Download conference booklet - Po Leung Kuk Laws Foundation College

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
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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.
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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
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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.
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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
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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
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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
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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.
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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
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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]
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
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]
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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.
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"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."
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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.
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Day 1 (November 13, 2010)
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Day 2 (November 14, 2010)
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Day 3 (November 15, 2010)
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Day 4 (November 16, 2010)
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Day 5 (November 17, 2010)
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Day 6 (November 18, 2010)
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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?
Title: __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __
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