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– 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) – 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

Short-term Memory

Long-term Memory

Consolidation

DeclarativeImplicit

Sensory Information

Sensory RegisterAttention

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– 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-4-

isoxazole 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-phos-

phorylation– 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.