[Murg] Volatility of Human Memory

[Eugen Leitl]

Link: http://slashdot.org/article.pl?sid=05/01/24/2312251
Posted by: samzenpus, on 2005-01-25 01:13:00

   from the help-finding-your-keys dept.
   [1]prostoalex writes "Scientific Americans [2]looks into the human
   brain, trying to figure out why some events just tend to stick in our
   memories forever, while the others are gone: "How does a gene "know"
   when to strengthen a synapse permanently and when to let a fleeting
   moment fade unrecorded? And how do the proteins encoded by the gene
   "know" which of thousands of synapses to strengthen? The same
   questions have implications for understanding fetal brain development,
   a time when the brain is deciding which synaptic connections to keep
   and which to discard. In studying that phenomenon, my lab came up with
   an intriguing solution to one of these mysteries of memory.""

   [3]Ads are broken 

References

   1. http://www.moskalyuk.com/blog/
   2. http://www.sciam.com/print_version.cfm?articleID=000519BF-3128-11E8-A28583414B7F0000

----- End forwarded message -----

January 24, 2005
		
Making Memories Stick
		
Some moments become lasting recollections while others just evaporate. The
reason may involve the same processes that shape our brains to begin with
		
By R. Douglas Fields
		
In the movie thriller Memento, the principal character, Leonard, can remember
everything that happened before his head injury on the night his wife was
attacked, but anyone he meets or anything he has done since that fateful
night simply vanishes. He has lost the ability to convert short-term memory
into long-term memory. Leonard is driven to find his wife's killer and avenge
her death, but trapped permanently in the present, he must resort to
tattooing the clues of his investigation all over his body.

That disturbing story was inspired by the real case history of a patient
known in the medical literature only as "HM." When HM was nine years old, a
head injury in a bicycle accident left him with debilitating epilepsy. To
relieve his seizures that could not be controlled in any other way, surgeons
removed parts of HM's hippocampus and adjoining brain regions. The operation
succeeded in reducing the brain seizures but inadvertently severed the
mysterious link between short-term and long-term memory. Information destined
for what is known as declarative memory--people, places, events--must pass
through the hippocampus before being recorded in the cerebral cortex. Thus,
memories from long ago that were already stored in HM's brain remained clear,
but all his experiences of the present soon faded into nothing. HM saw his
doctor on a monthly basis, but at each visit it was as if the two had never
met.

This transition from the present mental experience to an enduring memory has
long fascinated neuroscientists. A person's name when you are first
introduced is stored in short-term memory and may be gone within a few
minutes. But some information, like your best friend's name, is converted
into long-term memory and can persist a lifetime. The mechanism by which the
brain preserves certain moments and allows others to fade has recently become
clearer, but first neuroscientists had to resolve a central paradox.

Both long- and short-term memories arise from the connections between
neurons, at points of contact called synapses, where one neuron's
signal-emitting extension, called an axon, meets any of an adjacent neuron's
dozens of signal-receiving fingers, called dendrites. When a short-term
memory is created, stimulation of the synapse is enough to temporarily
"strengthen," or sensitize, it to subsequent signals. For a long-term memory,
the synapse strengthening becomes permanent. Scientists have been aware since
the 1960s, however, that this requires genes in the neuron's nucleus to
activate, initiating the production of proteins.

Memory researchers have puzzled over how gene activity deep in the cell
nucleus could govern activities at faraway synapses. How does a gene "know"
when to strengthen a synapse permanently and when to let a fleeting moment
fade unrecorded? And how do the proteins encoded by the gene "know" which of
thousands of synapses to strengthen? The same questions have implications for
understanding fetal brain development, a time when the brain is deciding
which synaptic connections to keep and which to discard. In studying that
phenomenon, my lab came up with an intriguing solution to one of these
mysteries of memory. And just like Dorothy, we realized that the answer was
there all the time.

Genetic Memory
Early molecular biologists discovered that genes play a role in the
conversion of a memory from short- to long-term. Their experiments with
animals trained to perform simple tasks demonstrated that learning required
new proteins to be synthesized in the brain within minutes of training, or
else the memory would be lost [see "Memory and Protein Synthesis," by Bernard
W. Agranoff; Scientific American, June 1967].

For a protein to be produced, a stretch of DNA inside the cell nucleus must
be transcribed into a portable form called messenger RNA (mRNA), which then
travels out to the cell's cytoplasm, where cellular machinery translates its
encoded instructions into a protein. These researchers had found that
blocking the transcription of DNA into mRNA or the translation of mRNA into a
protein would impede long-term memory formation but that short-term memory
was unaffected.

How does a gene "know" when to strengthen a synapse permanently?

Because one neuron can form tens of thousands of synaptic connections and
there could not possibly be a gene dedicated to each one, cellular
neuroscientists sought to explain how the cell nucleus was controlling the
strength of these individual connections. They theorized that an unknown
signaling molecule must be generated by a synapse when it was sufficiently
stimulated. With its connection temporarily strengthened, this synapse could
hold the memory for a short time while the signaling molecule departed,
wending its way to the nucleus of the nerve cell. There this messenger
molecule would activate appropriate genes needed to synthesize proteins that
would permanently strengthen the synaptic connection. Yet a second problem
was how this protein, once it was manufactured in the cell body of the
neuron, could then find the one synapse among thousands that had called for
it.

By the mid-1990s, memory researchers had a more detailed picture of events.
Several of them had shown that a transcription factor named CREB played a key
role in converting short-term memory into long-term memory in animals as
distantly related as flies and mice. Transcription factors are master
proteins inside the cell nucleus that find and bind to specific sequences of
DNA. They are thus the ultimate on/off switches that control a gene's
transcription. So CREB activation within a neuron leads to gene activation,
leading to manufacture of the mysterious synapse-strengthening proteins that
transform a short-term memory into a long-term one.

In 1997 elegant experiments by Uwe Frey of the German Federal Institute for
Neurobiology, Gene Regulation and Plasticity and Richard G. M. Morris of the
University of Edinburgh further showed that whatever these "memory proteins"
were, they did not need to be addressed to a particular synapse. They could
be broadcast throughout the cell but would only affect the synapse that was
already temporarily strengthened and make that connection permanently
stronger.

These revelations still left at least one more burning question: What is the
synapse-to-nucleus signaling molecule that determines when CREB should be
activated and a memory preserved? Around this time, my colleagues and I found
ourselves approaching the same problems as the memory researchers from a
different perspective. In my laboratory at the National Institute of Child
Health and Human Development, we study how the brain becomes wired up during
fetal development. So while memory researchers were wondering how mental
experience could affect genes, which could in turn affect certain synaptic
connections, we were wondering how genes could specify all the millions of
connections in the developing brain in the first place.

We and other developmental neuroscientists already suspected that mental
experience might have some role in honing the brain's wiring plan. The fetal
brain could start out with a rough neural circuitry that was specified by
genetic instructions. Then, as the young brain developed and tested those
connections, it would preserve the most effective ones and eliminate the poor
ones. But how, we wondered, does the brain identify which connections are
worth keeping?

Building a Brain
As far back as 1949, a psychologist named Donald Hebb proposed a simple rule
that could govern how experience might bolster certain neural circuits.
Inspired by the famous Pavlovian dog experiments, Hebb theorized that
connections among neurons that fired at the same time should become
strengthened. For example, a neuron that fired when a bell sounded and a
nearby neuron that fired when food was presented simultaneously should become
more strongly connected to each other, forming a cellular circuit that learns
that the two events are connected.

Not every input to a nerve cell is strong enough to make that cell fire a
signal of its own. A neuron is like a microprocessor chip in that it receives
thousands of signals through its dendrites and constantly integrates all the
input it receives from these connections. But unlike a microprocessor that
has many output wires, a neuron has only one, its axon. Thus, a neuron can
respond to inputs in only one way: it can either decide to send a signal on
to the next neuron in the circuit by firing an impulse through its axon, or
not.

When a neuron receives such a signal, the voltage of the membrane on its
dendrite changes slightly in the positive direction. This local change in
voltage is described as a "firing" of the neuron's synapse. When a synapse
fires in brief, high-frequency bursts, the temporary strengthening observed
in short-term memory formation occurs. But a single synapse firing briefly is
generally not enough to make the neuron fire an impulse, technically termed
an action potential, of its own. When many of the neurons' synapses fire
together, however, their combined effort changes the voltage of the neuronal
membrane enough to make the neuron fire action potentials and relay the
message on to the next neuron in the circuit.

Hebb proposed that, like an orchestra player who cannot keep up, a synapse on
a neuron that fires out of sync with the other inputs to the neuron will
stand out as odd and should be eliminated, but synapses that fire
together--enough so as to make the neuron fire an action potential--should be
strengthened. The brain would thus wire itself up in accordance with the flow
of impulses through developing neural circuits, refining the original general
outline.

Moving from Hebb's theory to sorting out the actual mechanics of this
process, however, one again confronts the fact that the enzymes and proteins
that strengthen or weaken synaptic connections during brain wiring must be
synthesized from specific genes. So our group set out to find the signals
that activate those genes.

Because information in the nervous system is coded in the pattern of neural
impulse activity in the brain, I began with an assumption that certain genes
in nerve cells must be turned on and off by the pattern of impulse firing. To
test this hypothesis, a postdoctoral fellow in my lab, Kouichi Itoh, and I
took neurons from fetal mice and grew them in cell culture, where we could
stimulate them using electrodes in the culture dish. By stimulating neurons
to fire action potentials in different patterns and then measuring the amount
of mRNA from genes known to be important in forming neural circuits or in
adapting to the environment, we found our prediction to be true. We could
turn on or off particular genes simply by dialing up the correct stimulus
frequency on our electrophysiological stimulator, just as one tunes into a
particular radio station by selecting the correct signal frequency.

Time Code
Once we observed that neuronal genes could be regulated according to the
pattern of impulses the cell was emitting, we wanted to investigate a deeper
question: How could the pattern of electrical depolarizations at the surface
of the cell membrane control genes deep in the nucleus of the neuron? To do
so, we needed to peer into the cell cytoplasm and see how information was
translated on its way from the surface to the nucleus.

What we found was not a single pathway leading from the neuron's membrane to
its nucleus but rather a highly interconnected network of chemical reactions.
Like the maze of roads leading to Rome, there were multiple intersecting
biochemical pathways crisscrossing as they carried signals from the cell
membrane throughout the cell. Somehow electrical signals of varying
frequencies on the membrane flowed through this traffic in the cytoplasm to
reach their proper destination in the nucleus. We wanted to understand how.

finally, we began to appreciate that the important factor was time

The primary way that information about the neuronal membrane's electrical
state enters this system of chemical reactions in the cytoplasm is by
regulating the influx of calcium ions through voltage-sensitive channels in
the cell membrane. Neurons live in a virtual sea of calcium ions, but inside
a neuron the concentration of calcium is kept extremely low--20,000 times
lower than the concentration outside. When the voltage across the neuronal
membrane reaches a critical level, the cell fires an action potential,
causing the calcium channels to open briefly. Admitting a spurt of calcium
ions into the neuron with the firing of each neural impulse translates the
electrical code into a chemical code that cellular biochemistry inside the
neuron can understand.

In domino fashion, as calcium ions enter the cytoplasm, they activate enzymes
called protein kinases. Protein kinases turn on other enzymes by a chemical
reaction called phosphorylation that adds phosphate tags to proteins. Like
runners passing the baton, the phosphate-tagged enzymes become activated from
a dormant state and stimulate the activity of transcription factors. CREB,
for instance, is activated by calcium-dependent enzymes that phosphorylate it
and inactivated by enzymes that remove the phosphate tag. But there are
hundredBy filling the neurons with dye that fluoresces green when the calcium
concentration in the cytoplasm increases, we were able to track how different
action-potential firing patterns translated into dynamic fluctuations in
intracellular calcium. One simple possibility was that gene transcription
might be regulated by the amount of calcium rise in a neuron, with different
genes responding better to different levels of calcium. Yet we observed a
more interesting result: the amount of calcium increase in the neuron was
much less important in regulating specific genes than the temporal patterns
of calcium flashes, echoing the temporal code of the neural impulse that had
generated them.

Another postdoc in my lab, Feleke Eshete, followed these calcium signals to
the enzymes they activate and the transcription factors those enzymes
regulate, and finally we began to appreciate how different patterns of neural
impulses could be transmitted through different intracellular signaling
pathways. The important factor was time.

We found that one could not represent the pathway from the cell's membrane to
its DNA in a simple sequence of chemical reactions. At each step, starting
from calcium entering the membrane, the reactions branched off into a highly
interconnected network of signaling pathways, each of which had its own speed
limits governing how well it could respond to intermittent signals. This
property determined which signaling pathway a particular frequency of action
potentials would follow to the nucleus.

Some signaling pathways responded quickly and recovered rapidly; thus, they
could react to high-frequency patterns of action potentials but could not
sustain activation in response to bursts of action potentials separated by
long intervals of inactivity. Other pathways were sluggish and could not
respond well to rapid bursts of impulses, but once activated, their slowness
to inactivate meant that they could sustain signals between bursts of action
potentials that were separated by long intervals of inactivity. The genes
activated by this pathway would therefore respond to stimuli that are
delivered repeatedThese results clearly showed that there was no need for a
messenger from the synapse to the nucleus. Just as in our developmental
studies, membrane depolarization by action potentials opened calcium channels
in the neuronal membrane, activating signaling pathways to the nucleus and
turning on appropriate genes. It seems to make good sense that memory should
work this way. Rather than each synapse on the neuron having to send private
messages to the nucleus, the transcriptional machinery in the nucleus listens
instead to the output of the neuron to decide whether or not to synthesize
the memory-fixing proteins.

Molecular Memento
Perhaps undiscovered synapse-to-nucleus signaling molecules do participate in
some way in the memory process, but our experiments indicate that they are
not absolutely necessary. As predicted by Hebbian rules of learning, the
firing of a neuron, resulting from the combined excitation of all synaptic
input to the cell, is the necessary event for consolidating memory.

This understanding offers a very appealing cellular analogue of our everyday
experience with memory. Like Leonard in Memento or any witness to a crime
scene, one does not always know beforehand what events should be committed
permanently to memory. The moment-to-moment memories necessary for operating
in the present are handled well by transient adjustments in the strength of
individual synapses. But when an event is important enough or is repeated
enough, synapses fire to make the neuron in turn fire neural impulses
repeatedly and strongly, declaring "this is an event that should be
recorded." The relevant genes turn on, and the synapses that are holding the
short-term memory when the synapse-strengthening proteins find them, become,
in effect, tattooed. 

-- 
Eugen* Leitl <a href="http://leitl.org">leitl</a>
______________________________________________________________
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http://moleculardevices.org         http://nanomachines.net
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