Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca 2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1 -/-mice displayed profound deficiencies in hypochlorite-and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.

Technological and methodological innovations are equipping researchers with unprecedented capabilities for detecting and characterizing pathologic processes in the developing human brain. As a result, ambitions to achieve clinically useful tools to assist in the diagnosis and management of mental health and learning disorders are gaining momentum. To this end, it is critical to accrue large-scale multimodal datasets that capture a broad range of commonly encountered clinical psychopathology. The Child Mind Institute has launched the Healthy Brain Network (HBN), an ongoing initiative focused on creating and sharing a biobank of data from 10,000 New York area participants (ages 5–21). The HBN Biobank houses data about psychiatric, behavioral, cognitive, and lifestyle phenotypes, as well as multimodal brain imaging (resting and naturalistic viewing fMRI, diffusion MRI, morphometric MRI), electroencephalography, eye-tracking, voice and video recordings, genetics and actigraphy. Here, we present the rationale, design and implementation of HBN protocols. We describe the first data release (n=664) and the potential of the biobank to advance related areas (e.g., biophysical modeling, voice analysis).

Allergic contact dermatitis is a common skin disease associated with inflammation and persistent pruritus. Transient receptor potential (TRP) ion channels in skin‐innervating sensory neurons mediate acute inflammatory and pruritic responses following exogenous stimulation and may contribute to allergic responses. Genetic ablation or pharmacological inhibition of TRPA1, but not TRPV1, inhibited skin edema, keratinocyte hyperplasia, nerve growth, leukocyte infiltration, and antihistamine‐resistant scratching behavior in mice exposed to the haptens, oxazolone and urushiol, the contact allergen of poison ivy. Hapten‐challenged skin of TRPA1‐deficient mice contained diminished levels of inflammatory cytokines, nerve growth factor, and endogenous pruritogens, such as substance P (SP) and serotonin. TRPA1‐deficient sensory neurons were defective in SP signaling, and SP‐induced scratching behavior was abolished in Trpa1–/– mice. SP receptor antagonists, such as aprepitant inhibited both hapten‐induced cutaneous inflammation and scratching behavior. These findings support a central role for TRPA1 and SP in the integration of immune and neuronal mechanisms leading to chronic inflammatory responses and pruritus associated with contact dermatitis.—Liu, B., Escalera, J., Balakrishna, S., Fan, L., Caceres, A. I., Robinson, E., Sui, A., McKay, M. C., McAlexander, M. A., Herrick, C. A., Jordt, S. E., TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 27, 3549–3563 (2013). http://www.fasebj.org

Technological and methodological innovations are equipping researchers with unprecedented capabilities for detecting and characterizing pathologic processes in the developing human brain. As a result, ambitions to achieve clinically useful tools to assist in the diagnosis and management of mental health and learning disorders are gaining momentum. To this end, it is critical to accrue large-scale multimodal datasets that capture a broad range of commonly encountered clinical psychopathology. The Child Mind Institute has launched the Healthy Brain Network (HBN), an ongoing initiative focused on creating and sharing a biobank of data from 10,000 New York area participants (ages 5-21). The HBN Biobank houses data about psychiatric, behavioral, cognitive, and lifestyle phenotypes, as well as multimodal brain imaging (resting and naturalistic viewing fMRI, diffusion MRI, morphometric MRI), electroencephalography, eye-tracking, voice and video recordings, genetics, and actigraphy. Here, we present the rationale, design and implementation of HBN protocols. We describe the first data release (n = 664) and the potential of the biobank to advance related areas (e.g., biophysical modeling, voice analysis).. CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/149369 doi: bioRxiv preprint first posted online Jun. 13, 2017; PURPOSE OF DATA COLLECTIONPsychiatric and learning disorders are among the most common and debilitating illnesses across the lifespan. Epidemiologic studies indicate that 75% of all diagnosable psychiatric disorders begin prior to age 241 . This underscores the need for increased focus on studies of the developing brain 2 . Beyond improving our understanding of the pathophysiology that underlies the emergence of psychiatric illness throughout development, such research has the potential to identify clinically useful markers of illness that can improve the early detection of pathology and guide interventions. Although the use of neuroimaging, neuropsychology, neurophysiology and genetics has made significant strides in revealing biological correlates for a broad array of illnesses, findings have been lacking in specificity 3 . Consequently, progress in finding clinically useful brain-based biomarkers has been disappointing 4,5 .Given the slow pace in biomarker identification, investigators have been prompted to rethink research paradigms and practices. Most notably, the emphasis on mapping diagnostic labels from a clinically defined nosology (e.g., the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases) to varying biological indices has proven to be problematic, as it assumes consistent biological relationships with broad constellations of signs and symptoms 6,7 . Epidemiologists, psychopathologists, geneticists and neuroscientists are reconsidering the relevance of diagnostic boundaries due to the lack of specif...

The release of methyl isocyanate in Bhopal, India, caused the worst industrial accident in history. Exposures to industrial isocyanates induce lacrimation, pain, airway irritation, and edema. Similar responses are elicited by chemicals used as tear gases. Despite frequent exposures, the biological targets of isocyanates and tear gases in vivo have not been identified, precluding the development of effective countermeasures. We use Ca(2+) imaging and electrophysiology to show that the noxious effects of isocyanates and those of all major tear gas agents are caused by activation of Ca(2+) influx and membrane currents in mustard oil-sensitive sensory neurons. These responses are mediated by transient receptor potential ankyrin 1 (TRPA1), an ion channel serving as a detector for reactive chemicals. In mice, genetic ablation or pharmacological inhibition of TRPA1 dramatically reduces isocyanate- and tear gas-induced nocifensive behavior after both ocular and cutaneous exposures. We conclude that isocyanates and tear gas agents target the same neuronal receptor, TRPA1. Treatment with TRPA1 antagonists may prevent and alleviate chemical irritation of the eyes, skin, and airways and reduce the adverse health effects of exposures to a wide range of toxic noxious chemicals.

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Plants, fungi, and animals generate a diverse array of deterrent natural products that induce avoidance behavior in biological adversaries. The largest known chemical family of deterrents are terpenes characterized by reactive ␣,␤-unsaturated dialdehyde moieties, including the drimane sesquiterpenes and other terpene species. Deterrent sesquiterpenes are potent activators of mammalian peripheral chemosensory neurons, causing pain and neurogenic inflammation. Despite their widespread synthesis and medicinal use as desensitizing analgesics, their molecular targets remain unknown. Here we show that isovelleral, a noxious fungal sesquiterpene, excites sensory neurons through activation of TPRA1, an ion channel involved in inflammatory pain signaling. TRPA1 is also activated by polygodial, a drimane sesquiterpene synthesized by plants and animals. TRPA1-deficient mice show greatly reduced nocifensive behavior in response to isovelleral, indicating that TRPA1 is the major receptor for deterrent sesquiterpenes in vivo. Isovelleral and polygodial represent the first fungal and animal small molecule agonists of nociceptive transient receptor potential channels.Terpenes represent the largest group of natural products synthesized by plants, fungi, animals, and microorganisms (1). Although some terpenes function as hormonal messengers or as constituents of biological membranes and enzymatic cofactors, the biological functions of most of the ϳ25,000 different terpenes remain to be determined (1). Recent studies investigating the biochemical interactions of plants, fungi, and animals suggest that one of the major biological roles of terpenes is to act as chemical deterrents against herbivores, fungivores, and predators, respectively (1, 2). Deterrent terpenes interact with chemosensory detection systems in target organisms to induce avoidance behavior. In animals, it has been speculated that chemodefensive terpenes could activate gustatory and olfactory pathways as well as pain-sensing neuronal pathways. Indeed, some terpenes produce a painfully pungent taste in humans, probably related to their deterrent function.Recent research on terpene deterrents has focused on sesquiterpenes, a class of terpenes consisting of three isoprene units. One of the most intensively studied defensive sesquiterpenes is isovelleral, the pungent product of the fungus Lactarius vellereus. Isovelleral is thought to be part of a fungal chemical defense system against predators (3, 4) and is rapidly synthesized in response to injury from chemical precursors stored in the fungal laticiferous hyphae (5, 6). In behavioral tests, fungivorous mammals were strongly repelled by isovelleral (5, 6). In humans, skin contact with the fungal milky exudate often leads to painful inflammatory responses, including eczema and blistering (7,8). Another pungent sesquiterpene is polygodial, initially isolated from the leaves of water pepper (Polygonum hydropiper) (9). Polygodial is also a major product of winter's bark (Drimys winteri), a South American medicinal tree, ...

Background: Although typically measured during the resting state, a growing literature is illustrating the ability to map intrinsic connectivity with functional MRI during task and naturalistic viewing conditions. These paradigms are drawing excitement due to their greater tolerability in clinical and developing populations and because they enable a wider range of analyses (e.g., inter-subject correlations). To be clinically useful, the test-retest reliability of connectivity measured during these paradigms needs to be established. This resource provides data for evaluating test-retest reliability for full-brain connectivity patterns detected during each of four scan conditions that differ with respect to level of engagement (rest, abstract animations, movie clips, flanker task). Data are provided for 13 participants, each scanned in 12 sessions with 10 minutes for each scan of the four conditions. Diffusion kurtosis imaging data was also obtained at each session. Findings: Technical validation and demonstrative reliability analyses were carried out at the connection-level using the Intraclass Correlation Coefficient and at network-level representations of the data using the Image Intraclass Correlation Coefficient. Variation in intrinsic functional connectivity across sessions was generally found to be greater than that attributable to scan condition. Between-condition reliability was generally high, particularly for the frontoparietal and default networks. Between-session reliabilities obtained separately for the different scan conditions were comparable, though notably lower than between-condition reliabilities.