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Science Forum Index » Cognitive Science Forum » Longley versus a Nobel Laureate
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| OmegaZero2003 |
 Posted: Wed Nov 12, 2003 1:59 pm |
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"David Longley" <David@longley.demon.co.uk> wrote in message
news:bg4JJ1ZWoms$EwEz@longley.demon.co.uk...
<Longley Frag nonsense on some backward page on a backward server>
Longley says:
" Except that it's [cognitive neuroscience] a load of old useless nonsense,
supported by a hopeless
Real cognitive neuroscience added below to show Longley what real cognitive
neuroscience is: (yeah David - the methodology used by a Nobel winner to get
real results makes you a BIG LIAR and Know-Nothing):
"
Cognitive psychological studies in patients with brain lesions and in normal
subjects indicate that there are two distinct types of memory storage:
explicit (or declarative) memory storage-the conscious recall of information
about people, places, and things; and implicit (or procedural) memory
storage-the unconscious use of information about motor skills and perceptual
strategies.
Our laboratory has been interested in the question, To what degree do these
different memory processes share molecular steps? One clue to shared
mechanisms came from the study of stages in memory storage. Both implicit
and explicit forms of memory have a short-term phase lasting minutes and a
long-term phase lasting days or longer. In each case, long-term memory but
not short-term memory requires gene expression and the synthesis of new
proteins. Earlier studies in our lab of implicit memory in Aplysia and of
explicit memory in mice suggested that the requirement for protein synthesis
that characterizes long-term memory is reflected on the cellular level by
changes in the strength of synaptic connections. These changes result from
the activation of a cascade of gene expression, beginning with recruitment
of cAMP-dependent protein kinase (PKA) and the mitogen-activated protein
kinase (MAPK) and the activation of the cAMP response element-binding
protein (CREB1) and other transcription factors leading to the growth of new
synaptic connections.
In recent years, our lab has focused on how these changes come about. In
Aplysia, we have focused on the mechanisms of implicit memory for
sensitization, a simple form of learned fear, a process that involves
synapse-specific anatomical changes. In mice, the lab has examined the
synaptic mechanisms contributing to memory for space, a complex form of
explicit memory storage.
The Switch from Short- to Long-Term Memory Requires Modification of
Chromatin Structure
In almost all cells, gene expression is regulated by changes in
transcription and translation. In addition, certain genes can be regulated
by alterations of chromatin structure, a level of regulation that can impose
long-term persistent changes in gene expression. However, not all
transcription requires chromatin modification. In yeast, for example, the
expression of only about one-fourth of all genes is thought to require
chromatin modification, presumably because in most genes chromatin structure
is not inherently inhibitory. The existence of both chromatin-dependent and
chromatin-independent gene regulation raises the question: What is the
importance of regulating chromatin structure in differentiated cells? This
question is of particular interest in the mature nervous system, which is
composed primarily of postmitotic neurons. It is especially relevant in the
context of long-term memory storage, which requires alterations in gene
expression that, in some cases, can persist for the lifetime of the
organism.
Gene expression critically distinguishes long-term from short-term memory.
Studies of simple implicit memory for sensitization in defensive withdrawal
reflexes of Aplysia revealed that this requirement for transcription in
long- but not in short-term memory results from temporally and
mechanistically distinct phases of synaptic plasticity within the neurons
that participate in memory storage. In Aplysia, a core signaling pathway has
been delineated that is conserved from mollusks to flies and mice. It is
critical both for the conversion of short- to long-term changes in synaptic
plasticity and for the conversion of short- to long-term memory. Thus, a
single pulse of serotonin (5-hydroxytryptamine, 5-HT), a facilitating
neurotransmitter released during learning in Aplysia, induces short-term
synaptic plasticity by activating PKA in the sensory neurons that mediate
the withdrawal reflex. With long-term synaptic plasticity induced by
repeated pulses of 5-HT, PKA and activated p42MAPK are both imported into
the nucleus, where they initiate a cascade of gene expression in sensory
neurons. This cascade suppresses the transcriptional inhibitor CREB2 (ATF4)
and activates CREB1. CREB1, in turn, results in the induction of the
CAAT-box enhancer-binding protein (C/EBP), an immediate-response gene that
encodes a transcription factor that acts on downstream effector genes
critical for the long-term process.
An intriguing feature of memory-related long-term synaptic plasticity is
that it can be regulated bidirectionally. Thus, whereas repeated pulses of
5-HT produce long-term facilitation in the strength of the connections
between the sensory and motor neurons of the withdrawal reflex, repeated
pulses of FMRFamide (FMRFa), a neuropeptide related to the enkephalins,
produce long-term depression of these same connections. This finding leads
to several interesting questions. What is the locus of integration for
long-term synaptic plasticity? One clue comes from the finding that CREB1
can activate transcription by recruiting the CREB-binding protein (CBP), a
histone acetylase that acetylates lysine residues on core histones and is
thereby capable of altering chromatin structure. Previously, these chromatin
modifications have been studied primarily in the context of development and
differentiation, where they have been found to participate in regulating
gene transcription. We now asked: Do the inputs leading to long-term memory
storage elicit alterations in chromatin structure that are responsible for
the transcription necessary for the production of long-term synaptic
plasticity?
We focused on the chromatin around the promoter of C/EBP, a downstream gene
critical for the long-term process with several CRE elements in its
5'-untranslated region. This gene is rapidly induced by CREB1 during the
formation of long-term facilitation. We find that 5-HT and FMRFa converge on
the promoter of Aplysia C/EBP to produce bidirectional modification of
chromatin that leads to gene activation on the one hand and gene repression
on the other. 5-HT induces the expression of C/EBP by activating CREBl,
which recruits CBP (the CREB-binding protein), a histone acetylase that
selectively acetylates specific lysine residues in the histones. In
contrast, FMRFa represses C/EBP by recruiting CREB2, a type II deacetylase
that removes acetyl groups from histones of nucleosomes at the C/EBP
promoter. When both neurotransmitters are given together, FMRFa completely
overrides 5-HT. This inhibitory dominance results from the ability of CREB2
and the deacetylase it recruits to displace CREB1 and CBP. Thus, our studies
provide insight into the integrative control of long-term synaptic
plasticity. The results show that the facilitatory and inhibitory modulatory
transmitters important for long-term memory activate signal transduction
pathways that alter nucleosome structure bidirectionally through acetylation
and deacetylation.
Long-Term Stabilization Requires the Growth of New Synaptic Connections and
Local Protein Synthesis
Synapse-specific long-term facilitation requires local protein synthesis at
the activated synapse. In Aplysia, synaptic protein synthesis serves two
functions: (1) it marks the activated synapse that confers synapse
specificity, and (2) it stabilizes the synaptic growth associated with
long-term facilitation. We have now found that a neuron-specific isoform of
cytoplasmic polyadenylation element-binding protein (CPEB) regulates this
synaptic protein synthesis in an activity-dependent manner. Aplysia CPEB is
up-regulated locally in activated synapses, and it is needed for the stable
maintenance of long-term facilitation but not for the initiation. These data
suggest that Aplysia CPEB is a component of the marking signal that
indicates that a particular synapse has been active.
Prion proteins have the unusual capacity to fold into functionally distinct
self-perpetuating conformations. When prions switch state they can cause
disease (in mammals) or the inheritance of new phenotypes (in yeast). What
is particularly interesting is that this neuron-specific isoform of CPEB has
the properties of a prion. CPEB contains an amino-terminal region that
shares characteristics of yeast prion determinants: a high-glutamine content
and conformational flexibility. When fused to a nonprion reporter protein in
yeast, the region is sufficient to confer upon that reporter the
prototypical epigenetic changes in state that characterize yeast prions.
Full-length CPEB undergoes similar changes, but surprisingly, it is the
dominant, self-perpetuating prion-like form that has the greatest capacity
to stimulate translation of CPEB-regulated mRNA. We think that conversion of
CPEB to a prion-like state in stimulated synapses may aid in the
prolongation of the long-term synaptic changes associated with memory
storage.
Stabilization of the Hippocampal Representation of Space in Mice Requires
Attention
In humans, the hippocampal formation is involved in the storage of explicit
memories: those memories requiring conscious attention, e.g., the memory of
places. In rodents, hippocampal pyramidal neurons fire in a
location-specific manner and are therefore called "place" cells. We have
compared the firing patterns of place cells in four groups of mice differing
only in behavioral task demands and found that long-term place field
stability correlated strongly with the behavioral relevance of the
environment, spatial task performance, and increased dopaminergic
neurotransmission. These data suggest an intimate relationship between
explicit memory, attention, and hippocampal place cell stability.
Learned Fear in the Mouse Can Now Be Studied at the Molecular Level
The amygdala is a highly conserved and well-studied region of the mammalian
brain responsible for processing information about fear. As a result, we now
have a beginning understanding of the cellular mechanisms contributing to
learned fear in mice and rats, which can provide the basis for a molecular
analysis. Using representation difference analysis and differential
screening of single-cell cDNA libraries, we have identified the Grp gene.
This gene codes for the gastrin-releasing peptide (GRP), which is highly
expressed in the lateral nucleus of the amygdala, where associations for
Pavlovian learned fear are formed between a neutral (auditory) conditional
stimulus and an aversive (shock) unconditional stimulus. The Grp gene is
also expressed in the auditory thalamus and auditory cortex, two regions
that send information about auditory cues to the lateral nucleus during fear
learning. Additionally, we found that the receptor for GRP, GRPR, which also
is a candidate gene for certain forms of autism, is functionally expressed
in GABAergic interneurons of the lateral nucleus that project back to
principal cells. Activation of the receptors by GRP excites these inhibitory
interneurons and increases their tonic inhibition of the principal neurons.
Mice in which the gene encoding GRPR was knocked out showed a decrease in
the inhibitory control of principal neurons by interneurons. This is
accompanied by enhanced long-term potentiation (LTP) in the cortico-amygdala
pathway and better, more-persistent long-term memory for fear. In contrast,
these mice performed normally in a hippocampus-dependent Morris water maze
task. These experiments pinpoint that GRP and the neural circuitry on which
it operates is an inhibitory, negative-feedback mechanism regulating fear.
They also provide the first genetic evidence of a causal relationship
between changes in amygdala expression of a candidate gene potentially
important for autism and LTP changes in amygdala-dependent memory for fear.
"
You are a fool, a liar, an idiot and a know-nothing.
Try Eric Kandel for someone who has done more in the practical applications
of neuroscience theory and contributed to the theories themselves in 1
minute while shitting on his pot at home, than you have in your whole life.
We are waiting for your response telling how Kandel is a fool and full on
nonsense!
Quote: Except that it's a load of old useless nonsense, supported by a hopeless
methodology.
Yeah - credibility of Longley - 0
"Cognitive Neuroscience--With its concern about perception, action, memory,
language and selective attention---will increasingly come to represent the
central focus of all Neurosciences in the 21st century." -Eric R. Kandel,
M.D. (Nobel Laureate)
Credibility of a Nobel Laureate -
10000000000000000000000000000^10000000000000000000 |
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