Learning & memory 2013

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Learning & memory 2013

  1. 1. LEARNING & MEMORY MDSC 2002: Neuroscience & Behaviour Farid F Youssef
  2. 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. 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. 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. 5. LEARNING FROM MOVIES???
  6. 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. 7. PATIENT HM
  8. 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. 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. 10. AMNESIA
  11. 11. WHAT DID WE LEARN FROM HM?
  12. 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. 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
  14. 14. 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
  15. 15. HOW ARE MEMORIES STORED
  16. 16. IMPLICIT MEMORY Associative learning • Classical Conditioning • Operant Conditioning Non-associative learning •Habituatition, •Dishabituation •Sensitization
  17. 17. 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
  18. 18. NON-ASSOCIATIVE LEARNING Sensitization An increase in response to an irritant or harmful stimulus e.g. post-traumatic stress syndrome
  19. 19. STUDIES IN APLYSIA CALIFORNICA
  20. 20. 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
  21. 21. “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”
  22. 22. STUDIES IN APLYSIA CALIFORNICA
  23. 23. 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 -
  24. 24. HABITUATION: MOLECULAR MECHANISMS After habituation, fewer quanta per action potential were released. The sensitivity of the postsynaptic cell to NT did not change.
  25. 25. SENSITIZATION
  26. 26. 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
  27. 27. SENSITIZATION: MOLECULAR MECHANISMS Effect of decreased potassium conductance in sensory axon terminal More calcium ions admitted into terminal and more transmitter release
  28. 28. ASSOCIATIVE LEARNING Classical conditioning  One stimulus (e.g. bell; CS) predicts the occurrence of another stimulus (e.g. food; US)
  29. 29. 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
  30. 30. ASSOCIATIVE LEARNING
  31. 31. MOLECULAR MECHANISM: MAMMALS
  32. 32. 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
  33. 33. 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
  34. 34. LONG TERM DEPRESSION LTD: An enduring weakening of synaptic strength following long- term, low frequency stimulation of afferent fibres
  35. 35. 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
  36. 36. 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 
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. MECHANISMS OF LTP & LTD
  42. 42. 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
  43. 43. PRACTICAL & CLINICAL CORRELATES
  44. 44. 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
  45. 45. 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
  46. 46. 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.
  47. 47. 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
  48. 48. 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.
  49. 49. 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
  50. 50. ALZHEIMER’S DISEASE Acetylcholinesterase Inhibitors 1. tacrine [Cognex®] 2. donepezil [Aricept®] 3. rivastigmine [Exelon®] NMDA-receptor Antagonists 1. memantine [Namenda®]
  51. 51. LEARNING & MEMORY MDSC 2002: Neuroscience & Behaviour Farid F Youssef

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