring et al., 2018) and others (Baumbauer et al., 2015) has demonstrated that keratinocytes are also critical for normal mechanotransduction and mechanically-evoked behavioral responses in mice. Here, we asked whether keratinocyte activity is also required for normal cold and heat sensation. Using calcium imaging, we determined that keratinocyte cold activity is conserved across mammalian species and requires the release of intracellular calcium through one or more unknown cold-sensitive proteins. Both epidermal cell optogenetic inhibition and interruption of ATP-P2X4 signaling reduced reflexive behavioral responses to cold and heat stimuli. Based on these data and our previous findings, keratinocyte purinergic signaling is a modality-conserved amplification system that is required for normal somatosensation in vivo.

Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling.

Zuckerman's theory proposes individual differences in optimal arousal and arousability level as the root of the sensation-seeking trait. The current study addressed how sensation seeking influences responses to emotional arousal at the electrophysiological level during a passive viewing task and at the psychometrical level during a self-assessment task. Electrophysiologically, high sensation seekers (HSSs) compared to low sensation seekers (LSSs) exhibited a reduced P300 for high-arousing stimuli (adventure and surreal pictures), but not for low-arousing stimuli (leisure and neutral pictures). Psychometrically, HSSs displayed a higher preference for adventure and surreal pictures whereas LSSs showed a higher preference for leisure pictures. Instead of supporting the optimal arousal hypothesis, these findings suggest that sensation seeking is associated with diminished P300 to physical risk, which may be driven by a hypoactive avoidance system in sensation seeking.

Many studies examining genetic influences on physical activity (PA) have evaluated the impact of single nucleotide polymorphisms (SNPs) related to the development of lifestyle-related chronic diseases, under the hypothesis that they would be associated with PA. However, PA is a multidetermined behavior and associated with a multitude of health consequences. Thus, examining a broader range of candidate genes associated with a broader range of PA correlates may provide new insights into the genetic underpinnings of PA. In this study, we focus on one such correlate - sensation-seeking behavior. Participants (N = 1130 Mexican origin youth) provided a saliva sample and data on PA and sensation-seeking tendencies in 2008-2009. Participants were genotyped for 630 functional and tagging variants in the dopamine, serotonin and cannabinoid pathways. Overall 30% of participants (males - 37.6% and females - 22.0%) reported ≥60 min of PA on 5 of 7 days. After adjusting for gender, age and population stratification, and applying the Bayesian False Discovery Probability approach for assessing noteworthiness, four gene variants were significantly associated with PA. In a multivariable model, being male, having higher sensation-seeking tendencies and at least one copy of the minor allele for SNPs in angiotensin I-converting enzyme gene [ACE; rs8066276 odds ratio (OR) = 1.44; P = 0.012] and tryptophan hydroxylase 2 gene (TPH2; rs11615016 OR = 1.73; P = 0.021) were associated with increased likelihood of meeting PA recommendations. Participants with at least one copy of the minor allele for SNPs in synaptosomal-associated protein 25 gene (SNAP25; rs363035 OR = 0.53; P = 0.005) and cannabinoid receptor 1 gene (CNR1; rs6454672 OR = 0.62; P = 0.022) have decreased likelihood of meeting PA recommendations. Our findings extend current knowledge of the complex relationship between PA and possible genetic underpinnings.

An increasing number of biometeorological and psychological studies have demonstrated the importance and complexity of the processes involved in environmental thermal perception in humans. However, extant functional imaging data on thermal perception have yet to fully reveal the neural mechanisms underlying these processes because most studies were performed using local thermal stimulation and did not dissociate thermal sensation from comfort. Thus, for the first time, the present study employed functional magnetic resonance imaging (fMRI) and manipulated ambient temperature during brain measurement to independently explore the neural correlates of thermal sensation and comfort. There were significant correlations between the sensation of a lower temperature and activation in the left dorsal posterior insula, putamen, amygdala, and bilateral retrosplenial cortices but no significant correlations were observed between brain activation and thermal comfort. The dorsal posterior insula corresponds to the phylogenetically new thermosensory cortex whereas the limbic structures (i.e., amygdala and retrosplenial cortex) and dorsal striatum may be associated with supramodal emotional representations and the behavioral motivation to obtain heat, respectively. The co-involvement of these phylogenetically new and old systems may explain the psychological processes underlying the flexible psychological and behavioral thermo-environmental adaptations that are unique to humans.

During active somatosensation, neural signals expected from movement of the sensors are suppressed in the cortex, whereas information related to touch is enhanced. This tactile suppression underlies low-noise encoding of relevant tactile features and the brain's ability to make fine tactile discriminations. Layer (L) 4 excitatory neurons in the barrel cortex, the major target of the somatosensory thalamus (VPM), respond to touch, but have low spike rates and low sensitivity to the movement of whiskers. Most neurons in VPM respond to touch and also show an increase in spike rate with whisker movement. Therefore, signals related to self-movement are suppressed in L4. Fast-spiking (FS) interneurons in L4 show similar dynamics to VPM neurons. Stimulation of halorhodopsin in FS interneurons causes a reduction in FS neuron activity and an increase in L4 excitatory neuron activity. This decrease of activity of L4 FS neurons contradicts the "paradoxical effect" predicted in networks stabilized by inhibition and in strongly-coupled networks. To explain these observations, we constructed a model of the L4 circuit, with connectivity constrained by in vitro measurements. The model explores the various synaptic conductance strengths for which L4 FS neurons actively suppress baseline and movement-related activity in layer 4 excitatory neurons. Feedforward inhibition, in concert with recurrent intracortical circuitry, produces tactile suppression. Synaptic delays in feedforward inhibition allow transmission of temporally brief volleys of activity associated with touch. Our model provides a mechanistic explanation of a behavior-related computation implemented by the thalamocortical circuit.

Swallowing is an essential step of eating and drinking. However, how the quality of a food bolus is sensed by pharyngeal neurons is largely unknown. Here we find that mechanical receptors along the Drosophila pharynx are required for control of meal size, especially for food of high viscosity. The mechanical force exerted by the bolus passing across the pharynx is detected by neurons expressing the mechanotransduction channel NOMPC (no mechanoreceptor potential C) and is relayed, together with gustatory information, to IN1 neurons in the subesophageal zone (SEZ) of the brain. IN1 (ingestion neurons) neurons act directly upstream of a group of peptidergic neurons that encode satiety. Prolonged activation of IN1 neurons suppresses feeding. IN1 neurons receive inhibition from DSOG1 (descending subesophageal neurons) neurons, a group of GABAergic neurons that non-selectively suppress feeding. Our results reveal the function of pharyngeal mechanoreceptors and their downstream neural circuits in the control of food ingestion.

Active haptic sensation is critical for object identification, but its neural circuit basis is poorly understood. We combined optogenetics, two-photon imaging, and high-speed behavioral tracking in mice solving a whisker-based object orientation discrimination task. We found that orientation discrimination required animals to summate input from multiple whiskers specifically along the whisker arc. Animals discriminated the orientation of the stimulus per se as their performance was invariant to the location of the presented stimulus. Populations of barrel cortex neurons summated across whiskers to encode each orientation. Finally, acute optogenetic inactivation of the barrel cortex and cell-type-specific optogenetic suppression of layer 4 excitatory neurons degraded performance, implying that infragranular layers alone are not sufficient to solve the task. These data suggest that spatial summation over an active haptic array generates representations of an object's orientation, which may facilitate encoding of complex three-dimensional objects during active exploration.

Rosacea is a skin inflammatory condition that is accompanied by not only redness and flushing but also unseen symptoms, such as burning, stinging, and itching. TRPV1 expression in UVB-exposed skin can lead to a painful burning sensation. Upregulated TRPV1 expression helps release neuropeptides, including calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide, which can activate macrophage and inflammatory molecules. In this study, we found that radiofrequency (RF) irradiation reduced TRPV1 activation and neuropeptide expression in a UVB-exposed in vivo model and UVB- or heat-treated in an in vitro model. RF irradiation attenuated neuropeptide-induced macrophage activation and inflammatory molecule expression. Interestingly, the burning sensation in the skin of UVB-exposed mice and patients with rosacea was significantly decreased by RF irradiation. These results can provide experimental and molecular evidence on the effective use of RF irradiation for the burning sensation in patients with rosacea.

Genetic factors have been implicated in the development of substance abuse disorders, but the role of pre-existing vulnerability in addiction is still poorly understood. Personality traits of impulsivity and sensation-seeking are highly prevalent in chronic drug users and have been linked with an increased risk for substance abuse. However, it has not been clear whether these personality traits are a cause or an effect of stimulant drug dependence.