PL2033: The Nervous System

FM2101: Foundations of Medicine: Neuroscience

PL3020: Neurophysiology

Learning and Memory

Dr Dervla O’Malley

d.omalley@ucc.ie

Learning OutcomesFollowing successful study for this lecture students should be able to • Define learning• Describe classical and operant learning• Explain the concept of reinforcement• Describe the evidence for structural changes during learning and

provide examples• Distinguish between declarative and non-declarative memory• Describe the main features of sensory stores, STM and LTM• Explain the differences between anteretrograde and retrograde

amnesia• What might cause memory defects?

• Describe some methods used to improve memory (mainly for your benefit!)

Suggested Reading

• Learning & Memory: • G&H: Ch 57 pg 705 – 720• B&L: Ch 10, pg 210• K, S and J: Ch 62

• http://hstalks.com/main/view_talk.php?t=1711&r=445&j=759&c=252• Henry Stewart Lecture on the neural basis of memory by Prof James L

McClelland ‘What you know is in your connections’.

Cognition in terms of physiology• Cognitive states such as motivation, learning and memory

were once considered in the realm of psychology rather than physiology

• However, cellular events that influence plasticity underlie these cognitive functions

• Changes in neuronal connections as a response to experiences is fundamental to learning and memory

Learning and Memory• Behaviour is the result of interactions between genes and the

environment

• In humans one of the most important mechanisms by which the environment alters behaviour is learning and memory

• Learning: the acquisition of knowledge about our environment

• Memory: the process by which that knowledge is encoded, stored and later retrieved.

• Eric Kandell: Mapping Memory in the Brain

http://www.youtube.com/watch?v=MCkji-0aqHo

Learning

• Any relatively permanent change in behaviour brought about by past experience

• Associative learning:• Forming new association between two events• Include classical and operant learning

• Cognitive (non-associative) learning: • Interpretation of present information in light of past

experience• Includes habituation and sensitisation

Associative Learning – Classical Conditioning

• Pavlov, 1927• Simplest form of learning• Learning a simple behavioural response in the presence

of a given stimulus

• Concerned with reflex behaviour: an unconditioned stimulus (US) e.g. food leads to an unconditioned response e.g. salivation

• If a novel stimulus (e.g. light/bell) is paired with the US, the novel stimulus alone soon elicits the response • i.e. it becomes a conditioned stimulus and the response

becomes a conditioned response.

Steps in classical conditioning• Neutral stimulus (NS) has no effect on the subject

• Unconditioned stimulus (US) elicits an unconditioned response (UR)

• NS is paired repeatedly with

the US; UR occurs

• NS is presented alone, UR occurs• Neutral stimulus is now the conditioned

stimulus (CS)

+

Classical conditioning in the Office: http://www.youtube.com/watch?v=nE8pFWP5QDM

Associative Learning – Operant Conditioning

• Skinner, 1938• Operant conditioning increases the likelihood of a

response by following its occurrence with a reinforcer• Involves a voluntary response (behaviour), with which an

organism ‘operates’ on its environment; • initially happens by chance, consequences determine likelihood of

doing it again.

• Classical conditioning: organism is passive, simply responds to stimuli

• Operant conditioning: organism is active, own behaviour brings on reinforcement (e.g. foot pedal causes food to be released).

Procedures for classical conditioning and operant conditioning. (a) In classical

conditioning, two stimuli (CS and US) are presented at certain times regardless of what the learner does.

(b) In operant conditioning, the learner’s behavior controls the presentation of reinforcer or punishment.

http://www.youtube.com/watch?v=guroaQRFsX4

Reinforcement

• Any event which increases the likelihood of a response

• May be positive (reward training) or negative (escape/avoidance training- not punishment)• Primary reinforcer: satisfies a basic drive e.g. food, pain

avoidance• Secondary reinforcer: conditioned e.g. money

• Only that which has relevance to drive reduction, reward/ punishment is learned

Structural Changes in Learning• In humans, disruption of brain activity within 10 minutes of

learning abolishes the memory, but if greater than 1 hour, it does not.

• Structural changes do occur during learning • e.g. rats reared in a visually enriched environment have much

thicker visual cortices; • disuse atrophy of neurons occurs.

• Inhibition of protein synthesis within 30 minutes of learning disrupts learning.

Habituation• repeated exposure to a stimulus results in

reduced responding to that stimulus• generally neutral, non-noxious stimuli

Sensitization• repeated exposure to a stimulus results in

increased responding to that stimulus• generally biologically relevant• also refers to augmentation of responding

following exposure to a second stimulus

Non-associative/cognitive learning

• Eric Kandel and his collaborators used Aplysia to unravel synaptic mechanisms for

• Short- and long-term habituation

• Short- and long-term sensitization

• Classical conditioning.

• Eric Kandel won the Nobel Prize for Physiology and Medicine 2000 for this work.

Research on neural mechanisms has focused on non- associative learning and classical conditioning.

Aplysia

http://www.youtube.com/watch?v=K0cnyqzqgkQ&feature=related

Very good lecture by Eric Kandel on memory formation

Gill withdrawal reflex in Aplysia Californica

• The gill is used for breathing• The gill can be covered with

the mantle shelf• Waste and seawater are

released through the siphon• The gill-withdrawal reflex

occurs when touching the siphon produces a retraction of the gill

Gill withdrawal reflex in Aplysia Californica

• Mechanism for habituation: ↑ K+ conductance → hyperpolarisation → ↓Ca2+ influx → ↓NT release

• Mechanism for facilitation: 5-HT → ↑cAMP → ↓K+ conductance → prolonged depolarisation → ↑ Ca2+ influx → ↑ NT release

• Repeated stimulation of sensory afferent leads to a gradual diminution of gill-withdrawal reflex – habituation

• Co-stimulation of facilitator terminal leads to increased response – facilitation (lasts days/weeks)

Habituation in Aplysia

Sensitization in Aplysia

Kandel termed the neural mechanisms that underlie behavioral sensitization,“heterosynaptic facilitation,” which is produced by a second (usually stronger) stimulus

Memory in Aplysia also involves structural changes in the presynaptic terminal

group active zones active zone area

vesicles/active zone

vesicles/neuron

naïve 100% 0.16 um 13 2250

habituated 28 0.11 um 4 500

sensitized 183 0.28 um 20 6300

Long-term Changes

• Normal Aplysia showed 1300 axon terminals on sensory neurons

• Aplysia experiencing sensitization had 2800 terminals

• Aplysia experiencing habituation had 800 terminals

group active zones

active zone area

vesicles/active zone

vesicles/neuron

naïve 100% 0.16 um 13 2250

habituated 28 0.11 um 4 500

sensitized 183 0.28 um 20 6300

With regard to learning, which of the following statements is true?

A) classical conditioning is concerned with voluntary behaviour.B) operant conditioning is concerned with reflex behaviour.C) partial reinforcement brings about longer-lasting responses

than continuous reinforcement.D) in experimental situations, learning can be prevented by

pretreatment with protein inhibitors.E) presynaptic facilitation is brought about by serotonin (5HT)

in the Aplysia model of learning.

In aplysia, short term sensitization results from a(n):

A) decrease in glutamate released from the sensory neurons.B) decrease in the number of sensory neurons.C) increase in glutamate released from the sensory neurons.D) increase in the number of motor neurons.E) increase in the number of post-synaptic receptors for the

neurotransmitter released from the sensory neurons.

MemoryRefers to the processes of:

• Acquiring information• Storing it in the brain• Subsequent retrieval and use

Qualitatively, there are also different kinds of learning• Declarative (explicit) - conscious, expressed by language

• Episodic – associated with a time • Semantic – factual knowledge

• Non-declarative (implicit) – a memory recalled unconsciously• Procedural or skill learning• Priming• Conditioning

Organizational Aspects of Learning and Memory

Information Processing Model of Memory

Organizational Aspects of Learning and Memory

• Memory can be categorized according to its duration or persistence

• Sensory traces• e.g. iconic (visual) and echoic (auditory) ‘after images’

(example on next slide)• at most a few seconds in duration

• Allows an initial evaluation of physical characteristics or psychological meaning, and a decision as to whether to send the info to STM i.e. to attend to it (decided by the limbic system)

• Selective attention:• Voluntary e.g. studying• Involuntary e.g. we attend to loud noises, moving objects,

psychologically-significant words i.e. potentially threatening/ rewarding

Short-term memory/working memory

• Information attended to passes into STM

• Encoding: mainly acoustic (sound)

• Storage: memory span 7±2 items, for ~30 secs (if unrehearsed)

• Forgetting: a) decay over time b) displacement of new information

• Maintenance rehearsal (repetition) keeps information in ST store

Let’s take a quick look at WORKING MEMORY in action

Commit this set of letters to memory - NO WRITING THEM DOWN!

STM : Working Memory

FBIPHDHSEIBM

Which set of letters did you just see?

A. FBIPHDHSEIMB

B. FBIHPHDSEIBM

C. BFIPHHSDEBMB

D. FBIPHDHSEIBM

E. FBIHPDSHIEMB

STM : Working Memory

Now try this...

IBM HSE FBI PHD

STM : Working Memory

Which set of letters did you just see?

A. IBMHTEFBIPHO

B. IBMHSEPHDFBI

C. IBMHSEFBIPHD

D. IPMHSEPHEFPI

E. IPMASTPHDFPI

STM : Working Memory

4789231638901254

Commit this set of numbers to memory - write them down when they disappear!

STM : Working Memory

How many did you get correct?

4789231638901254

STM : Working Memory

4 70 68 70 99 54 291 10

Now try this...

STM : Working Memory

How many did you get correct this time?

4 70 68 70 99 54 291 10

STM : Working Memory

Why were the second letter and number tasks easier?Capacity of short term memory digit /item span (aka working memory

load) is ~7±2 items (Miller, 1956). Modern estimates are lower: 4-5

items.

However, an “item” can be a single letter or digit, or a CHUNK of several letters or numbers.

The sequences FBI, PHD or 99 & 54 are both single items because they have been “chunked”.

Chunking makes more efficient use of short-term memory by recoding information.

Various kinds of memory training systems and mnemonics include training and drill in specially-designed recoding or chunking schemes.

STM : Working Memory

Functions of STM

• Working Memory: what we are ‘thinking’ about • cognitive processes e.g. conversation, reading, computation,

problem solving

• Evaluation of information and a decision re whether to send it to LTM (selected by the limbic system)

Organizational Aspects of Learning and Memory

Memory can be categorized according to its duration or persistence

• Sensory traces• Short-term memory (STM) or working memory

• Intermediate-term memory• distinguishable from STM and LTM?• up to a few days in duration

• Long-term memory• indefinite duration

Characterisation of memory

• Sensory traces• persistent activity in sensory pathways

• Short-term memory (STM) or working memory• reverberating circuits• electrical basis• limited capacity• can be disrupted by intrusion of other activity

• E.g. Stroop test – example of interference

Recite the word

Green

Blue

Black

Red

Orange

Purple

Yellow

The stroop test

Recite the colours not the words

Neural Basis of STM• Due to reverberating circuits: self exciting chains of

neurones in the relevant sensory, association and motor areas (neural networks)

• Medial temporal lobe and mamillary bodies (Papez circuit) form and consolidate verbal memories which are stored in the appropriate areas of the cortex.

• STM is very susceptible to disruption of the electrical activity of the brain, e.g. during concussion, epileptic fits or general anaesthetics, leading to amnesia for the immediate preceding events.

Neural Basis of ST Memory

Characterisation of memory

• Sensory traces• persistent activity in sensory pathways

• Short-term memory (STM) or working memory• reverberating circuits• electrical basis• limited capacity• can be disrupted by intrusion of other activity

• Long-term memory (LTM)• structural or anatomical basis• protein synthesis essential• unlimited(?) capacity

Short-term memory:

A) has a larger storage capacity than long-term memoryB) involves transient modifications in the functions of pre-

existing synapsesC) is believed to be consolidated into long-term memory

during slow wave sleepD) is not affected by general anaesthetics or concussionE) is normal in patients with bilateral damage to the

Papez circuit (Korsakof’s syndrome)

Longterm Memory (LTM)• Small amount of information in STM transferred to LTM

• Ability to store very large amounts of information for very long periods of time

• Encoding: mainly semantic (meaning), also visual (faces), auditory (voices), olfactory (scents).

• Transfer requires elaborative rehearsal • i.e. coding, relating to stored information, devising associations, organizing.

• Storage: probably unlimited capacity, for very long periods of time

Longterm Memory (LTM)• Retrieval ‘cues’ ‘unlock’ correct ‘box’ for memories

(recognition is easier than recall).• ‘Forgetting’ in LTM is usually due to retrieval failure.

• Retrieval is increased by elaboration, organization (information in many boxes).

• Increased if recalled in context• Decreased by interference e.g anxiety

• Influence of emotional factors:• Rehearsal of emotionally-charged items leads to increased storage• Negative emotions interfere with retrieval• Freud: retrieval of traumatic experiences blocked

Locating the Memory Trace (Engram)• Engram: physical

representation or location of a memory

• Karl Lashley (1930s) observed the effects of lesions on rats’learning in a maze

• The larger the amount of cortex damaged, the more errors the rats made

• Lashley believed that the engram was distributed across the cortex

• However, the lesions were so large they damaged several cortical regions. Moreover, the rats might solve the maze using sight, smell and feel in addition to memory.

• Lashley was incorrect. All cortical regions don’t contribute equally to memory but they are distributed through the cortex.

Patient H.M. (Henry Molaison)• Sustained a head injury at age 7• Experienced his first major seizure aged 10• Experimental surgery carried out in 1953, (H.M aged 27) where

both hippocampus and amygdala removed at a treatment for the seizures

• Epilepsy much improved, controlled by Meds

• However, H.M had great difficulty forming new long-term memories.

• STM or working memory remained intact.• Suggested that the hippocampus/amygdala is vital for the

formation of new long-term memories.

Scoville and Milner, 1957

Major findings from H.M• Memory could be impaired selectively without loss of other

cognitive functions• Memory functions localised to the medial temporal lobe• The hippocampus thought to be a key structure for

memory, but impairment may be due to combined damage of the hippocampus and the amygdala- localisation of memory not completely clear

What H.M can and cannot remember

• Impaired: anterograde amnesia is the inability to form new memories after onset of a disorder.

• Partially spared: Retrograde amnesia is the loss of memories formed before onset of amnesia

** This means that the medial temporal lobe is critical for the initial formation/encoding of new memory but not the place where well established long term memories are stored**

A man is the sum of his memories….

Life without memory: the case of Clive Wearing

http://www.youtube.com/watch?v=OmkiMlvLKto

Damage to other areas can also cause memory loss.

Patient N.A. has amnesia due to accidental damage to the dorsomedial thalamus, which is part of the same memory circuit affected by H.M.’s surgery.

Like H.M. he has short-term memory but cannot form declarative long-term memories.

Neural Basis of LTM• Depends on permanent structural changes in the relevant

sensorimotor and association areas:• Disruption of the brain’s electrical activity does not

abolish LTM• Highly specific cortical activation occurs during recall,

and retrograde amnesia is specific for cortical area damaged.

• Consolidation: process of transfer of information from STM to LTM, when structural changes occur; corresponds to period of elaborative rehearsal, ~1 hr

Neural Basis of LTM• Interneural hypothesis: changes in synaptic activity in a

neural circuit lead to facilitation of that circuit- a ‘memory engram’.• E.g. increased number of presynaptic terminals, vesicle-

release sites and transmitter vesicles.• Altered post synaptic dendritic spines

• Long Term Potentiation (LTP): well documented mechanism of learning in hippocampus, cerebellum.

• Long Term Depression (LTD)

LTP in the hippocampus – molecular model of learningHippocampus most studied because of it's organization-

• complete circuitry represented in thin slices (100-400um thick)• can be placed in a dish for in vitro electrophysiological experiments• also thought to be important for memory consolidation in vivo

 

LTPTypical LTP experiment

1. stimulate neuron A, record PSP from neuron B2. stimulate neuron A tetanically (e.g. burst of stimuli @ 100 Hz)3. record PSP from B w/test pulses at varying intervals4. PSP augmented for several days or even up to months5. this augmentation is what is called LTP

LTP in the hippocampusNormal synaptic transmission

CaMKII: Calcium/calmodulindependent kinase II

PKA, PKC: Protein kinase A, C

CREB: cAMP-responsive element-binding protein

Low-frequency stimulation results in small increases in [Ca2+] in the postsynaptic cell, which in turn results in fewer AMPA channels opening in response to glutamate. This is called low-frequency depression and is a mechanism for weakening synaptic strength.

http://www.sumanasinc.com/webcontent/anisamples/neurobiology/receptors.html

With regard to long-term memory, which one of the following statements is correct?

A) it is encoded semantically (according to its meaning)B) it has a limited capacity of approximately 7 itemsC) it is entirely stored in the temporal lobeD) it is disrupted by transient loss of consciousnessE) the cerebellum is important in the formation of verbal (explicit) memory

Learning, Memory, Amnesia & Brain Functioning

• Different kinds of brain damage result in different types

of amnesia.

• Two common types of brain damage include:

Korsakoff’s syndrome

• Prolonged thiamine (vitamin B1) deficiency. Often due to

chronic alcoholism

• Impedes the ability of the brain to metabolize glucose.

• Leads to a loss of or shrinkage of neurons in the brain.

• Symptoms include apathy, confusion, and forgetting and

confabulation (taking guesses to fill in gaps in memory).

Learning, Memory, Amnesia & Brain Functioning

Alzheimer’s disease • Associated with a gradually progressive loss of memory

often occurring in old age.• Affects 50% of people over 85.• Early onset seems to be influenced by genes, but 99%

of cases are late onset.• About half of all patients with late onset have no known

relative with the disease.

Figure 13.13: Neuronal degeneration in Alzheimer’s disease.(a) A cell in the prefrontal cortex of a normal human; (b) cells from the same area of cortex in Alzheimer’s disease patients at various stages of deterioration. Note the shrinkage of the dendritic tree. (Source: After “Dendritic changes,” by A. B. Scheibel, p. 70. In B. Reisberg, Ed., Alzheimer’s Disease, 1983. Free Press)

• Alzheimer’s disease is associated with an accumulation and clumping of the following brain proteins:• Amyloid beta protein 42 which produces widespread atrophy of the

cerebral cortex, hippocampus and other areas.• An abnormal form of the tau protein, part of the intracellular

support system of neurons.

• Accumulation of the tau protein results in:• Plaques – structures formed from degenerating neurons.• Tangles – structures formed from degenerating structures within a

neuronal body.

Learning, Memory, Amnesia & Brain Functioning

• Lessons from studying amnesiac patients include:• There can be deficiencies of very different aspects of

memory.• There are independent kinds of memory.• Various kinds of memory depend on different brain

areas.

Learning, Memory, Amnesia & Brain Functioning

Improving Declarative memory• Chunking: Grouping items in STM may be recoded, using

information from LTM, into larger more meaningful units (chunks) – memory span is still 7±2 items

• Elaboration, organisation – hierarchical most efficient

• Context: recreating learning situation in imagination

• Imagery: meaningful connection between two words e.g. method of loci, key-word system, mnemonics

• PQ4R (Preview, Question, Read, Reflect, Recite, Review• Practicing retrieval as one learns ↑↑ retrieval later