Transcript Memory Intro - Walker Bioscience

Memory and learning
LeDoux, chapters 5 and 6
Types of memory
• There is general agreement that there are
several different types of memory, each of
which is predominantly in a different part
of the brain.
Declarative vs. procedural memory
• Declarative memory (explicit memory):
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facts
dates
events
Hippocampus is critical
• Procedural memory (non-declarative/implicit):
– how to perform an act (ride a bicycle)
– basal ganglia (dorsal striatum / caudate-putamen) is
critical
• Patients with Alzheimer's disease are
unable to learn or remember ordinary facts
(declarative memory) but are normal or
nearly normal at learning and
remembering how to do things (procedural
memory).
Memory experiment
• Alzheimer's patients learned and
remembered how to read complex words
in a mirror as well as normal control
subjects
• Were unable to recall the training session
or the fact that they had acquired this skill.
Classical (Pavlovian) conditioning
• Another kind of memory is distinct, both
behaviorally and anatomically, from
declarative or procedural memory.
• Pavlovian conditioning is a form of
learning based on the tendency of certain
natural events (food presentation) to elicit
involuntary responses (salivation) with little
or no training.
• Initiating event: Unconditioned stimulus
(US)
• Response pattern: Unconditioned
response (UR)
• Another "neutral" stimulus (ringing a bell),
besides the US, does not usually elicit the
UR.
• If another "neutral" stimulus (ringing a bell)
is presented simultaneously several times
with the Unconditioned stimulus (food), the
"neutral" will be able to elicit the
Unconditioned response (salivation).
• The "neutral" stimulus (ringing a bell) is
then called the Conditioned stimulus (CS).
• The response (salivation) is then called
the Conditioned response (CR)
• This process of learning an association
between a CS and a CR is called
Pavlovian or classical conditioning, or
sometimes "associative learning".
• Pavlovian conditioning occurs
automatically, with no control, voluntary
participation, or (usually) even awareness
on the part of the individual to whom it
occurs.
• Evidence in animals and humans indicate
that the amygdala is critical for classical
conditioning.
• The studies indicate that the amygdala
mediates expression of conditioned
rewarding and approach behaviors as well
as conditioned aversive and escape
responses (e.g., "freezing" in mice).
Fear conditioning
• A simple form of associative learning (Pavlovian
conditioning)
• Animals learn to "fear" a previously neutral
stimulus (conditioned stimulus, CS), because the
US has been presented at the same time as an
aversive stimulus (unconditioned stimulus, US)
such as a foot shock.
• Conditioned animals, when exposed to the CS,
tend to refrain from all movement except
breathing ("freezing").
• Freezing responses can be triggered with two
different types of CS, each working via different
parts of the brain:
• - In "cued conditioning", the CS is simply a tone
(e.g., 85 dB, 2800 Hz), and lesions in the
amygdala, but not the hippocampus, appear to
disrupt this type of conditioning.
• - In "contextual conditioning", rodents become
conditioned to the "context" in which they were
exposed, such as a particular location.
Contextual conditioning is thought to depend on
both the amygdala and the hippocampus.
Memory and the hippocampus
• In 1950, a young man, known now by his
initials, H.M. underwent brain surgery in
Hartford, Connecticut.
• H.M. was one of several patients in whom
parts of the temporal lobe were removed
in an effort to control epilepsy.
• The temporal lobe is one of the four major
divisions (lobes) of the brain, and is often
the place in the brain attacked by epilepsy.
• In H.M’s case, temporal lobe areas were
removed on both sides of his brain.
• After the surgery, his epilepsy was better,
but he no longer had the ability to acquire
new memories.
• H.M became probably the most famous
case in neurological history, and has been
the subject of many studies.
• Much of the initial work was carried out by
Brenda Milner and her colleagues in
Montreal.
• Milner found that, although H.M could
recall many of the events of his earlier life,
he was unable to form new memories for
experiences that occurred after the
surgery.
• He could remember things for a few
seconds (short-term memories) but he
couldn’t convert this information into longterm memories.
• Analysis of H.M.’s lesion, based on the
surgical report, indicated that the main
temporal lobe areas affected were the
hippocampus, amygdala, and parts of the
surrounding cortex.
• By comparing H.M.’s lesion with those in
other patients, it seemed that the
hippocampus was the area damaged most
consistently in memory deficits.
• At first, it was thought that H.M. had lost all
ability to acquire new memories.
• However, it was found that he could learn
certain tasks.
• Brenda Milner asked H.M. to copy a
picture of a star viewed through a mirror.
• To do this, the movements had to be done
in the direction opposite from the way the
seemed they should be made.
• This task is hard at first, but eventually
most people can do it, and H.M. was no
exception.
• H.M. learning the mirror drawing task, and
he retained the learning.
• But if asked about drawing using the
mirror, he had no conscious memory of
having done it.
• Suzanne Corkin of MIT found that H.M. also
improved with practice in another manual skill
learning task – one in which he was required to
keep a stick held in his hand on a dot spinning
on a turntable.
• As with the mirror drawing task, the more times
he did it, the better he got.
• His ability to form memories about how to make
precise movements (motor skills) seemed intact.
• Subsequent work has shown that other regions
of the brain (the basal ganglia) are primarily
responsible for remembering motor skills.
• Much is now known about the
hippocampus, but we will mention just a
few points.
• Information about the external world
comes into the brain through sensory
systems that relay signals to the cortex,
where sensory representations of objects
and events are created
• Outputs of each of the cortical sensory
systems converge in parahippocampal
region (also known as the rhinal cortical
areas) which surrounds the hippocampus.
• The parahippocampal region integrates
information from the different sensory
modalities before sending it to the
hippocampus proper.
• The hippocampus and parahippocampal
region make up what is now called the
medial temporal lobe memory system,
which is involved in explicit or declarative
memory.
• The connections between the hippocampus and
the neocortex are all more or less reciprocal
• The pathways that take information from the
neocortex to the rhinal areas and then into the
hippocampus are mirrored by pathways going in
the opposite direction.
• Cortical areas involved in processing a stimulus
can thereby also participate in the long-term
storage of memories of that stimulus.
• The rhinal areas serves as convergence
zones, brain regions that integrate
information across sensory modalities and
create representations that are
independent of the original modailty.
• As a result, sights, sounds, and smells can
be put together in the form of a global
memory of a situation.
• Convergence zones allow mental
representations to go beyond perceptions
to become conceptions.
• They make possible abstract
representations that are independent of
concrete stimulus.
• The primate neocortex has several cortical
areas, more than in other mammals.
• Because the hippocampus receives inputs from
several convergence zones in the rhinal region,
it can be thought of as a superconvergence
zone.
• It can form explicit memories about many
domain-specific systems, such as face- and
language-processing systems, allowing us, for
example, to form a memory that includes both
what someone says and what he looks like.
• Many researchers believe that explicit
memories are stored in the corical
systems that were involved in the initial
processing of the stimulus, and that the
hippocampus is needed to direct the
storage process.
Early experiments on drug effects
on memory
• Certain post-training treatments can
modulate memory storage in ways that
enhance or prevent retention.
• First observed with stimulant drugs
– strychnine (very low doses)
– amphetamine
– caffeine
• Early studies showed that drugs that
inhibit protein synthesis also inhibit longterm memory formation.
• Several inhibitors of RNA synthesis or
protein synthesis block long-term memory,
but do not affect short-term memory.
Gene transcription, translation, and
memory
• DNA is transcribed to produce RNA
• RNA is translated to produce protein
• DNA -> RNA -> protein
• Transcription factors are proteins that regulate
what genes are transcribed (expressed).
• Transcription factors typically bind near the
promoter region of a gene (the on/off switch).
Amphetamine improves learning
• Rats were put into a cage where they could drink
water.
• After being put in the cage, the rats heard a
series of 10 second tones, each terminated with
a brief foot shock.
• The shock caused the animals to stop moving
(freeze).
• After several such tone-shock pairings, the rats
acquired a conditioned freezing response, which
lasted for several minutes each time the tone
was presented.
• The next day, the rats were placed in the
drinking cage.
• Tone came on when they began to drink.
• Animals froze
• Duration of freezing was used as a measure of
the rats' memory for the tone-freezing
association.
• Rats that experiences more pairings (12) froze
significantly longer than rats that had fewer
pairings (2).
• Some rats got drug injections immediately after
their experience of the tone-shock pairings.
• Rats that got two pairings followed immediately
by a saline injection froze for slightly longer than
rats that got two pairings but no injection.
• However, rats that got two pairings followed
immediately by an amphetamine injection froze
for about the same length of time as rats that got
12 pairings (but no drug).
• => Amphetamine improves learning if it is given
immediately after training
• Another group of rats got 2 pairings
followed by amphetamine injection 2 hours
later.
• These rats froze for the same length of
time as rates that received saline or no
injection,
• => amphetamine had no effect if it was
given 2 hours after the training
• The results indicate that the immediate
amphetamine injections improved the rats'
memory for the tone-freezing association.
• The fact that the delayed drug injection
had no effect is consistent with the idea
that the memory was susceptible to
modulation only during a consolidation
period that lasted less than two hours.
How drugs act on synapses
• Neurons communicate with each other at
synapses using chemical neurotransmitters.
• This provides the bases for drugs (and poisons)
to affect synaptic transmission.
• Drugs with chemical properties similar in some
way to those of neurotransmitters can act on
synapses to alter behavior and thoughts
(psychotropic or psychoactive drugs)
• Drugs that increase synaptic transmission
are "agonists".
• Drugs that block or reduce synaptic
transmission are "antagonists".
• About 25 neurotransmitters are known in
the mammalian brain.
• Most psychoactive drugs act on the
synapses of a single neurotransmitter.
• These synapses often occur in different,
functionally unrelated parts of the brain,
controlling many different behaviors
• The psychological actions of drugs can be
quite complex and difficult to predict
To affect the brain, drugs must
cross the blood-brain barrier
• Access to the brain from the circulatory
system is controlled by the blood-brain
barrier (BBB).
• This barrier is made up of a layer of cell
surrounding the blood vessels that supply
the brain.
• These cells determine the degree to which
substances in the blood can enter the
brain.
• Fat-soluble substances (e.g., alcohol) cross the
BBB more easily than water –soluble
substances.
• Drugs and hormones with large molecular
weights do not easily pass the BBB.
• Some substances, including glucose and insulin,
are actively transported into the brain.
• The degree to which drugs cross the BBB is
critical to their effects on memory.
Learning and memory
• What is the nature of the neural changes
that constitute learning and memory?
• Most neuroscientists today believe that
alterations in synaptic connectivity underlie
learning, and that memory is the
stabilization and maintenance of these
changes over time.
• How does experience change synapses,
and what makes changes last?
• Changes in synapses resulting from the
simultaneous (or near simultaneous) activation
of neurons is generally thought to be the basis of
all learning, including procedural, declarative,
and conditioned learning.
• We will see that the central role of synaptic
changes in learning and memory provides the
bases for the action of neurologic drugs.
• By the early 1950’s, several studies had
shown that repeated delivery of a brief
electrical stimulus to a nerve pathway
could alter synaptic transmission in that
pathway – could, in other words, produce
synaptic plasticity.
Hebbian learning
• The most-widely accepted theory of how
information is stored in the nervous system is
based on a concept first described by D.O.
Hebb, now called Hebbian learning.
• Start with the idea that each perception evokes a
unique set pattern of neural activity.
• The set of activated neurons are connected to
each other, and reactivate each other for a short
period of time.
• Hebb suggested that this period of recurrent
activation repeatedly activates the synapses
connecting the neurons, causing the synapses
to undergo permanent changes. These changes
facilitate future activation of the synapses.
• The pattern of permanently facilitated synapses
increases the probability that on future
occasions activation of one part of some of the
neurons will activate the rest of the neurons,
leading to recall of the information it represents.
Hebb’s proposal
• “when an axon of cell A is near enough to
excite cell B or repeatedly and consistently
takes part in firing it, some growth process
or metabolic changes take place in one or
both cells such that A’s efficiency, as one
of the cells firing B, is increased.”
Memory consolidation
• When first acquired, memories are stored in a
labile state (represented by Hebb's recurrent
activation phase) and are subject to disruption
by external events.
• With the passage of time their storage may
become more permanent (Hebb's synaptic
changes) and are less susceptible to disruption.
• This process by which memories become
permanent is called "consolidation". The interval
during which the hypothesized process of
synaptic change occurs is called the
consolidation period.
Long Term Potentiation: A
mechanism for memory
• In the mid-1960’s Terje Lomo in Oslo noticed
that a brief burst of electrical stimuli delivered to
nerves going to the hippocampus in a rabbit led
to a dramatic and long-lasting increase in
transmission (a bigger electrical response to a
test stimulus after, as compared to before, the
burst) at synapses in the hippocampus.
• This is now called Long Term Potentiation (LTP)
• Later, Lomo and Bliss put a stimulating electrode
in the nerve pathway going into the
hippocampus and a recording electrode in the
hippocampus itself.
• They delivered a single electrical stimulus to the
pathway, and recorded the electrical response of
the postsynaptic neurons.
• This served as the baseline, the standard
against which the rest of the experiment was
gauged.
• Next, they gave the potentiating stimulus –
a brief burst of many repeated pulses.
Then they started testing again with a
single pulse, and continued testing
periodically for several hours.
• They found that, after the potentiating
pulses, the synaptic response got bigger,
relative to the baseline response, and
remained bigger for hours.
• Although Bliss and Lomo had produced
long-lasting change in the postsynaptic
response by electrically stimulating neural
pathways, rather than by having the
animals actually learn something, they
realized that they had identified a
mechanism that might be able to translate
neural activity generated by environmental
stimuli into changes in synaptic efficiency.
• This mechanism might be used for
learning and memory.
• The fact that the discovery was made in
hippocampal tissue supported their
speculation that changes in the efficiency
of synaptic transmission might account for
memory.
• LTP has since been induced in many
areas of the nervous system.
• Computer simulations have demonstrated
that information (memories) can be stored
and recalled in a "neural network" in which
the weights between "neurons" are altered
as a result of learning.