This document discusses learning and memory. It defines learning, memory, and the three facets of learning and memory - acquisition, storage, and retrieval. It describes studies on patient HM which showed the role of the hippocampus in forming new memories. It discusses explicit and implicit memory, as well as non-associative and associative learning. It explains synaptic plasticity mechanisms like long-term potentiation and long-term depression that are involved in memory formation. It also discusses dementia, with a focus on Alzheimer's disease.

1. LEARNING & MEMORY
MDSC 2002:
Neuroscience &
Behaviour
Farid F Youssef

2. LEARNING OBJECTIVES
1. Describe the types of memory.
2. Describe the areas of the CNS involved in
learning and memory.
3. Explain the role of synaptic plasticity in
learning.
4. Describe the characteristics of dementia with
particular reference to Alzheimer’s disease.

3. DEFINITIONS
Learning - this is the process by which an organism
acquires knowledge about its environment.
Memory- the storage or retention of that knowledge.
Retrieval mechanism – search and readout of stored of
information

4. Two fundamental questions
1. Where in the brain are memories stored?
2. What are the mechanisms by which memories are
Three facets of
learning and
memory
i. Acquisition
ii. Storage
iii. Retrieval

5. LEARNING FROM MOVIES???

6. PATIENT HM
Henry Molaison, suffered
from intractable epilepsy
In 1953 he underwent
bilateral removal of his
medial temporal lobes
The surgery worked but he
developed a severe memory
deficit; he could no longer
form any new memories.

7. PATIENT HM

8. PATIENT HM
HM demonstrates:
i. above-normal intelligence
ii. normal STM shown by digit span
performance
iii. a striking inability to consciously
recall events that occurred after
surgery
iv. intact ability to learn mirror
drawing, but with no recollection of
having done the task before

9. HM’S AMNESIA
HM has anterograde amnesia which is characterised by:
i. intact STM
ii. preserved memory for remote events (i.e., before
surgery)
iii. inability to form new long-term memories
He shows a dissociation of explicit (declarative memory)
which is severely impaired and implicit (non-declarative)
memory which is intact

10. AMNESIA

11. WHAT DID WE LEARN FROM HM?

12. EXPLICIT MEMORY
Knowledge about the environment
It is usually autobiographical and factual e.g.
places, people, things
Demonstrated by a statement of fact

13. IMPLICIT MEMORY
Knowledge/memory of how to do things i.e. motor
skills
Demonstrated by improved performance
Does not require conscious recall, i.e. it is reflexive
and does not depend on higher cognitive functions
Acquired slowly over several trials
Repeated application of declarative learning may lead
to implicit memory e.g. learning to drive a car

16. THE ROLE OF THE HIPPOCAMPUS
Hippocampal damage
disrupts memory processes,
not products: the temporal
lobe is not the repository of
LTM
The hippocampus appears to
be engaged in the process of
consolidation of memory
from STM to LTM

17. HOW ARE MEMORIES
STORED

18. IMPLICIT
MEMORY
Associative learning
• Classical Conditioning
• Operant Conditioning
Non-associative learning
•Habituatition,
•Dishabituation
•Sensitization

19. NON-ASSOCIATIVE LEARNING
Habituation
A decrease in response to a benign
stimulus that has lost meaning or
novelty
e.g. on entering a room, a clock
ticking may be irritating but soon is
not noticed
Dishabituation
Partial or complete restoration of a
habituated response following

20. NON-ASSOCIATIVE LEARNING
Sensitization
An increase in response to
an irritant or harmful
stimulus
e.g. post-traumatic stress
syndrome

21. STUDIES IN APLYSIA CALIFORNICA

22. STUDIES IN APLYSIA
Work by led by Eric Kandel who received
the Nobel Prize for Medicine and
Physiology in 2000.
Provided the first physiological evidence
for Hebb’s postulate and the concept of
synaptic plasticity.
Memories are stored in neural networks
(including the synapses)
Hebb’s rule: when pre-synaptic cell A
repeatedly takes part in firing post-
synaptic cell B, the ability of A to excite B
will be increased.
A
B

23. “HEBBIAN RULES” FOR SYNAPTIC
MODIFICATION
When the presynaptic axon is active, and at the same time
the postsynaptic neuron is strongly activated by other
inputs, then the synapse formed by the presynaptic axon is
strengthened
“Neurons that fire together wire together”
When the presynaptic axon is active, and at the same time
the postsynaptic neuron is weakly activated by other
inputs, then the synapse formed by the presynaptic axon is
weakened
“Neurons that fire out of sync lose their link”

24. STUDIES IN APLYSIA CALIFORNICA

25. 1. Aplysia restrained in
aquarium with gill
revealed
2. Photocell under gill
used to detect
amplitude and
duration of response
3. Tactile stimulus to
siphon delivered once
every 90 s -
habituation
4. Tail shock -

27. HABITUATION: MOLECULAR
MECHANISMS
After habituation, fewer quanta per action potential were released.
The sensitivity of the postsynaptic cell to NT did not change.

28. SENSITIZATION

29. SENSITIZATION: MOLECULAR
MECHANISMS
Serotonin released in
response to shock leads to
G-protein coupled
activation of adenylyl
cyclase in sensory axon
terminal.
Cyclic AMP production
activates protein kinase A.
Phosphate groups attach to
a potassium channel,
causing it to close

30. SENSITIZATION: MOLECULAR
MECHANISMS
Effect of decreased
potassium conductance
in sensory axon
terminal
More calcium ions
admitted into terminal
and more transmitter
release

31. ASSOCIATIVE LEARNING
Classical
conditioning
 One stimulus (e.g. bell;
CS) predicts the
occurrence of another
stimulus (e.g. food; US)

32. ASSOCIATIVE LEARNING
Operant conditioning
 A stimulus predicts a
response
 behavioural modification
occurs thro’ anticipated
reward or punishment
e.g. punishing children in
schools to decrease
misconduct

33. ASSOCIATIVE LEARNING

34. MOLECULAR MECHANISM:
MAMMALS

35. LONG TERM POTENTIATION
LTP: An enduring (long
lasting) increase in
synaptic efficacy
following a high
frequency (tetanic)
stimulation of afferent
fibres
Bliss and Lomo (1973)
High frequency
electrical stimulation of
excitatory pathway in

36. LTP = MEMORY???
Preventing LTP reduces or even
attenuates learning
 blocking LTP with NMDA
antsgonists disrupts performance
in the Morris water maze
 Knockout studies also have shown
similar results
LTP-like recording seen during
and after learning in
hippocampus and the
amygdala
The powerful endogenous
theta rhythm of the
hippocampus produces robust

37. LONG TERM DEPRESSION
LTD: An
enduring
weakening of
synaptic strength
following long-
term, low
frequency
stimulation of
afferent fibres

38. MECHANISMS OF LTP
NMDA receptors are
the key.
They function as
“coincidence
detectors”.
Their channel opens
only when two events
happen concurrently:
i. Presynaptic activity
ii. Strong post-
synaptic
depolarization

39. MECHANISMS OF LTP
Glutamate released
from presynaptic
terminal acts on AMPA
receptors to cause
depolarisation of
postsynaptic
membrane 
Removal of voltage-
dependent Mg++
block of NMDA
receptors 

40. MECHANISMS OF LTP
Glutamate released from
presynaptic terminal
acts on AMPA receptors
to cause depolarisation
of postsynaptic
membrane 
Removal of voltage-
dependent Mg++ block
of NMDA receptors 
Ca2+ influx via
NMDA receptor 
Activation of kinases

41. MECHANISMS OF LTP
Activation of kinases 
1. release of retrograde
messenger which
leads to greater
neurotransmitter
release
2. trafficking of AMPA
receptors from
extrasynaptic
membrane and
intracellular
compartments to
postsyanptic sites

42. MECHANISMS OF LTP
Long lasting meory requires
the actual growth and
change of neurons in the
brain.
This will involve both gene
activation and protein
synthesis

43. MECHANISMS OF LTP & LTD
NMDA receptor
activation and
bidirectional
synaptic plasticity
The level of
intracellular Ca2+
determines
whether LTP or
LTD takes place.
High Ca2+
concentration
favours LTP

44. MECHANISMS OF LTP & LTD

45. LTP VS LTD: SUMMARY
LTP: An enduring
increase in synaptic
efficacy following a high
frequency stimulation of
afferent fibres
Involves
1. activation of NR2A
subunits of NMDA
receptors in hippocampus
2. activation of intracellular
kinases e.g CAM Kinase II
3. insertion of AMPA
receptors at post synaptic
sites
LTD: An enduring
weakening of synaptic
strength following long-
term, low frequency
stimulation of afferent
fibres
Involves
1. activation of NR2B
subunits of NMDA
receptors in hippocampus
2. activation of intracellular
phosphatases
3. removal AMPA receptors
from post synaptic site

46. PRACTICAL & CLINICAL
CORRELATES

47. MEMORY STORAGE & RETRIEVAL
There is selection of information for storage: the brain
can’t store or recall everything. Possible criteria for
selection are:
1. Reliability
 neocortical synapses may change slowly so repetition is
required for long-term structural change
2. Importance:
 emotional arousal facilitates retention
 arousing stories recalled better than neutral stories

48. MEMORY STORAGE & RETRIEVAL
Pre and Post learning events affect storage
 e.g. minimizing activities that cause anterograde and retrograde amnesia facilitate
retention
Sleep
 there is replay of information from hippocampus to cortex
 Less replay with age
 filters information and promotes retention of essentials
 minimises anterograde and retrograde amnesia
 Loss of sleep leads to inc. phosphodiesterase (PDE4A5) and breakdown of cAMP
necessary for memory formation with loss of episodic memory when awake

49. DEMENTIA
WHO Definition
Dementia is a syndrome –
usually of a chronic or
progressive nature – in which
there is deterioration in
cognitive function (i.e. the
ability to process thought)
beyond what might be
expected from normal ageing.
It affects memory, thinking,
orientation, comprehension,
calculation, learning capacity,
language, and judgement.

50. DEMENTIA: COMMOM CAUSES
1. Alzheimer’s
2. Multi-infarct (vascular)
 Hypertension
 Diabetes
3. HIV associated dementia
4. Metabolic diseases
 B12 deficiency
 Hypothyroidism
5. Dementia associated with other diseases
 Parkinson’s disease
 Huntington’s disease

51. 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.

52. ALZHEIMER’S DISEASE
Alzheimer’s disease is associated with an
accumulation and clumping of the
following brain proteins:
1. Amyloid beta protein 42 which
produces widespread atrophy of the
cerebral cortex, hippocampus and
other areas.
2. An abnormal form of the tau protein,
part of the intracellular support system
of neurons.
Accumulation of the tau protein
results in:
 Plaques (extracellular and associated
with amyloid beta) – structures formed
from degenerating neurons.
 Tangles (intracellular and associated

53. ALZHEIMER’S DISEASE
Acetylcholinesterase
Inhibitors
1. tacrine [Cognex®]
2. donepezil [Aricept®]
3. rivastigmine [Exelon®]
NMDA-receptor
Antagonists
1. memantine [Namenda®]

54. LEARNING & MEMORY
MDSC 2002:
Neuroscience &
Behaviour
Farid F Youssef