Memory, Learning and Amnesia
Memory, Learning and Amnesia
• Memory = site and/or process where knowledge and
experiences are stored.
• Learning = the process of committing new knowledge
and experiences into (semi-) permanent storage.
– Classical conditioning
– Operant conditioning
– Other neural mechanisms
• Amnesia = the inability to form or recall memories.
Memory, Learning and Amnesia
• Types of memory and amnesia
• Brain areas involved in memory
– Sensory and working short-term memory
– Procedural memories
– Declarative memories
• Neural mechanisms of learning
History of Memory Studies
• The study of memory
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1885 Ebbinghaus publishes first studies on memory.
1889 Korsakoff describes severe anterograde amnesia.
1915 Karl Lashley begins a long-term study of memory.
1950 Lashley states “… the engram is represented
throughout the region.”
– 1953 Dr. William Scoville removes the bilateral medial
temporal lobes of H. M. to stop epileptic seizures and
inadvertently discovers the role of the hippocampus.
Areas of Memory
• Lashley was wrong. Memories are not evenly
distributed over the cortex.
• Memories are not all stored in the same place.
Different types of memory are found in different
areas, but all rely on synaptic connections.
• There is no “grandma” neuron.
• All parts of the nervous system can learn and
remember.
• Multimodal information is remembered better.
Types of Memory - Data
• Declarative or explicit (conscious)
– Facts & events
– Easily formed, and easily forgotten
• Nondeclarative or implicit (unconscious)
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a.k.a. procedural memory
Skills, habits and conditioning
Skeletal muscle practiced movements.
Emotional responses
Requires repetition, but rarely forgotten
Types of Memory - Data
Types of Memory - Time
• Short-term
– Only good for seconds to hours
– Easily disruptable
• Long-term
– Lasts for days, months or years
– Permanent
Short-term Memory
• Average capacity is 7 +/- 2 chunks,
generally proportional to intelligence.
– Kept in right orbital cortex (frontal lobe).
• Data only remains there for a few seconds
without rehearsal. Modulated by attention.
• Easily disrupted.
• Unrelated to long-term memory.
Short-term Memory
• Short-term sensory memory
– The senses have independent short-term storage.
– Kept in the cortical area of the sense.
• Temporal lobe for audio data, etc.
• The lateral intraparietal cortex (LIP) seems to hold
short-term visual memories in monkeys.
– If there is sufficient attention, the sensory
information can be moved to short-term working
memory areas. If not, the information will be lost.
Types of Memory
Sensory Information
Attention
Sensory Register
Declarative
Implicit
Short-term Memory
Consolidation
Long-term Memory
Loss of Memory
• Amnesia = The loss of (declarative) memory
– Retrograde
• Can’t recall previously available information.
• Sometimes very old memories are still available.
– Anterograde amnesia
• Can’t learn new information.
• Can affect short-term, long-term, or both.
• Usually accompanied by retrograde amnesia.
– Specific deficits
• Prosopagnosia, anomia, etc.
Procedural Memory Areas
• The striatum seems to be strongly involved in
procedural memories and conditioning.
– Huntington’s and Parkinson’s patients have
difficulties learning procedural tasks because of
damage to the striatum.
• The cerebellum is the primary site of
coordinated movement learning.
Declarative Memory Areas
• Amnesia, lobectomy and stimulation
studies point to the temporal lobe as the
primary site for declarative memories, or
at least their recall.
• Stimulation of the temporal cortex
produces more complex memories and
hallucinations than any other brain area.
• Anomia and prosopagnosia tied to
temporal lobe.
Declarative Memory Areas – H.M.
• Case study: H. M. (1953, M, 27 y.o.)
– Dr. Scoville removed both medial temporal lobes
to alleviate untreatable epileptic seizures.
– Seizures were greatly reduced, BUT…
– H. M. had severe post-op anterograde amnesia
which never improved, but little retrograde or
motor amnesia or short-term memory problems.
– From previous understanding (distributed
memory), this could not occur.
– Research changed from place to process.
Declarative Memory Areas
• Medial temporal lobe
– Removed in H.M.
– Hippocampus is
directly below the
amygdala (highlighted
in pink).
Implicit Memory Areas
– H.M.’s working memory is intact.
– H.M. can still learn habits and trained tasks.
– This shows that lack of the hippocampus impairs
consolidation required for conscious recall, but
not for implicit memories.
• Priming
– Exposure to a stimulus makes it easier to
recognize that stimulus again (it is remembered).
– H. M. shows very limited signs of recognizing
prior stimuli without cognitively realizing it.
Declarative Memory Areas
• 8 other psychotic patients were examined
– Only those who had a hippocampusectomy had
anterograde amnesia.
– They deduced the hippocampus is necessary for
new memory formation, but not recall.
– It is not necessary for short-term memory.
– Modern procedures call for only one
hippocampus to be removed, and it is now
tested for functionality before the operation.
Declarative Memory Areas
• Alzheimer’s disease
– A progressive disease causing loss of cells and
deterioration in the association cortex.
– Marked by anterograde amnesia and later also
by retrograde amnesia.
– Damage begins in medial temporal cortex and
spreads to other areas.
– This is evidence that anterograde amnesia is
related to the medial temporal cortex.
Declarative Memory Areas
• Korsakoff’s Syndrome
– Symptoms
• Severe anterograde amnesia
• Confabulation
– Make up stories based on fragments of recent occurrences
– Caused by thiamine (vitamin B1) deficiency
• Alcoholism
• Malnutrition
– Damages the mammillary bodies, which relay
information from the hippocampus to the
thalamus via the fornix.
Declarative Memory Areas
• Patient R. B.
– Permanent anterograde amnesia caused by
anoxic ischemia of the hippocampus.
– On autopsy, it was found that the CA1 region of
the hippocampus was gone.
– The CA1 region is especially rich in NMDA
receptors (involved in learning).
• If only CA1 damaged: anterograde amnesia only.
• Anoxia causes NMDA receptors to allow excessive
Ca++ influx, damaging cells.
Declarative Memory Areas
• Further evidence of NMDA-Hippocampus
connection:
– Mice with NMDA receptor knock out learn
very slowly, if at all.
– Mice with excess NMDA receptor genes learn
quicker than normal.
Declarative Memory Areas
• Neuromodulation in the hippocampus
– 5-HT inhibits memory formation.
– NE, E, D, cocaine enhance memory formation.
– Cholinergic theta rhythms (5-8 Hz) from medial
septum seem to be necessary.
– In rats, theta activity is correlated with
exploratory behaviors.
• Info sampled into dentate gyrus and CA3 on theta.
• Info moved to CA1 when theta waves subside.
Declarative Memory Areas
• Anatomical structures:
– Thalamus, sensory relay
– Amygdala, emotional memory
– Hippocampus, spatial memory
• Rat radial maze performance: evidence of place neurons
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Rhinal cortex, object & recognition memory
Fornix and mammilary bodies
Prefrontal cortex
Surrounding limbic structures
Neural Mechanisms
Classical Conditioning
• A form of learning where an otherwise
unimportant stimulus acquires the
properties of an important stimulus.
• Forms an association between two stimuli,
one which would normally cause a behavior
and one which would not.
• Implicit memory
Classical Conditioning
• Ex. Rabbit eye blink
– A puff of air directed at a rabbit’s eye causes
the rabbit to blink, an unconditioned response.
– A 1000 Hz tone is played independently and
causes no eye blink response.
– A tone is played and shortly followed by an air
puff and this sequence is repeated.
– The rabbit quickly learns to blink as soon as the
tone is sounded, a conditioned response.
Hebb’s Rule
• 1949 Donald Hebb proposes that a synaptic
connection will be strengthened if a synapse
repeatedly becomes active at the same time
or just after the postsynaptic nerve fires (he
could not verify his own theory).
Operant Conditioning
• Similar to classical conditioning, except that
it involves an association between a learned
behavior and a response (instead of an
automatic behavior and another stimulus).
• Permits an organism to adjust its behavior
according to the consequences.
• Reinforcing stimuli increase the likelihood of
the response, punishing stimuli decrease it.
Operant
Conditioning
Dr. Skinner and his
famous box
Operant Conditioning
• Ex. Skinner Box - Training
– A hungry rat is placed in a box with a lever.
– It has no particular reason to press the lever.
– By random interaction, the rat learns that it will
get a food reward for pressing the lever.
– This will increase the likelihood that the rat will
press the lever to get more food (reinforcing
stimulus).
Operant Conditioning
• Ex. Skinner Box - Extinction
– Once trained, the rat is then also shocked (a
punishing stimulus) when the lever is pressed,
decreasing the likelihood of further lever presses.
– The lever pressing behavior is extinguished.
– Recent research suggests 2 mechanisms:
• Immediate: The new synaptic connection destroyed.
• Delayed: A separate learned inhibitory pathway forms.
– Consolidation seems to be required.
Neural Mechanisms
• The basis of all learning is plasticity, the
ability of the nervous system to change its
neural connections by:
– Forming or destroying neural connections.
– Forming or destroying receptors.
– Activating or deactivating receptors.
Learning
• Two major plasticity mechanisms
– Long-term potentiation (LTP)
• Creates associations by synaptic enhancement
– Long-term depression (LTD)
• Loosens associations by synaptic degradation
Anatomy Review
• Hippocampus (a.k.a. Ammon’s Horn =
cornu ammonis) is heavily involved in new
memory formation.
• Neurons enter through the entorhinal cortex,
relay through the granule cells of the
dentate gyrus, and project to pyramidal cells
of CA3 (30,000+ spines per dendrite).
• Output is from CA1.
Long-term Potentiation
• Glutamate is the predominant interneuronal
neurotransmitter in the CNS.
• Two major glutamate receptor types:
– AMPA (α-amino-3-hydroxy-5-methyl-4isoxazole propionate)
• Na+ ion channels
– NMDA (n-methyl-D-aspartate)
• Voltage and glutamate controlled Ca++ ion channel
• The channel is normally blocked by a Mg++ ion, which
is expelled when the cell becomes depolarized.
Long-term Potentiation
• “Silent synapse” theory - new dendritic
spines only contain NMDA receptors (no
AMPA receptors).
• If the new synapse receives stimulation at
the same time as the nerve fires, AMPA
receptors will be created, unsilencing the
synapse.
Long-term Potentiation
• The NMDA receptors are assumed to be
responsible for LTP.
– AP5 (2-amino-5-nopentanoate) blocks NMDA
channels and temporarily inhibits learning, but
not recall.
• Ca++ acts as a 2nd messenger, regulating the
creation of new AMPA receptors.
– EGTA, which binds to Ca++ and makes it
insoluble, also blocks learning.
Long-term Potentiation
• Ca++ influx
– Activates type II calcium-calmodulin kinase
(CaM-KII).
– Converts arginine to nitrous oxide (NO). Which
signals presynaptic neuron to release Glu.
• CaM-KII self-phosphorylates, allowing
continued action after Ca++ influx.
• CaM-KII controls synthesis of receptors,
protein kinases and cytoskeleton, and
phosphorylates the AMPA receptors.
LTP Summary
• Initially only NMDA
channels.
• Simultaneous presynaptic
glutamate and postsynaptic
depolarization let Ca++
enter NMDA channels.
• AMPA receptors are
synthesized and strengthen
the synaptic connection.
LTP
• CaM-KII
effects:
– Self-phosphorylation
– Creation of
new AMPA
receptors
– Arginine to
nitrous oxide
conversion
Long-term Potentiation
• NO release by the
postsynaptic cell has
retrograde causes
further presynaptic
glutamate release.
Long-term Potentiation
• Recent evidence also shows that the
presynaptic terminal button projects a
finger-like extension into the postsynaptic
dendritic spine.
• The projection divides the spine and causes
a split into two buttons and two spines.
Long-term Potentiation
Long-term Potentiation
• Protein synthesis in LTP
– Proteins (i.e. AMPA receptors) don’t last long, but
memories do.
– Something else must make memories permanent.
– Protein synthesis inhibitors have been found to
interfere with the formation of long-term memories.
Long-term Potentiation
• Protein synthesis experiments
– Experiments with Drosophila identified two proteins
involved with long term learning, cAMP Response
Element Binding proteins CREB-1 and CREB-2.
– CREB2 repressed memory formation.
– CREB1 gave super-memory.
– CREB formation is governed by protein kinases that
results from varying Ca++ influx.
Long-term Potentiation
• CREB-2 does not
permit synthesis
• CREB-1 readily
replaces CREB-2,
but does not permit
synthesis either.
• Phosphorylated
CREB-1 does
permit synthesis.
Long-term Depression
• CPP, an NMDA antagonist blocks LTP but
not LTD.
• This suggests at least two subtypes of
NMDA receptors.
• AMPA receptors are dephosphorylated,
decreasing their sensitivity to glutamate.
• AMPA receptors also decrease in number.
Long-term Potentiation
Hebb’s Rule
• After 50 years and many new tools (cellular
recording, drugs, electron microscopy) we
now have solid evidence for at least one
mechanism of learning predicted by Hebb.
• Other mechanisms also exist, but they are
not yet well understood.