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The Earth's oceans brim with an incredible diversity of microscopic lifeforms, including motile planktonic larvae, whose survival critically depends on effective dispersal in the water column and subsequent exploration of the seafloor to identify a suitable settlement site. How their nervous systems mediate sensing of diverse multimodal cues remains enigmatic. Here, we uncover that the tunicate Ciona intestinalis larvae employ ectodermal sensory cells to sense various mechanical and chemical cues. Combining whole-brain imaging and chemogenetics, we demonstrate that stimuli encoded at the periphery are sufficient to drive global brain-state changes to promote or impede both larval attachment and metamorphosis behaviors. The ability of C. intestinalis larvae to leverage polymodal sensory perception to support information coding and chemotactile behaviors may explain how marine larvae make complex decisions despite streamlined nervous systems.

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Pain and itch coding mechanisms in polymodal sensory neurons remain elusive. MrgprD+ neurons represent a major polymodal population and mediate both mechanical pain and nonhistaminergic itch. Here, we show that chemogenetic activation of MrgprD+ neurons elicited both pain- and itch-related behavior in a dose-dependent manner, revealing an unanticipated compatibility between pain and itch in polymodal neurons. While VGlut2-dependent glutamate release is required for both pain and itch transmission from MrgprD+ neurons, the neuropeptide neuromedin B (NMB) is selectively required for itch signaling. Electrophysiological recordings further demonstrated that glutamate synergizes with NMB to excite NMB-sensitive postsynaptic neurons. Ablation of these spinal neurons selectively abolished itch signals from MrgprD+ neurons, without affecting pain signals, suggesting a dedicated itch-processing central circuit. These findings reveal distinct neurotransmitters and neural circuit requirements for pain and itch signaling from MrgprD+ polymodal sensory neurons, providing new insights on coding and processing of pain and itch.

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It is well established that temperature affects the functioning of almost all biomolecules and, consequently, all cellular functions. Here, we show how temperature variations within a physiological range affect primary afferents' spontaneous activity in response to chemical nociceptive stimulation. An ex vivo mouse hind limb skin-saphenous nerve preparation was used to study the temperature dependence of single C-mechanoheat (C-MH) fibers' spontaneous activity. Nociceptive fibers showed a basal spike frequency of 0.097 ± 0.013 Hz in control conditions (30°C). Non-surprisingly, this activity decreased at 20°C and increased at 40°C, showing moderate temperature dependence with Q10∼2.01. The fibers' conduction velocity was also temperature-dependent, with an apparent Q10 of 1.38. Both Q10 for spike frequency and conduction velocity were found to be in good correspondence with an apparent Q10 for ion channels gating. Then we examined the temperature dependence of nociceptor responses to high K+, ATP, and H+. Receptive fields of nociceptors were superfused with solutions containing 10.8 mM K+, 200 µM ATP, and H+ (pH 6.7) at three different temperatures: 20, 30, and 40°C. We found that at 30 and 20°C, all the examined fibers were sensitive to K+, but not to ATP or H+. At 20°C, only 53% of fibers were responsible for ATP; increasing the temperature to 40°C resulted in 100% of sensitive fibers. Moreover, at 20°C, all observed fibers were silent to pH, but at 40°C, this number was gradually increased to 87.9%. We have found that the temperature increase from 20 to 30°C significantly facilitated responses to ATP (Q10∼3.11) and H+ (Q10∼3.25), leaving high K+ virtually untouched (Q10∼1.88 vs. 2.01 in control conditions). These data suggest a possible role of P2X receptors in coding the intensity of non-noxious thermal stimuli.

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The carotid body (CB) is a bilateral arterial chemoreceptor located in the carotid artery bifurcation with an essential role in cardiorespiratory homeostasis. It is composed of highly perfused cell clusters, or glomeruli, innervated by sensory fibers. Glomus cells, the most abundant in each glomerulus, are neuron-like multimodal sensory elements able to detect and integrate changes in several physical and chemical parameters of the blood, in particular O2 tension, CO2 and pH, as well as glucose, lactate, or blood flow. Activation of glomus cells (e.g., during hypoxia or hypercapnia) stimulates the afferent fibers which impinge on brainstem neurons to elicit rapid compensatory responses (hyperventilation and sympathetic activation). This chapter presents an updated view of the structural organization of the CB and the mechanisms underlying the chemosensory responses of glomus cells, with special emphasis on the molecular processes responsible for acute O2 sensing. The properties of the glomus cell-sensory fiber synapse as well as the organization of CB output are discussed. The chapter includes the description of recently discovered CB stem cells and progenitor cells, and their role in CB growth during acclimatization to hypoxemia. Finally, the participation of the CB in the mechanisms of disease is briefly discussed.

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Sensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

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Sensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca

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Humans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3-/- triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates.

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Administration of chemicals (pruritogens) into the skin evokes itch based on signal transduction mechanisms that generate action potentials mainly in mechanically sensitive and insensitive primary afferent C-fibers (pruriceptors). These signals from peripheral neurons are processed in spinal and supra-spinal centers of the central nervous system and finally generate the sensation of itch. Compared to chemical stimulation, electrical activation of pruriceptors would allow for better temporal control and thereby a more direct functional assessment of their activation. Here, we review the electrical stimulation paradigms which were used to evoke itch in humans in the past. We further evaluate recent attempts to explore electrically induced itch in atopic dermatitis patients. Possible mechanisms underlying successful pruritus generation in chronic itch patients by transdermal slowly depolarizing electrical stimulation are discussed.

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Neurons convert synaptic or sensory inputs into cellular outputs. It is not well understood how a single neuron senses, processes multiple stimuli, and generates distinct neuronal outcomes. Here, we describe the mechanism by which the C. elegans PVD neurons sense two mechanical stimuli: external touch and proprioceptive body movement. These two stimuli are detected by distinct mechanosensitive DEG/ENaC/ASIC channels, which trigger distinct cellular outputs linked to mechanonociception and proprioception. Mechanonociception depends on DEGT-1 and activates PVD's downstream command interneurons through its axon, while proprioception depends on DEL-1, UNC-8, and MEC-10 to induce local dendritic Ca2+ increase and dendritic release of a neuropeptide NLP-12. NLP-12 directly modulates neuromuscular junction activity through the cholecystokinin receptor homolog on motor axons, setting muscle tone and movement vigor. Thus, the same neuron simultaneously uses both its axon and dendrites as output apparatus to drive distinct sensorimotor outcomes.

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Transcripts of noxious stimulus-detecting TrpA1 channels are alternatively spliced. Despite the importance of nociception for survival, the in vivo significance of expressing different TrpA1 isoforms is largely unknown. Here, we develop a novel genetic approach to generate Drosophila knockin strains expressing single TrpA1 isoforms. Drosophila TrpA1 mediates heat and UVC-triggered nociception. We show that TrpA1-C and TrpA1-D, two alternative isoforms, are co-expressed in nociceptors. When examined in heterologous cells, both TrpA1-C and TrpA1-D are activated by heat and UVC. By contrast, analysis of knockin flies reveals the striking functional specificity; TrpA1-C mediates UVC-nociception, whereas TrpA1-D mediates heat-nociception. Therefore, in vivo functions of TrpA1-C and TrpA1-D are different from each other and are different from their in vitro properties. Our results indicate that a given sensory stimulus preferentially activates a single TrpA1 isoform in vivo and that polymodal nociception requires co-expression of TrpA1 isoforms, providing novel insights of how alternative splicing regulates nociception.

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Transient receptor potential vanilloid 4 (TRPV4) channel is a polymodal receptor activated by moderate heat and hypoosmolarity. TRPV4 expressed in the skin area contributes to several skin functions as a barrier to maintain internal body physiology and a transporter of external stimuli. The skin condition such as skin temperature and osmolarity varies with internal and external changes, and may influence the activity of TRPV4 contributing to skin physiology, thermal sensation, and thermoregulation. However, the combination effect of skin conditions such as temperature and osmolarity on the activity of TRPV4 has not been examined. In the current study, we investigated the effect of temporal adaptation (5-10 min) to different temperature (25-35 °C) and osmolarity (250-350 mOsm) conditions on the heat response (until 40 °C) of human TRPV4 in cultured cells using Ca2+ imaging. The temperature to activate TRPV4 increased with elevation of the adaptation temperature, and decreased with the adaptation to hypoosmolarity in the range of 25-35 °C. In addition, the heat response was inhibited with the adaptation to hyperosmolarity in the range of 25-35 °C. Thus, we demonstrated that the activation temperature of TRPV4 varied with the temporal sensory adaptation to different temperature and osmolarity conditions. These findings may contribute to gaining better understanding of the variation in several TRPV4-mediated skin functions.

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Tactile information is detected by thermoreceptors and mechanoreceptors in the skin and integrated by the central nervous system to produce the perception of somatosensation. Here we investigate the mechanism by which thermal and mechanical stimuli begin to interact and report that it is achieved by the mechanotransduction apparatus in cutaneous mechanoreceptors. We show that moderate cold potentiates the conversion of mechanical force into excitatory current in all types of mechanoreceptors from mice and tactile-specialist birds. This effect is observed at the level of mechanosensitive Piezo2 channels and can be replicated in heterologous systems using Piezo2 orthologs from different species. The cold sensitivity of Piezo2 is dependent on its blade domains, which render the channel resistant to cold-induced perturbations of the physical properties of the plasma membrane and give rise to a different mechanism of mechanical activation than that of Piezo1. Our data reveal that Piezo2 is an evolutionarily conserved mediator of thermal-tactile integration in cutaneous mechanoreceptors.

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The structural and functional properties of neurons have intrigued scientists since the pioneering work of Santiago Ramón y Cajal. Since then, emerging cutting-edge technologies, including light and electron microscopy, electrophysiology, biochemistry, optogenetics, and molecular biology, have dramatically increased our understanding of dendritic properties. This advancement was also facilitated by the establishment of different animal model organisms, from flies to mammals. Here we describe the emerging model system of a Caenorhabditis elegans polymodal neuron named PVD, whose dendritic tree follows a stereotypical structure characterized by repeating candelabra-like structural units. In the past decade, progress has been made in understanding PVD's functions, morphogenesis, regeneration, and aging, yet many questions still remain.

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Analytical techniques such HPSEC, DSC, and TGA have been employed for amylose determination in starch samples, though spectrophotometry by iodine binding is most commonly used. The vast majority of these techniques require an analytical curve, using amylose and amylopectin standards with physicochemical properties similar to those found in the original starch. The current study aimed to obtain the amylose and amylopectin fractions from potato, banana, corn, and cassava starches, characterize them, and evaluate their behavior via thermogravimetric curves. Blue amylose iodine complex and HPSEC-DRI methods have obtained high purity amylose and amylopectin fractions. All molecular weights of the obtained amylose and amylopectin fractions were similar to those presented in other reports. Different results were obtained by deconvolution of the amylopectin polymodal distribution. All amyloses presented as semi-crystalline V-type polymorphs, while all amylopectin fractions were amorphous. The Tg of all Vamyloses presented were directly proportional to their respective crystalline index. TGA evaluations have shown that selective precipitation of amylose with 1-butanol strongly changes its thermal behavior. Therefore, the separation procedure used was an ineffective pathway for obtaining standards for thermal studies.

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Respiratory chemoreceptors in vertebrates are specialized cells that detect chemical changes in the environment or arterial blood supply and initiate autonomic responses, such as hyperventilation or changes in heart rate, to improve O2 uptake and delivery to tissues. These chemoreceptors are sensitive to changes in O2, CO2 and/or H+. In fish and mammals, respiratory chemoreceptors may be additionally sensitive to ammonia, hypoglycemia, and numerous other stimuli. Thus, chemoreceptors that affect respiration respond to different types of stimuli (or modalities) and are considered to be "polymodal". This review discusses the polymodal nature of respiratory chemoreceptors in vertebrates with a particular emphasis on chemoreceptors of the carotid body and pulmonary epithelium in mammals, and on neuroepithelial cells in water- and air-breathing fish. A major goal will be to examine the evidence for putative polymodal chemoreceptors in fish within the context of studies on mammalian models, for which polymodal chemoreceptors are well described, in order to improve our understanding of the evolution of polymodal chemoreceptors in vertebrates, and to aid in future studies that aim to identify putative receptors in air- and water-breathing fish.

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Empirical evidence is reviewed indicating that the extraordinary aspects of the human mind are due to our species' ability to go beyond simple "dyadic associations" and to process the relations among three items of information simultaneously. Classic explanations of the "triadic" nature of human skills have been advocated by various scholars in the context of the evolution of human cognition. Here I summarize the core processes as found in (i) the syntax of language, (ii) tool-usage, and (iii) joint attention. I then review the triadic foundations of two perceptual phenomena of great importance in human aesthetics: (iv) harmony perception and (v) pictorial depth perception. In all five subfields of human psychology, most previous work has emphasized the recursive, hierarchical complexity of such "higher cognition," but a strongly reductionist approach indicates that the core mechanisms are triadic. It is concluded that the cognitive skills traditionally considered to be "uniquely" human require three-way associational processing that most non-Primate animal species find difficult or impossible, but all members of Homo sapiens - regardless of small cultural differences - find easy and inherently intriguing.

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Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.

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The design, synthesis and activity of polymodal compounds for the treatment of inflammatory bowel disease are reported. The compounds, being based on a metal-Schiff base motif, are designed to degrade during intestinal transit to release the bioactive components in the gut. The compounds have been developed sequential with the biomodal compounds combining copper or zinc with a salicylaldehyde adduct. These compounds were tested in a formalin induced colonic inflammation model in BK:A mice. From these studies a trimodal compound based on a zinc Schiff base analogue of sulfasalazine was designed. This was tested against a trinitrobenzenesulfonic acid (TNB) induced colitic model in Wistar rats. The use of two models allows us to test our compounds in both an acute and a chronic model. The trimodal compound reported is observed to provide anticolitic properties in the chronic TNB induced colitis model commensurate with that of SASP. However, the design of trimodal compound still has the capacity for further development. This the platform reported may offer a route into compounds which can markedly outperform the anti-colitic properties of SASP.

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Mechanistic insights into pain pathways are essential for a rational approach to treating this vast and increasing clinical problem. Sensory neurons that respond to tissue damage (nociceptors) may evoke pain sensations and are typically classified on the basis of action potential velocity. Electrophysiological studies have suggested that most of the C-fiber nociceptors are polymodal, responding to a variety of insults. In contrast, gene deletion studies in the sensory neurons of transgenic mice have frequently resulted in modality-specific deficits. We have used an in vivo imaging approach using the genetically encoded fluorescent calcium indicator GCaMP to study the activity of dorsal root ganglion sensory neurons in live animals challenged with painful stimuli. Using this approach, we can visualize spatially distinct neuronal responses and find that >85% of responsive dorsal root ganglion neurons are modality-specific, responding to either noxious mechanical, cold, or heat stimuli. These observations are mirrored in behavioral studies of transgenic mice. For example, deleting sodium channel Nav1.8 silences mechanical- but not heat-sensing sensory neurons, consistent with behavioral deficits. In contrast, primary cultures of axotomized sensory neurons show high levels of polymodality. After intraplantar treatment with prostaglandin E2, neurons in vivo respond more intensely to noxious thermal and mechanical stimuli, and additional neurons (silent nociceptors) are unmasked. Together, these studies define polymodality as an infrequent feature of nociceptive neurons in normal animals.

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BACKGROUND: Auditory hallucinations are experienced by 60-80% of all patients diagnosed with a schizophrenia spectrum disorder. However, in this patient group, the prevalence of hallucinations in multiple sensory modalities, i.e. multimodal hallucinations (MMHs), is unknown. AIMS: To assess the prevalence of MMHs in patients diagnosed with a schizophrenia spectrum disorder, data were analyzed from 750 patients who participated in the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. METHOD: We drew on the section of the CASH (Comprehensive Assessment of Symptoms and History) that probes into the lifetime presence of auditory, visual, somatic/tactile, and olfactory hallucinations. RESULTS: A lifetime prevalence of 80% was found in this group for hallucinations in any of these modalities. Within the whole group, 27% of the participants reported unimodal hallucinations and 53% MMHs. There were no significant differences in prevalence rate for Dutch versus migrant participants from Morocco, Turkey, Surinam or the (former) Dutch Antilles. CONCLUSION: We conclude that MMHs, rather than auditory hallucinations, are the most frequent perceptual symptom of patients diagnosed with a schizophrenia spectrum disorder. Our data also suggest that hallucinations experienced in a single sensory modality (notably auditory ones) stochastically increase the risk for more sensory modalities to join in. We recommend that future studies take into account all 14 sensory modalities in which hallucinations can be experienced. For this we provide a classification of MMHs that allows characterization of their serial versus simultaneous occurrence and their congruent versus incongruent nature.

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