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PO LEUNG KUK LAWS FOUNDATION COLLEGE Board of Science Neuroscience Club Conference Trip (San Diego, CA, USA) Conference Booklet November 13 – 19, 2010 Name: _______________________ Class: ________ Abstract of the scientific research (to be presented on Nov 16 (Tue) at 4:00 – 5:00 pm) Elicitation of a pungent sensation does not implicate memory modulation in adolescents aged 14-16. Ka-Chun Suen1, Yat-Hei Wong1, Chun-Ting Yuen1, Ngo-Hung Lam1, Ho-Yin Ho1, Yuen-Tat Lau1, Chi-Keung Cheng1, Ho-Cheung Lam1, Dominic Hiu-Fung Tam1, Sin-Pang Lau1, Raymond Chuen-Chung Chang2 1 2 Po Leung Kuk Laws Foundation College, Tseung Kwan O, Hong Kong, China Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China Pungent sensation induced by allyl isothiocyanate which is a functional ingredient in a Japanese horseradish called wasabi involves the activation of transient receptor potential ankyrin 1 (TRPA1). It has been suggested that TRPA1 is associated with cognitive impairment in Alzheimer’s disease and neuroprotection on dentate gyrus granule cells. As our previous studies focus on daily-life strategies such as physical exercise and sleep for memory enhancement in adolescents, we further investigate whether elicitation of a pungent sensation would modulate memory recall. In the present study, children aged 14-16 spend 1 minute to orally taste wasabi to acquire a pungent sense, followed by an immediate 5-minute memory recall test displaying ten random combinations of three to four English alphabets plus one to two Arabic numbers in each attempt. Our results showed that the pungent sensation induced by wasabi showed no significant modulation on memory recall in the adolescents. This implicates that immediate elicitation of a pungent sensation in which TRPA1 may be involved does not help memory recall in adolescents. 2 Poster of the scientific research 3 Abstract of the educational research Development of a school-based neuroscience curriculum in a high school in Hong Kong (to be presented on Nov 13 (Sat) at 1:00 – 2:00 pm) Ka-Chun Suen1, Wing-Kwong Chan1, Raymond Chuen-Chung Chang2 1 Po Leung Kuk Laws Foundation College, Tseung Kwan O, Hong Kong, China 2 Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China We are the pioneer to develop a school-based neuroscience curriculum in a high school in Hong Kong. Although the functions and basic structure of the brain and neurons, neuromuscular junction, neurotransmission, spinal reflexes, roles of cone and rod cells in vision and cochlea in audition are included in Hong Kong’s high-school science curricula including Integrated Science and Biology, a comprehensive neuroscience curriculum and neuroscience teachers to cultivate young neuroscientists and to raise student’s awareness and understanding on some common neurodegenerative diseases such as Alzheimer disease and Parkinson’s disease are absent. Since 2004, our school has set up a school-based neuroscience program in which research-based learning mode is applied to engage students in learning neurodegenerative diseases. Neuronal cell culture is also included as a tool for students to study the growth and death of neurons. To further promote neuroscience education, student’s participation in neuroscience research and attendance in neuroscience conferences are encouraged. 4 Collaboration with neuroscientists in university is highly supportive to neuroscience education in our school. To further develop the school-based neuroscience curriculum, more diverse examples about neuroscience such as studies on invertebrate nervous system will be introduced. To evaluate our school-based neuroscience curriculum, student’s awareness and interest on neuroscience are enhanced. This implicates that our school-based neuroscience curriculum is constructive to the neuroscience education in our school. 5 Poster of the educational research 6 Abstract about TRPA1 Biochim Biophys Acta. 2007 Aug;1772(8):958-67. Epub 2007 Mar 31. Transient receptor potential channels in Alzheimer's disease. Yamamoto S, Wajima T, Hara Y, Nishida M, Mori Y. Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan. Abstract Cognitive impairment and emotional disturbances in Alzheimer's disease (AD) result from the degeneration of synapses and neuronal death in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid beta-peptide (Abeta) in the brain. Abeta can render neurons vulnerable to excitotoxicity and apoptosis by disruption of cellular Ca(2+) homeostasis and neurotoxic factors including reactive oxygen species (ROS), nitric oxide (NO), and cytokines. Many lines of evidence have suggested that transient receptor potential (TRP) channels consisting of six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) are involved in Ca(2+) homeostasis disruption. Thus, emerging evidence of the pathophysiological role of TRP channels has yielded promising candidates for molecular entities mediating Ca(2+) homeostasis disruption in AD. In this review, we focus on the TRP channels in AD and highlight some TRP "suspects" for which a role in AD can be anticipated. An understanding of the involvement of TRP channels in AD may lead to the development of new target therapies. 7 Nature. 2010 Mar 25;464(7288):597-600. Epub 2010 Mar 17. Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception. Kang K, Pulver SR, Panzano VC, Chang EC, Griffith LC, Theobald DL, Garrity PA. National Center for Behavioral Genomics, Waltham, Massachusetts 02454, USA. Abstract Chemical nociception, the detection of tissue-damaging chemicals, is important for animal survival and causes human pain and inflammation, but its evolutionary origins are largely unknown. Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, such as allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke). Diverse animals, from insects to humans, find reactive electrophiles aversive, but whether this reflects conservation of an ancient sensory modality has been unclear. Here we identify the molecular basis of reactive electrophile detection in flies. We demonstrate that Drosophila TRPA1 (Transient receptor potential A1), the Drosophila melanogaster orthologue of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. We show that fly and mosquito TRPA1 orthologues are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phylogenetic analyses indicate that invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings support emergence of TRPA1-based electrophile detection in a common bilaterian 8 ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. We propose that human pain perception relies on an ancient chemical sensor conserved across approximately 500 million years of animal evolution. PMID: 20237474 [PubMed - indexed for MEDLINE]PMCID: PMC2845738 [Available on 2010/9/25] 9 PLoS One. 2010 Feb 17;5(2):e9267. Allyl isothiocyanate that induces GST and UGT expression confers oxidative stress resistance on C. elegans, as demonstrated by nematode biosensor. Hasegawa K, Miwa S, Tsutsumiuchi K, Miwa J. College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi, Japan. Abstract BACKGROUND: Electrophilic xenobiotics and endogenous products from oxidative stresses induce the glutathione S-transferases (GSTs), which form a large family within the phase II enzymes over both animal and plant kingdoms. The GSTs thus induced in turn detoxify these external as well as internal stresses. Because these stresses are often linked to ageing and damage to health, the induction of phase II enzymes without causing adverse effects would be beneficial in slowing down ageing and keeping healthy conditions. METHODOLOGY/PRINCIPAL FINDINGS: We have tested this hypothesis by choosing allyl isothiocyanate (AITC), a functional ingredient in wasabi, as a candidate food ingredient that induces GSTs without causing adverse effects on animals' lives. To monitor the GST induction, we constructed a gst::gfp fusion gene and used it to transform Caenorhabditis elegans for use as a nematode biosensor. With the nematode biosensor, we found that AITC induced GST expression and conferred tolerance on the nematode against various oxidative stresses. We also present evidence that the transcription factor SKN-1 is involved in regulating 10 the GST expression induced by AITC. CONCLUSIONS/SIGNIFICANCE: We show the applicability of the nematode biosensor for discovering and evaluating functional food substances and chemicals that would provide anti-ageing or healthful benefits. 11 J Nutr Sci Vitaminol (Tokyo). 2009 Apr;55(2):195-200. The effect of wasabi rhizome extract on atopic dermatitis-like symptoms in HR-1 hairless mice. Nagai M, Okunishi I. Kinjirushi Co., Ltd., Nagoya, Japan. [email protected] Abstract We investigated the effect of wasabi rhizome extract on atopic dermatitis (AD) model mice. The wasabi extract was fed to the HR-1 hairless mice, which develop AD-like symptoms with a special diet (HR-AD diet). The extract was expected to reduce the symptoms induced. Wasabi rhizome-containing HR-AD diet (5% and 10%) reduced the scratching behavior, and the 10% wasabi rhizome HR-AD diet significantly reduced scratching behavior on days 28, 35 and 42. Plasma components (histamine, eotaxin, IgE and thymus and activation-regulated chemokine (TARC)) were decreased in the 10% wasabi rhizome HR-AD diet. In histopathological examinations (toluidine blue (T.B.), major basic protein (MBP), CD4, IL-4, IL-5, eotaxin, TARC and IgE), the wasabi rhizome-containing HR-AD diet (5% and 10%) significantly reduced the number of positive stained cells. These results suggested that the wasabi rhizome extract improved the AD-like symptoms of HR-1 hairless mice. 12 J Cell Physiol. 2009 Oct;221(1):67-74. Differentiation dependent expression of TRPA1 and TRPM8 channels in IMR-32 human neuroblastoma cells. Louhivuori LM, Bart G, Larsson KP, Louhivuori V, Näsman J, Nordström T, Koivisto AP, Akerman KE. Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland. Abstract TRPA1 and TRPM8 are transient receptor potential (TRP) channels involved in sensory perception. TRPA1 is a non-selective calcium permeable channel activated by irritants and proalgesic agents. TRPM8 reacts to chemical cooling agents such as menthol. The human neuroblastoma cell line IMR-32 undergoes a remarkable differentiation in response to treatment with 5-bromo-2-deoxyuridine. The cells acquire a neuronal morphology with increased expression of N-type voltage gated calcium channels and neurotransmitters. Here we show using RT-PCR, that mRNA for TRPA1 and TRPM8 are strongly upregulated in differentiating IMR-32 cells. Using whole cell patch clamp recordings, we demonstrate that activators of these channels, wasabi, allyl-isothiocyanate (AITC) and menthol activate membrane currents in differentiated cells. Calcium imaging experiments demonstrated that AITC mediated elevation of intracellular calcium levels were attenuated by ruthenium red, spermine, and HC-030031 as well as by siRNA directed against the channel. This indicates that the detected mRNA level correlate with the presence of functional channels of both types in the membrane of differentiated cells. 13 Although the differentiated IMR-32 cells responded to cooling many of the cells showing this response did not respond to TRPA1/TRPM8 channel activators (60% and 90% for AITC and menthol respectively). Conversely many of the cells responding to these activators did not respond to cooling (30%). This suggests that these channels have also other functions than cold perception in these cells. Furthermore, our results suggest that IMR-32 cells have sensory characteristics and can be used to study native TRPA1 and TRPM8 channel function as well as developmental expression. Copyright 2009 Wiley-Liss, Inc. 14 Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19564-8. Epub 2006 Dec 12. TRP channel activation by reversible covalent modification. Hinman A, Chuang HH, Bautista DM, Julius D. Department of Physiology, University of California, San Francisco, CA 94158, USA. Abstract Allyl isothiocyanate, the pungent principle of wasabi and other mustard oils, produces pain by activating TRPA1, an excitatory ion channel on sensory nerve endings. Isothiocyanates are membrane-permeable electrophiles that form adducts with thiols and primary amines, suggesting that covalent modification, rather than classical lock-and-key binding, accounts for their agonist properties. Indeed, we show that thiol reactive compounds of diverse structure activate TRPA1 in a manner that relies on covalent modification of cysteine residues within the cytoplasmic N terminus of the channel. These findings suggest an unusual paradigm whereby natural products activate a receptor through direct, reversible, and covalent protein modification. 15 Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12248-52. Epub 2005 Aug 15. Pungent products from garlic activate the sensory ion channel TRPA1. Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Högestätt ED, Julius D, Jordt SE, Zygmunt PM. Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94143, USA. Abstract Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary 16 convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence. 17 Curr Biol. 2006 May 23;16(10):1034-40. Epub 2006 Apr 27. Response of Drosophila to wasabi is mediated by painless, the fly homolog of mammalian TRPA1/ANKTM1. Al-Anzi B, Tracey WD Jr, Benzer S. Division of Biology 156-29, California Institute of Technology, Pasadena, California 91125, USA. Abstract A number of repellent compounds produced by plants elicit a spicy or pungent sensation in mammals . In several cases, this has been found to occur through activation of ion channels in the transient receptor potential (TRP) family . We report that isothiocyanate (ITC), the pungent ingredient of wasabi, is a repellent to the insect Drosophila melanogaster, and that the painless gene, previously known to be required for larval nociception, is required for this avoidance behavior. A painless reporter gene is expressed in gustatory receptor neurons of the labial palpus, tarsus, and wing anterior margin, but not in olfactory receptor neurons, suggesting a gustatory role. Indeed, painless expression overlaps with a variety of gustatory-receptor gene reporters. Some, such as Gr66a, are known to be expressed in neurons that mediate gustatory repulsion . painless mutants are not taste blind; they show normal aversive gustatory behavior with salt and quinine and attractive responses to sugars and capsaicin. The painless gene is an evolutionary homolog of the mammalian "wasabi receptor" TRPA1/ANKTM1 , also thought to be involved in nociception. Our results suggest that the stinging sensation of isothiocyanate is caused by 18 activation of an evolutionarily conserved molecular pathway that is also used for nociception. 19 Genes Brain Behav. 2009 Jul;8(5):546-57. Epub 2009 May 8. The Drosophila TRPA channel, Painless, regulates sexual receptivity in virgin females. Sakai T, Kasuya J, Kitamoto T, Aigaki T. Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan. [email protected] Abstract Transient receptor potential (TRP) channels play crucial roles in sensory perception. Expression of the Drosophila painless (pain) gene, a homolog of the mammalian TRPA1/ANKTM1 gene, in the peripheral nervous system is required for avoidance behavior of noxious heat or wasabi. In this study, we report a novel role of the Pain TRP channel expressed in the nervous system in the sexual receptivity in Drosophila virgin females. Compared with wild-type females, pain mutant females copulated with wild-type males significantly earlier. Wild-type males showed comparable courtship latency and courtship index toward wild-type and pain mutant females. Therefore, the early copulation observed in wild-type male and pain mutant female pairs is the result of enhanced sexual receptivity in pain mutant females. Involvement of pain in enhanced female sexual receptivity was confirmed by rescue experiments in which expression of a pain transgene in a pain mutant background restored the female sexual receptivity to the wild-type level. Targeted expression of pain RNA interference (RNAi) in putative cholinergic or GABAergic neurons phenocopied the mutant phenotype of pain females. However, target expression of pain RNAi in dopaminergic neurons did not affect female 20 sexual receptivity. In addition, conditional suppression of neurotransmission in putative GABAergic neurons resulted in a similar enhanced sexual receptivity. Our results suggest that Pain TRP channels expressed in cholinergic and/or GABAergic neurons are involved in female sexual receptivity. 21 Nat Chem Biol. 2009 Mar;5(3):183-90. Epub 2009 Feb 8. Zinc activates damage-sensing TRPA1 ion channels. Hu H, Bandell M, Petrus MJ, Zhu MX, Patapoutian A. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA. Comment in: Nat Chem Biol. 2009 Mar;5(3):141-2. Abstract Zinc is an essential biological trace element. It is required for the structure or function of over 300 proteins, and it is increasingly recognized for its role in cell signaling. However, high concentrations of zinc have cytotoxic effects, and overexposure to zinc can cause pain and inflammation through unknown mechanisms. Here we show that zinc excites nociceptive somatosensory neurons and causes nociception in mice through TRPA1, a cation channel previously shown to mediate the pungency of wasabi and cinnamon through cysteine modification. Zinc activates TRPA1 through a unique mechanism that requires zinc influx through TRPA1 channels and subsequent activation via specific intracellular cysteine and histidine residues. TRPA1 is highly sensitive to intracellular zinc, as low nanomolar concentrations activate TRPA1 and modulate its sensitivity. These findings identify TRPA1 as an important target for the sensory effects of zinc and support an emerging role for zinc as a signaling molecule that can modulate sensory transmission. 22 Nature. 2004 Jan 15;427(6971):260-5. Epub 2004 Jan 7. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Högestätt ED, Meng ID, Julius D. Department of Cellular and Molecular Pharmacology University of California, San Francisco, California 94143-2140, USA. Abstract Wasabi, horseradish and mustard owe their pungency to isothiocyanate compounds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mechanical stimuli. Despite their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors. 23 Genes Brain Behav. 2009 Jul;8(5):546-57. Epub 2009 May 8. The Drosophila TRPA channel, Painless, regulates sexual receptivity in virgin females. Sakai T, Kasuya J, Kitamoto T, Aigaki T. Department of Biological Sciences, Tokyo Metropolitan University, Tokyo 192-0397, Japan. [email protected] Abstract Transient receptor potential (TRP) channels play crucial roles in sensory perception. Expression of the Drosophila painless (pain) gene, a homolog of the mammalian TRPA1/ANKTM1 gene, in the peripheral nervous system is required for avoidance behavior of noxious heat or wasabi. In this study, we report a novel role of the Pain TRP channel expressed in the nervous system in the sexual receptivity in Drosophila virgin females. Compared with wild-type females, pain mutant females copulated with wild-type males significantly earlier. Wild-type males showed comparable courtship latency and courtship index toward wild-type and pain mutant females. Therefore, the early copulation observed in wild-type male and pain mutant female pairs is the result of enhanced sexual receptivity in pain mutant females. Involvement of pain in enhanced female sexual receptivity was confirmed by rescue experiments in which expression of a pain transgene in a pain mutant background restored the female sexual receptivity to the wild-type level. Targeted expression of pain RNA interference (RNAi) in putative cholinergic or GABAergic neurons phenocopied the mutant phenotype of pain females. However, target expression of pain RNAi in dopaminergic neurons did not affect female sexual receptivity. In addition, conditional suppression of neurotransmission in putative GABAergic neurons resulted in a similar enhanced sexual receptivity. Our results 24 suggest that Pain TRP channels expressed in cholinergic and/or GABAergic neurons are involved in female sexual receptivity. 25 Yakugaku Zasshi. 2010 Mar;130(3):289-94. [Activation and regulation of nociceptive transient receptor potential (TRP) channels, TRPV1 and TRPA1] [Article in Chinese] Tominaga M. Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Japan. [email protected] Abstract TRP channels are well recognized for their contributions to sensory transduction, responding to a wide variety of stimuli including temperature, nociceptive stimuli, touch, osmolarity and pheromones. In particular, the involvement of TRP channels in nociception has been extensively studied following the cloning of the capsaicin receptor, TRPV1. Painful diabetic peripheral neuropathy is described as a superficial burning pain, and it is one of the most commonly encountered neuropathic pain syndromes in clinical practice. We found that hypoxic and high glucose conditions commonly observed in diabetes potentiate TRPV1 activity without affecting TRPV1 expression both in native rat sensory neurons and HEK293 cells expressing rat TRPV1. The potentiation seems to be caused by phosphorylation of the serine residues of TRPV1 by PKC. These data indicate that PKC-dependent potentiation of TRPV1 activities under hypoxia and hyperglycemia might be involved in early diabetic neuropathy. Mechanisms for the detection of alkaline pH by sensory neurons are not well understood, although it is well accepted that acidic pH monitoring can be attributed to several ion channels, including TRPV1 and ASICs. We found that alkaline pH activates TRPA1 and that 26 the TRPA1 activation is involved in nociception, using Ca(2+)-imaging and patch-clamp methods. In addition, intracellular alkalization activated TRPA1 at the whole-cell level, and single-channel openings were observed in the inside-out configuration. Furthermore, intraplantar injection of ammonium chloride into the mouse hind paw caused pain-related behaviors, which were not observed in TRPA1-deficient mice. These results suggest that alkaline pH causes pain sensation through activation of TRPA1. 27 Pain Physician. 2009 Sep-Oct;12(5):901-10. Hydrogen sulfide's nociception. involvement in modulating Smith HS. Albany Medical College, Department of Anesthesiology, Albany, NY 12208, USA. [email protected] Abstract Hydrogen sulfide (H2S) is a malodorous gas which functions as an endogenous gasotransmitter in humans. It is becoming appreciated that H2S may be involved in a wide variety of processes including nociceptive processes. The molecular mechanisms responsible for many of the activities of H2S remain uncertain, however, H2S increases cAMP levels in neuronal and glial cell lines and primary neuron cultures with hyperpolarization. H2S may be involved in multiple signaling pathways and produce various effects on ion channels (e.g. T-type calcium channel currents, ATP-sensitive K+ (KATP) channels) which may inhibit or promote nociception. It is also conceivable that H2S may affect the n-methyl-d aspartate (NMDA) receptor complex and/or TRPA1 ion channels which may modulate nociceptive processes. It appears that H2S may regulate key neuronal functions, including the induction of hippocampal long-term potentiation, a synaptic model of learning and memory thought to involve the NMDA receptor as well as the release of corticotrophin-releasing hormone from the hypothalamus. It seems that the primary role of H2S in nociceptive processes is the activation of T-type calcium channels leading to facilitation of pronociceptive processes. A secondary contribution to the facilitation of pronociceptive processes may come from H2S-induced activation. It would appear that much like other gasotransmitters (e.g. 28 nitric oxide), endogenous H2S may be involved in multiple physiologic processes and its effects remain complex, difficult to predict, and may vary depending on the specific environment/circumstances/location where it is generated. A greater understanding of the clinically significant human physiology of H2S and hydrogen sulfide's effects on modulating nociceptive processes may potentially lead to novel targets for improving analgesia. 29 Curr Opin Pharmacol. 2010 Apr;10(2):127-32. Epub 2010 Jan 7. TRP channels and the control of vascular function. Di A, Malik AB. Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL 60612, USA. Abstract Mammalian TRP channels are grouped into six subfamilies (TRPC, TRPM, TRPV, TRPA, TRPP, and TRPML) based on the homology of the amino acid sequence. They are nonselective cation-permeable channels, most of which are permeable for Ca(2+). Growing evidence demonstrates important roles of TRP channel in controlling vascular function including endothelial permeability, responses to oxidative stress, myogenic tone, cellular proliferative activity, and thermoregulation. TRP channels are activated by a variety of stimuli, including calcium store depletion, mechanical perturbations, receptor activation, and changes in temperature and osmolarity. This diversity of activating mechanisms could be consistent with the potential multiple functions of the TRP superfamily. This review summarizes the burgeoning understanding of these cation channels in the control of vascular function. Published by Elsevier Ltd. 30 Pflugers Arch. 2009 Sep;458(5):851-60. Epub 2009 May 8. Function and regulation of TRP family channels in C. elegans. Xiao R, Xu XZ. Life Sciences Institute and Department of Molecular & Integrative Physiology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA. Abstract Seventeen transient receptor potential (TRP) family proteins are encoded by the C. elegans genome, and they cover all of the seven TRP subfamilies, including TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML. Classical forward and reverse genetic screens have isolated mutant alleles in every C. elegans trp gene, and their characterizations have revealed novel functions and regulatory mechanisms of TRP channels. For example, the TRPC channels TRP-1 and TRP-2 control nicotine-dependent behavior, while TRP-3, a sperm TRPC channel, is regulated by sperm activation and required for sperm-egg interactions during fertilization. Similar to their vertebrate counterparts, C. elegans TRPs function in sensory physiology. For instance, the TRPV channels OSM-9 and OCR-2 act in chemosensation, osmosensation, and touch sensation, the TRPA member TRPA-1 regulates touch sensation, while the TRPN channel TRP-4 mediates proprioception. Some C. elegans TRPM, TRPP, and TRPML members exhibit cellular functions similar to their vertebrate homologues and have provided insights into human diseases, including polycystic kidney disease, hypomagnesemia, and mucolipidosis type IV. The availability of a complete set of trp gene mutants in conjunction with its facile genetics makes C. elegans a powerful model for studying the function and regulation of TRP family channels in vivo. 31 Annu Rev Physiol. 2006;68:619-47. An introduction to TRP channels. Ramsey IS, Delling M, Clapham DE. Howard Hughes Medical Institute, Cardiovascular Department, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. [email protected] Abstract The aim of this review is to provide a basic framework for understanding the function of mammalian transient receptor potential (TRP) channels, particularly as they have been elucidated in heterologous expression systems. Mammalian TRP channel proteins form six-transmembrane (6-TM) cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Selected functional properties of TRP channels from each subfamily are summarized in this review. Although a single defining characteristic of TRP channel function has not yet emerged, TRP channels may be generally described as calcium-permeable cation channels with polymodal activation properties. By integrating multiple concomitant stimuli and coupling their activity to downstream cellular signal amplification via calcium permeation and membrane depolarization, TRP channels appear well adapted to function in cellular sensation. Our review of recent literature implicating TRP channels in neuronal growth cone steering suggests that TRPs may function more widely in cellular guidance and chemotaxis. The TRP channel gene family and its nomenclature, the encoded proteins and alternatively spliced variants, and the rapidly expanding pharmacology of TRP channels are summarized in online supplemental material. 32 Annu Rev Biochem. 2007;76:387-417. TRP channels. Venkatachalam K, Montell C. Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. Abstract The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease. 33 Curr Opin Neurobiol. 2004 Jun;14(3):362-9. TRP ion channels in the nervous system. Moran MM, Xu H, Clapham DE. Department of Cardiology, Harvard Medical School, 1309 Enders Building, 320 Longwood Avenue, Children's Hospital, Boston, MA 02115, USA. Abstract The transient receptor potential (TRP) superfamily comprises a group of non-selective cation channels that sense and respond to changes in their local environments. TRP channels are found in many eukaryotes, from yeast to mammals. They are a diverse group of proteins organized into six families: classical (TRPC), vanilloid (TRPV), melastatin (TRPM), muclopins (TRPML), polycystin (TRPP), and ANKTM1 (TRPA). In the peripheral nervous system, stimuli including temperature, pressure, inflammatory agents, and receptor activation effect TRP-mediated responses. In the central nervous system, TRPs participate in neurite outgrowth, receptor signalling and excitotoxic cell death resulting from anoxia. TRP channels are emerging as essential cellular switches that allow animals to respond to their environments. 34 Acta Otolaryngol. 2008 Dec 8:1-11. [Epub ahead of print] Expression of transient receptor potential channel melastin (TRPM) 1-8 and TRPA1 (ankyrin) in mouse inner ear. Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M. Department of Otolaryngology, Hiroshima University Faculty of Medicine, Hiroshima, Japan. Abstract Conclusions: It has been shown that TRPMs may play a functional role in sensory cell physiology, fluid homeostasis, sensory cell death, and thermosensation in the inner ear, while TRPA1 plays an important role in sensory transduction. Objective: To study expression of TRPM1-8 and TRPA1 in the mouse inner ear. Materials and methods: The localization of TRPM1-8 and TRPA1 in the inner ear of normal and gentamicin-treated CBA/J mice was investigated by immunohistochemistry. Results: The stria vascularis displayed a positive immunofluorescent reaction to TRPM1, 2, 3, 6, and 7. In the organ of Corti, outer and inner hair cells (OHCs and IHCs) showed positive immunofluorescence to TRPM1, 2, 3, 6, 7, and 8. Spiral ganglion cells were immunoreactive to TRPM1, 2, 3, 6, 7, and 8. The nerve fibers in the spiral ganglion cells and the nerves innervating the OHCs or IHCs were noticeably immunofluorescent to TRPM8 and TRPA1. In the vestibular end organs, vestibular sensory cells showed immunofluorescence to TRPM1, 2, 3, 6, and 7. The vestibular dark cells showed immunofluorescence to TRPM1, 3, 6, and 7; only the apical portion reacted to TRPM4. The nerve fibers innervating the vestibular sensory cells were distinctly reactive to TRPM8 and TRPA1, while the vestibular ganglion cells reacted to TRPM1, 2, 3, 6, 7, and 8. 35 Hippocampus. 2010 Feb 4. [Epub ahead of print] The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB(1) receptors and modulated by TRPA1 and Ca(v)2.2 channels. Koch M, Kreutz S, Böttger C, Grabiec U, Ghadban C, Korf HW, Dehghani F. Dr. Senckenbergische Anatomie, Institut für Anatomie II, Goethe Universität Frankfurt am Main, Germany. Abstract Cannabinoids regulate numerous physiological and pathological events like inflammation or neurodegeneration via CB(1) and CB(2) receptors. The mechanisms behind cannabinoid effects show a high variability and may also involve transient receptor potential channels (TRP) and N-type voltage-gated Ca(2+) channels (Ca(v)2.2). In the present study we investigated the neuroprotective effects of the synthetic cannabinoid WIN 55,212-2 (WIN) on dentate gyrus (DG) granule cells and elucidated the involvement of TRP and Ca(v)2.2 that are shown to participate in inflammatory processes. Organotypic hippocampal slice cultures were excitotoxically lesioned using NMDA and subsequently incubated with different WIN concentrations (0.001-10 muM). WIN showed neuroprotective properties in an inverse concentration-dependent manner, most effectively at 0.01 muM. The CB(1) receptor antagonist AM251 blocked neuroprotection mediated by WIN whereas the CB(2) receptor antagonist AM630 showed no effects. Application of the TRPA1 blocker HC-030031 enhanced the neuroprotective efficacy of high (10 muM) WIN concentrations and the number of degenerating neurons became equal to that seen after application of the most effective WIN dose (0.01 muM). In contrast, the application of TRPA1 agonist icilin 36 or allyl isothiocyanate (AITC) led to a stronger neurodegeneration. The use of TRPV1 blocker neuroprotection. 6-iodo-nordihydrocapsaicin The selective Ca(v)2.2 did blocker not affect WIN-mediated omega-conotoxin (GVIA) completely blocked neuroprotection shown by 10 muM WIN. GVIA and HC-030031 exerted no effects at WIN concentrations lower than 10 muM. Our data show that WIN protects dentate gyrus granule cells in a concentration dependent manner by acting upon CB(1) receptors. At high (10 muM) concentrations WIN additionally activates TRPA1 and Ca(v)2.2 within the hippocampal formation that both interfere with CB(1) receptor-mediated neuroprotection. This leads to the conclusion that physiological and pharmacological effects of cannabinoids strongly depend on their concentration and the neuroprotective efficacy of cannabinoids may be determined by interaction of activated CB(1) receptor, TRPA1, and Ca(v)2.2. (c) 2010 Wiley-Liss, Inc. 37 Age (Dordr). 2010 Apr 27. [Epub ahead of print] Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain. Soontornniyomkij V, Risbrough VB, Young JW, Wallace CK, Soontornniyomkij B, Jeste DV, Achim CL. Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA, [email protected]. Abstract Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, 38 Dunn's post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (r (s) = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice. 39 Aging Clin Exp Res. 2010 Apr;22(2):157-63. Epub 2010 Mar 8. Development of a simplified Short-Term Memory recall Test (STMT) and its clinical evaluation. Kobayashi N, Nakano K, Tago H, Niwa S. Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan 960-1295. [email protected]. Abstract BACKGROUND AND AIMS: The early detection and prevention of dementia is attracting attention. We therefore developed an easily performed protocol to identify patients with memory impairment which may progress to dementia, and evaluated its validity. METHODS: We focused on short-term memory impairment alone, and named the test, consisting of 3 tasks, the simplified Short-Term Memory recall Test (STMT; with a maximum score of 8). Patients were classified into a memory impairment group of 26 subjects and a control group of 23 subjects. At the first examination, subjects underwent the STMT, MMSE and ADAS-Jcog. as cognitive function tests. Follow-up observations were performed for 2 years at 6-month intervals. RESULTS: There were significant differences in the mean scores for all tests, except for MMSE memory items between the 2 groups. When the cut-off value of STMT was established as 4 points, and scores lower than this value were defined as memory impairment, the sensitivity and specificity were highest, 73.1% and 82.6%, respectively. Sensitivity and specificity also rose to 92.3% and 95.7%, respectively, when STMT scores were added together with those of ADAS-Jcog. Results of logistic regression analysis indicated that development into Alzheimer's disease 2 years later was significantly correlated with STMT scores at first examination. The incidence of progression to Alzheimer's disease in patients with 40 scores </=4 (cut-off value) was about 5 times higher than that of patients with scores >/=5. CONCLUSIONS: This study suggests the usefulness of the STMT for identifying memory impairment as a pre-dementia state. 41 Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin Abstract • Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain. 42 TRPA1 Mediates the Inflammatory Actions of Environmental Irritants and Proalgesic Agents Summary • TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard 芥末 and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain. 43 Transient receptor potential ankyrin receptor 1 is a novel target for pro-tussive agents. The transient receptor potential ankyrin receptor 1 (TRPA1) is a cation channel, co-expressed with the pro-tussive transient receptor potential vanilloid type 1 (TRPV1) channel in primary sensory neurons. TRPA1 is activated by a series of irritant exogenous and endogenous alpha,beta-unsaturated aldehydes which seem to play a role in airway diseases. The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal1, 2. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons3, 4, 5. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants6, 7, 8, 9, 10, 11. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway. 44 TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but Is Not Essential for Hair-Cell Transduction Summary TRPA1, a member of the transient receptor potential (TRP) family of ion channels, is expressed by dorsal root ganglion neurons and by cells of the inner ear, where it has proposed roles in sensing sound, painful cold, and irritating chemicals. To test the in vivo roles of TRPA1, we generated a mouse in which the essential exons required for proper function of the Trpa1 gene were deleted. Knockout mice display behavioral deficits in response to mustard oil, to cold (∼0° C), and to punctate mechanical stimuli. These mice have a normal startle reflex to loud noise, a normal sense of balance, a normal auditory brainstem response, and normal transduction currents in vestibular hair cells. TRPA1 is apparently not essential for hair-cell transduction but contributes to the transduction of mechanical, cold, and chemical stimuli in nociceptor sensory neurons. 45 Transient receptor potential ankyrin 1; Emerging pharmacology and indications for cardiovascular biology. TRPA1 is a member of the TRP superfamily, representing the sole member of the TRPA subfamily. It has many identified endogenous and exogenous agonists, comprising largely of chemical irritants and products of oxidative stress. Classically located on sensory neurone endings, TRPA1 has developed a strong presence in pain and inflammatory studies, where it is now becoming an intriguing clinical drug target. TRPA1 is increasingly recognised in a growing number of neuronal and non-neuronal locations, with expanding expression and activity profiles providing evidence of a role for TRPA1 in other systems. Interest in discovering the pharmacological and functional roles of TRPA1 is increasing and diversifying into many areas. Historically, compounds now known as TRPA1 agonists have demonstrated cardiovascular activity, modulating activities in both the heart and the vasculature. Now TRPA1 has been identified as the receptor via which these compounds can act, these studies are being revisited and expanded on using current techniques. It is therefore timely to review the current knowledge of TRPA1 receptor presence and activities of relevance to the cardiovascular system, summarising findings to date and identifying potential areas for future investigation. 46 Nociceptor and Hair Cell Transducer Properties of TRPA1, a Channel for Pain and Hearing Keiichi Nagata,1 Anne Duggan,1,4 Gagan Kumar,1 and Jaime García-Añoveros1,2,3,4 Departments of 1Anesthesiology, 2Physiology, and 3Neurology, 4Northwestern University Institute for Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 Mechanosensory channels of sensory cells mediate the sensations of hearing, touch, and some forms of pain. The TRPA1 (a member of the TRP family of ion channel proteins) channel is activated by pain-producing chemicals, and its inhibition impairs hair cell mechanotransduction. As shown here and previously, TRPA1 is expressed by hair cells as well as by most nociceptors (small neurons of dorsal root, trigeminal, and nodose ganglia) and localizes to their sensory terminals (mechanosensory stereocilia and peripheral free nerves, respectively). Thus, TRPA1 channels are proposed to mediate transduction in both hair cells and nociceptors. Accordingly, we find that heterologously expressed TRPA1 display channel behaviors expected for both auditory and nociceptive transducers. First, TRPA1 and the hair cell transducer share a unique set of pore properties not described for any other channel (block by gadolinium, amiloride, gentamicin, and ruthenium red, a ranging conductance of 100 pS that is reduced to 54% by calcium, permeating calcium-induced potentiation followed by closure, and reopening by depolarization), supporting a direct role of TRPA1 as a pore-forming subunit of the hair cell transducer. Second, TRPA1 channels inactivate in hyperpolarized cells but remain open in depolarized cells. This property provides a mechanism for the lack of desensitization, coincidence detection, and allodynia that characterize pain by allowing a sensory neuron to respond constantly to 47 sustained stimulation that is suprathreshold (i.e., noxious) and yet permitting the same cell to ignore sustained stimulation that is subthreshold (i.e., innocuous). Our results support a TRPA1 role in both nociceptor and hair cell transduction 48 Wikipedia TRPA is a family of transient receptor potential ion channels. The sole member of the TRPA sub-family, TRPA1, contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical stress sensor. It is expressed in the dorsal root ganglion, trigeminal ganglion, and hair cells. The temperature sensitivity of TRPA1 is highly disputed, with some reports claiming that it is activated by noxiously cold stimuli and others disputing such a claim. TRPA1 is known to be activated by isothiocyanates, which are the pungent chemicals in substances such as mustard oil and wasabi, methyl salicylate in winter green oil, and cinnamaldehyde in cinnamon, amongst numerous other substances.[1] Transient receptor potential cation channel, subfamily A, member 1, also known as TRPA1, is a protein which in humans is encoded by the TRPA1 (and in other species by the Trpa1) gene.[1][2] TRPA1 is an ion channel located on the plasma membrane of many human and animal cells. This ion channel is best known as a sensor for environmental irritants, pain, cold and stretch TRPA1 is a member of the transient receptor potential channel family.[2] TRPA1, contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical stress sensor.[3] The specific function of this protein has not yet been determined; however, studies indicate the function may involve a role in signal transduction and growth control.[4] 49 Recent studies indicate that TRPA1 is activated by a number reactive compounds[5] (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, nicotine[6], formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[7]) and considered as a 'chemosensor' in the body.[8] TRPA1 is considered as an attractive pain target based on the fact that TRPA1 knockout mice showed near complete attenuation of formalin-induced pain behaviors.[9][10] TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin) Although it is not firmly confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro.[11][12] In 2008 it was observed that caffeine suppresses activity of human TRPA1, but it was found that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting they mediate the perception of caffeine.[13] TRPA1 has also been implicated in causing the skin irritation experienced by some smokers who are trying to quit by using nicotine replacement therapies such as inhalers, sprays or patches.[6] A missense mutation of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from Colombia suffers from "debilitating upper body pain starting in infancy" which is "usually triggered by fasting or fatigue (illness, cold temperature, and physical exertion being contributory factors)". A gain-of-function mutation in the fourth transmembrane domain causes the channel to be overly sensitive to pharmacological activation.[14] 50 Although several nonelectrophilic agents, such as thymol and menthol have been reported as TRPA1 agonists, most of the known activators are electrophilic chemicals which have been shown to activate the TRPA1 receptor via the formation of a reversible covalent bond with cysteine residues present in the ion channel.[15][16] For a broad range of electrophilic agents chemical reactivity in combination with a lipophilicity enabling membrane permeation dibenz[b,f][1,4]oxazepine is crucial to compound TRPA1 substituted agonistic by a effect. A carboxylic methylester at position 10 can be considered as the most potent TRPA1 agonist known to date (EC50 = 50 pM).[17] 51 Memory From Wikipedia, the free encyclopedia In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory. The late nineteenth and early twentieth century put memory within the paradigms of cognitive psychology. In recent decades, it has become one of the principal pillars of a branch of science called cognitive neuroscience, an interdisciplinary link between cognitive psychology and neuroscience. From an information processing perspective there are three main stages in the formation and retrieval of memory: Encoding or registration (receiving, processing and combining of received information) Storage (creation of a permanent record of the encoded information) Retrieval, recall or recollection (calling back the stored information in response to some cue for use in a process or activity) [edit] Sensory memory Main article: Sensory memory Sensory memory corresponds approximately to the initial 200–500 milliseconds after an item is perceived. The ability to look at an item, and 52 remember what it looked like with just a second of observation, or memorisation, is an example of sensory memory. With very short presentations, participants often report that they seem to "see" more than they can actually report. The first experiments exploring this form of sensory memory were conducted by George Sperling (1960) using the "partial report paradigm". Subjects were presented with a grid of 12 letters, arranged into three rows of four. After a brief presentation, subjects were then played either a high, medium or low tone, cuing them which of the rows to report. Based on these partial report experiments, Sperling was able to show that the capacity of sensory memory was approximately 12 items, but that it degraded very quickly (within a few hundred milliseconds). Because this form of memory degrades so quickly, participants would see the display, but be unable to report all of the items (12 in the "whole report" procedure) before they decayed. This type of memory cannot be prolonged via rehearsal. [edit] Short-term Main article: Short-term memory Short-term memory allows recall for a period of several seconds to a minute without rehearsal. Its capacity is also very limited: George A. Miller (1956), when working at Bell Laboratories, conducted experiments showing that the store of short-term memory was 7±2 items (the title of his famous paper, "The magical number 7±2"). Modern estimates of the capacity of short-term memory are lower, typically on the order of 4–5 items,[1] however, memory capacity can be increased through a process 53 called chunking.[citation needed] For example, in recalling a ten-digit telephone number, a person could chunk the digits into three groups: first, the area code (such as 215), then a three-digit chunk (123) and lastly a four-digit chunk (4567). This method of remembering telephone numbers is far more effective than attempting to remember a string of 10 digits; this is because we are able to chunk the information into meaningful groups of numbers. Herbert Simon showed that the ideal size for chunking letters and numbers, meaningful or not, was three.[citation needed] This may be reflected in some countries in the tendency to remember telephone numbers as several chunks of three numbers with the final four-number groups, generally broken down into two groups of two. Short-term memory is believed to rely mostly on an acoustic code for storing information, and to a lesser extent a visual code. Conrad (1964) [2] found that test subjects had more difficulty recalling collections of words that were acoustically similar (e.g. dog, hog, fog, bog, log). However, some individuals have been reported to be able to remember large amounts of information, quickly, and be able to recall that information in seconds.[citation needed] [edit] Long-term Olin Levi Warner, Memory (1896). Library of Congress Thomas Jefferson Building, Washington, D.C. Main article: Long-term memory 54 The storage in sensory memory and short-term memory generally have a strictly limited capacity and duration, which means that information is available only for a certain period of time, but is not retained indefinitely. By contrast, long-term memory can store much larger quantities of information for potentially unlimited duration (sometimes a whole life span). Its capacity is immeasurably large. For example, given a random seven-digit number we may remember it for only a few seconds before forgetting, suggesting it was stored in our short-term memory. On the other hand, we can remember telephone numbers for many years through repetition; this information is said to be stored in long-term memory. While short-term memory encodes information acoustically, long-term memory encodes it semantically[citation needed]: Baddeley (1966)[3] discovered that after 20 minutes, test subjects had the most difficulty recalling a collection of words that had similar meanings (e.g. big, large, great, huge). Short-term memory is supported by transient patterns of neuronal communication, dependent on regions of the frontal lobe (especially dorsolateral prefrontal cortex) and the parietal lobe. Long-term memories, on the other hand, are maintained by more stable and permanent changes in neural connections widely spread throughout the brain. The hippocampus is essential (for learning new information) to the consolidation of information from short-term to long-term memory, although it does not seem to store information itself. Without the hippocampus, new memories are unable to be stored into long-term memory, and there will be a very short attention span. Furthermore, it may be involved in changing neural connections for a period of three months or more after the initial 55 learning. One of the primary functions of sleep is thought to be improving consolidation of information, as several studies have demonstrated that memory depends on getting sufficient sleep between training and test. Additionally, data obtained from neuroimaging studies have shown activation patterns in the sleeping brain which mirror those recorded during the learning of tasks from the previous day, suggesting that new memories may be solidified through such rehearsal. [edit] Models Models of memory provide abstract representations of how memory is believed to work. Below are several models proposed over the years by various psychologists. Note that there is some controversy as to whether there are several memory structures, for example, Tarnow (2005) finds that it is likely that there is only one memory structure between 6 and 600 seconds. [edit] Atkinson-Shiffrin model See also: Memory consolidation The multi-store model (also known as Atkinson-Shiffrin memory model) was first recognised in 1968 by Atkinson and Shiffrin. 56 The multi-store model has been criticised for being too simplistic. For instance, long-term memory is believed to be actually made up of multiple subcomponents, such as episodic and procedural memory. It also proposes that rehearsal is the only mechanism by which information eventually reaches long-term storage, but evidence shows us capable of remembering things without rehearsal. The model also shows all the memory stores as being a single unit whereas research into this shows differently. For example, short-term memory can be broken up into different units such as visual information and acoustic information. Patient KF proves this. Patient KF was brain damaged and had problems with his short term memory. He had problems with things such as spoken numbers, letters and words and with significant sounds (such as doorbells and cats meowing). Other parts of short term memory were unaffected, such as visual (pictures).[4] It also shows the sensory store as a single unit whilst we know that the sensory store is split up into several different parts such as taste, vision, and hearing. [edit] Working memory 57 The working memory model. Main article: working memory In 1974 Baddeley and Hitch proposed a working memory model which replaced the concept of general short term memory with specific, active components. In this model, working memory consists of three basic stores: the central executive, the phonological loop and the visuo-spatial sketchpad. In 2000 this model was expanded with the multimodal episodic buffer.[5] The central executive essentially acts as attention. It channels information to the three component processes: the phonological loop, the visuo-spatial sketchpad, and the episodic buffer. The phonological loop stores auditory information by silently rehearsing sounds or words in a continuous loop: the articulatory process (for example the repetition of a telephone number over and over again). Then, a short list of data is easier to remember. 58 The visuospatial sketchpad stores visual and spatial information. It is engaged when performing spatial tasks (such as judging distances) or visual ones (such as counting the windows on a house or imagining images). The episodic buffer is dedicated to linking information across domains to form integrated units of visual, spatial, and verbal information and chronological ordering (e.g., the memory of a story or a movie scene). The episodic buffer is also assumed to have links to long-term memory and semantical meaning. The working memory model explains many practical observations, such as why it is easier to do two different tasks (one verbal and one visual) than two similar tasks (e.g., two visual), and the aforementioned word-length effect. However, the concept of a central executive as noted here has been criticised as inadequate and vague.[citation needed] [edit] Levels of processing Main article: Levels-of-processing effect Craik and Lockhart (1972) proposed that it is the method and depth of processing that affects how an experience is stored in memory, rather than rehearsal. Organization - Mandler (1967) gave participants a pack of word cards and asked them to sort them into any number of piles using any system of categorisation they liked. When they were later 59 asked to recall as many of the words as they could, those who used more categories remembered more words. This study suggested that the act of organising information makes it more memorable. Distinctiveness - Eysenck and Eysenck (1980) asked participants to say words in a distinctive way, e.g. spell the words out loud. Such participants recalled the words better than those who simply read them off a list. Effort - Tyler et al. (1979) had participants solve a series of anagrams, some easy (FAHTER) and some difficult (HREFAT). The participants recalled the difficult anagrams better, presumably because they put more effort into them. Elaboration - Palmere et al. (1983) gave participants descriptive paragraphs of a fictitious African nation. There were some short paragraphs and some with extra sentences elaborating the main idea. Recall was higher for the ideas in the elaborated paragraphs. [edit] Classification by information type Anderson (1976)[6] divides long-term memory into declarative (explicit) and procedural (implicit) memories. Declarative memory requires conscious recall, in that some conscious process must call back the information. It is sometimes called explicit memory, since it consists of information that is explicitly stored and retrieved. 60 Declarative memory can be further sub-divided into semantic memory, which concerns facts taken independent of context; and episodic memory, which concerns information specific to a particular context, such as a time and place. Semantic memory allows the encoding of abstract knowledge about the world, such as "Paris is the capital of France". Episodic memory, on the other hand, is used for more personal memories, such as the sensations, emotions, and personal associations of a particular place or time. Autobiographical memory - memory for particular events within one's own life - is generally viewed as either equivalent to, or a subset of, episodic memory. Visual memory is part of memory preserving some characteristics of our senses pertaining to visual experience. One is able to place in memory information that resembles objects, places, animals or people in sort of a mental image. Visual memory can result in priming and it is assumed some kind of perceptual representational system underlies this phenomenon. [2] In contrast, procedural memory (or implicit memory) is not based on the conscious recall of information, but on implicit learning. Procedural memory is primarily employed in learning motor skills and should be considered a subset of implicit memory. It is revealed when one does better in a given task due only to repetition - no new explicit memories have been formed, but one is unconsciously accessing aspects of those previous experiences. Procedural memory involved in motor learning depends on the cerebellum and basal ganglia. Topographic memory is the ability to orient oneself in space, to recognize and follow an itinerary, or to recognize familiar places. [7] Getting lost when 61 traveling alone is an example of the failure of topographic memory. This is often reported among elderly patients who are evaluated for dementia. The disorder could be caused by multiple impairments, including difficulties with perception, orientation, and memory.[8] [edit] Classification by temporal direction A further major way to distinguish different memory functions is whether the content to be remembered is in the past, retrospective memory, or whether the content is to be remembered in the future, prospective memory. Thus, retrospective memory as a category includes semantic, episodic and autobiographical memory. In contrast, prospective memory is memory for future intentions, or remembering to remember (Winograd, 1988). Prospective memory can be further broken down into event- and time-based prospective remembering. Time-based prospective memories are triggered by a time-cue, such as going to the doctor (action) at 4pm (cue). Event-based prospective memories are intentions triggered by cues, such as remembering to post a letter (action) after seeing a mailbox (cue). Cues do not need to be related to the action (as the mailbox example is), and lists, sticky-notes, knotted handkerchiefs, or string around the finger are all examples of cues that are produced by people as a strategy to enhance prospective memory. [edit] Physiology Brain areas involved in the neuroanatomy of memory such as the hippocampus, the amygdala, the striatum, or the mammillary bodies are thought to be involved in specific types of memory. For example, the 62 hippocampus is believed to be involved in spatial learning and declarative learning, while the amygdala is thought to be involved in emotional memory. Damage to certain areas in patients and animal models and subsequent memory deficits is a primary source of information. However, rather than implicating a specific area, it could be that damage to adjacent areas, or to a pathway traveling through the area is actually responsible for the observed deficit. Further, it is not sufficient to describe memory, and its counterpart, learning, as solely dependent on specific brain regions. Learning and memory are attributed to changes in neuronal synapses, thought to be mediated by long-term potentiation and long-term depression. Hebb distinguished between short-term and long-term memory. He postulated that any memory that stayed in short-term storage for a long enough time would be consolidated into a long-term memory. Later research showed this to be false. Research has shown that direct injections of cortisol or epinephrine help the storage of recent experiences. This is also true for stimulation of the amygdala. This proves that excitement enhances memory by the stimulation of hormones that affect the amygdala. Excessive or prolonged stress (with prolonged cortisol) may hurt memory storage. Patients with amygdalar damage are no more likely to remember emotionally charged words than nonemotionally charged ones. The hippocampus is important for explicit memory. The hippocampus is also important for memory consolidation. The hippocampus receives input from different parts of the cortex and sends its output out to different parts of the brain also. The input comes from secondary and tertiary sensory areas that have processed the information 63 a lot already. Hippocampal damage may also cause memory loss and problems with memory storage.[9] [edit] Genetics Study of the genetics of human memory is in its infancy. A notable initial success was the association of APOE with memory dysfunction in Alzheimer's Disease. The search for genes associated with normally-varying memory continues. One of the first candidates for normal variation in memory is the gene KIBRA, which appears to be associated with the rate at which material is forgotten over a delay period. [edit] Disorders Much of the current knowledge of memory has come from studying memory disorders. Loss of memory is known as amnesia. There are many sorts of amnesia, and by studying their different forms, it has become possible to observe apparent defects in individual sub-systems of the brain's memory systems, and thus hypothesize their function in the normally working brain. Other neurological disorders such as Alzheimer's disease can also affect memory and cognition. Hyperthymesia, or hyperthymesic syndrome, is a disorder which affects an individual's autobiographical memory, essentially meaning that they cannot forget small details that otherwise would not be stored.[10] Korsakoff's syndrome, also known as Korsakoff's psychosis, amnesic-confabulatory syndrome, is an organic brain disease that adversely affects memory. 64 While not a disorder, a common temporary failure of word retrieval from memory is the tip-of-the-tongue phenomenon. Sufferers of Nominal Aphasia (also called Anomia), however, do experience the tip-of-the-tongue phenomenon on an ongoing basis due to damage to the frontal and parietal lobes of the brain. [edit] Methods Methods to optimize memorization Memorization is a method of learning that allows an individual to recall information verbatim. Rote learning is the method most often used. Methods of memorizing things have been the subject of much discussion over the years with some writers, such as Cosmos Rossellius using visual alphabets. The spacing effect shows that an individual is more likely to remember a list of items when rehearsal is spaced over an extended period of time. In contrast to this is cramming which is intensive memorisation in a short period of time. Also relevant is the Zeigarnik effect which states that people remember uncompleted or interrupted tasks better than completed ones. Interference from previous knowledge At the Center for Cognitive Science at Ohio State University, researchers have found that memory accuracy of adults is hurt by the fact that they know more than children and tend to apply this knowledge when learning new information. The findings appeared in the August 2004 edition of the journal Psychological Science. 65 Interference can hamper memorisation and retrieval. There is retroactive interference when learning new information causes forgetting of old information, and proactive interference where learning one piece of information makes it harder to learn similar new information.[11] Influence of odors and emotions In March 2007 German researchers found they could use odors to re-activate new memories in the brains of people while they slept and the volunteers remembered better later.[12] Emotion can have a powerful impact on memory. Numerous studies have shown that the most vivid autobiographical memories tend to be of emotional events, which are likely to be recalled more often and with more clarity and detail than neutral events.[13] [edit] Memory and aging Main article: Memory and aging One of the key concerns of older adults is the experience of memory loss, especially as it is one of the hallmark symptoms of Alzheimer's disease. However, memory loss is qualitatively different in normal aging from the kind of memory loss associated with a diagnosis of Alzheimer's (Budson & Price, 2005). [edit] Improving memory 66 A UCLA research study published in the June 2006 issue of the American Journal of Geriatric Psychiatry found that people can improve cognitive function and brain efficiency through simple lifestyle changes such as incorporating memory exercises, healthy eating, physical fitness and stress reduction into their daily lives.[14] There are a loosely associated group of mnemonic principles and techniques that can be used to vastly improve memory known as the Art of memory. The International Longevity Center released in 2001 a report[15] which includes in pages 14–16 recommendations for keeping the mind in good functionality until advanced age. Some of the recommendations are to stay intellectually active through learning, training or reading, to keep physically active so to promote blood circulation to the brain, to socialize, to reduce stress, to keep sleep time regular, to avoid depression or emotional instability and to observe good nutrition. [edit] Memory tasks Paired associate learning - when one learns to associate one specific word with another. For example when given a word such as "safe" one must learn to say another specific word, such as "green". This is stimulus and response.[16] Free recall - during this task a subject would be asked to study a list of words and then sometime later they will be asked to recall or write down as many words that they can remember.[17] 67 Recognition - subjects are asked to remember a list of words or pictures, after which point they are asked to identify the previously presented words or pictures from among a list of alternatives that were not presented in the original list.[18] 68 MIT Team Discovers Memory Mechanism ScienceDaily (Feb. 9, 2004) — CAMBRIDGE, Mass. -- MIT neuroscientists have discovered a new brain mechanism controlling the formation of lasting memories. This mechanism explains how signals between neurons stimulate production of the protein building blocks needed for long-term memory storage. The study, which will appear in the Feb. 6 issue of the journal Cell, has broad implications for our understanding of how learning and memory normally occur, and how these abilities may be undermined in psychiatric and neurologic diseases. Long-lasting memories are stored in the brain through strengthening of the connections, or synapses, between neurons. Researchers have known for many years that neurons must turn on the synthesis of new proteins for long-term memory storage and synaptic strengthening to occur, but the mechanisms by which neurons accomplish these tasks have remained elusive. The MIT research team, led by Nobel laureate Susumu Tonegawa, director of the Picower Center for Learning and Memory, has now identified a crucial molecular pathway that allows neurons to boost their production of new proteins rapidly during long-term memory formation and synaptic strengthening. 69 "What we have discovered that hasn't been established before is that there is a direct activational signal from the synapse to the protein synthesis machinery," said Tonegawa, the Picower Professor of Biology and Neuroscience MIT's Departments of Brain and Cognitive Sciences and Biology. The central component of this pathway, an enzyme called "mitogen-activated protein kinase" (MAPK), effectively provides a molecular switch that triggers long-term memory storage by mobilizing the protein synthesis machinery. Acting on a hunch that MAPK might be an important part of such a "memory switch," Ray Kelleher, a postdoctoral fellow in Tonegawa's laboratory and lead author of the study, created mutant mice in which the function of MAPK was selectively inactivated in the adult brain. Intriguingly, he found that these mutant mice were deficient in long-term memory storage. In contrast to normal mice's ability to remember a behavioral task for weeks, the mutant mice could remember the task for only a few hours. Similarly, the researchers found that synaptic strengthening was also much more short-lived in neurons from the mutant mice than in neurons from normal mice. Realizing that the pattern of impairments in mutant mice suggested a problem with the production of new proteins, the researchers then performed an elegant series of experiments that revealed precisely how MAPK translates synaptic stimulation into increased protein synthesis. Based on molecular comparisons of neurons from normal and mutant mice, they found that synaptic stimulation normally activates MAPK, and the activated form of MAPK in turn activates several key components of the 70 protein synthesis machinery. This direct regulation of the protein synthesis machinery helps explain the observation that activation of MAPK enhanced the production of a broad range of neuronal proteins. "Many people had thought that long-term memory formation involved only boosting the synthesis of a very limited set of proteins," said Tonegawa. "But to our surprise, this process involves 'up-regulating' the synthesis of a very large number of proteins." An immediate question that Tonegawa and colleagues are pursuing is how neurons target the newly synthesized proteins to the specific synapses participating in memory formation while not modifying other synapses. In addition to Tonegawa and Kelleher, the study's other authors (all in Tonegawa's lab) are graduate student Arvind Govindarajan and postdoctoral fellows Hae-Yoon Jung and Hyejin Kang. Potential clinical impact About the potential clinical impact of the study, Tonegawa observed, "As we continue to map out the molecular and cellular mechanisms of cognitive function, we will better understand the basis of disorders of memory impairment. Improved understanding makes it far more likely that we can develop drugs for specific molecular targets." 71 Defects in the strengthening and growth of synaptic connections are associated with a variety of psychiatric and neurologic conditions affecting the developing and adult brain, raising the possibility that disturbances in the mechanism identified in this study may contribute to these disorders, said Tonegawa. The next step will be to determine whether abnormalities in the regulation of protein synthesis can be identified in the affected brain regions in specific neuropsychiatric disorders. 72 Day 1 (November 13, 2010) What have I learnt today? What is the most interesting thing/event today? _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ 73 Day 2 (November 14, 2010) What have I learnt today? What is the most interesting thing/event today? _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ 74 Day 3 (November 15, 2010) What have I learnt today? What is the most interesting thing/event today? _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ 75 Day 4 (November 16, 2010) What have I learnt today? What is the most interesting thing/event today? _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ 76 Day 5 (November 17, 2010) What have I learnt today? What is the most interesting thing/event today? _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ 77 Day 6 (November 18, 2010) What have I learnt today? What is the most interesting thing/event today? _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ _________________________________________________ 78 Write an article about the whole conference trip to San Diego Hints: (1) What have you learnt? (2) What have you done? (3) What is the most interesting thing in the trip? (4) Any new insight about science and research? 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