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  1. 1. Learning & Memory Vedran Lovic
  2. 2. Lecture Outline <ul><li>Introduction to Basic Concepts </li></ul><ul><li>Karl Lashley’s Search For Memory </li></ul><ul><li>Patient H.M. </li></ul><ul><li>Different Types of Learning and Memory </li></ul><ul><li>Non-human Animal Approaches </li></ul><ul><li>Cellular Basis of Learning and Memory </li></ul><ul><li>Genetic Manipulations </li></ul>
  3. 3. 1. Learning & Memory <ul><li>Speaking, bicycling, multiplication by 7s, urinary control, taste of oranges, balancing when standing, anxiety associated with public speaking, smell of bananas, the appearance of your face, your mothers name, first day of school……………… </li></ul><ul><li>Alzheimer’s Disease, Traumatic Brain Injury, Schizophrenia, Epilepsy, Dementia, Strokes, Tumors etc. </li></ul><ul><li>“ Life without memory is very unlike life as the rest of us know it; indeed, it is almost no life at all” </li></ul><ul><li>Luis Bunuel </li></ul>
  4. 4. 1. What is Learning and Memory? <ul><li>Learning – relatively permanent change in an organism’s behavior as a result of experience </li></ul><ul><li>Memory – the ability to recall or recognize previous experience </li></ul><ul><li>“ One cannot logically be a determinist in physics and chemistry and biology, and a mystic in psychology.” (D. Hebb) </li></ul>
  5. 5. 1. Memory Formation Stages <ul><li>1. Encoding – processing of incoming information </li></ul><ul><li>Acquisition – registers inputs in sensory buffers Consolidation – creation of strong representation over time </li></ul><ul><li>2. Storage – the result of acquisition and consolidation </li></ul><ul><li>3. Retrieval – utilizes stored information to crate a conscious representation or to execute a learned behavior </li></ul>
  6. 6. 1. Temporal (Time) Memory Subtypes <ul><li>Sensory memory (milliseconds to seconds) </li></ul><ul><li>Short-term/working/on-line (seconds to minutes) </li></ul><ul><li>Long-term memory (minutes to years) </li></ul>
  7. 7. <ul><li>Is all learning (and memories) the same? </li></ul><ul><li>If not, are there different neural circuits mediating different types of learning? </li></ul>1. Theoretical Questions About Memory
  8. 8. 2. Karl Lashley’s Search for the Engram <ul><li>Memory – new or strengthened connections between two brain areas??? </li></ul><ul><li>Engram – the physical representation of what has been learned </li></ul><ul><li>Cutting this connection will destroy memory </li></ul>
  9. 9. <ul><li>Lashley trained the rats to solve a maze then he cut different parts of the cortex </li></ul><ul><li>No knife cut significantly impaired rats’ performances </li></ul><ul><li>Removing parts of the cortex did impair performance, but the amount of retardation depended more on the amount of brain damage than on its location </li></ul>2. Karl Lashley’s Search for the Engram Page 499
  10. 10. <ul><li>“ it is not possible to demonstrate the isolated localization of a memory trace anywhere in the nervous system. Limited regions may be essential for learning or retention of a particular activity, but the engram is represented throughout the region” (1950) </li></ul><ul><li>EQUIPOTENTIALITY – all parts of the cortex contribute equally to complex behaviors such as learning: any part of the cortex can substitute for any other </li></ul><ul><li>MASS ACTION – the cortex works as a whole, and the more cortex the better </li></ul>2. Karl Lashley’s Search for the Engram
  11. 11. 3. Patient H.M. <ul><li>Epileptic seizures since the age 16 </li></ul><ul><li>Had to stop work at 27 because his seizures could not be controlled </li></ul><ul><li>Seizures originated in medial temporal lobes (much of hippocampus and amygdala removed) </li></ul><ul><li>1953 William Scoville – neurosurgeon – removed medial temporal lobe bilaterally </li></ul><ul><li>H.M. showed behavioral problems and Scoville sought help from young neuropsychologist, Brenda Milner </li></ul>Page 500
  12. 12. <ul><li>No language or perceptual deficits or motor deficits </li></ul><ul><li>IQ unchanged (118) </li></ul><ul><li>Intact digit span –short-term memory </li></ul><ul><li>No language or perceptual deficits </li></ul><ul><li>IQ unchanged </li></ul><ul><li>Severe memory impairment - amnesia </li></ul>3. Patient H.M. Page 500
  13. 13. 3. What is Amnesia? <ul><li>Partial or total impairment of memory </li></ul><ul><li>Infantile amnesia – inability to remember events from early infancy or early childhood </li></ul><ul><li>Fugue state – transient disturbance of consciousness in which a person performs purposeful acts but has no conscious recollection of those actions </li></ul><ul><li>Transient Global Amnesia – short-lived neurologic disturbance characterized by memory loss (usually loss of old memories and an inability to form new memories) most often caused by ischemia (interruption of blood flow to the brain; usually due to constriction or obstruction in blood vessels) </li></ul>
  14. 14. <ul><li>Amnesia can be specific </li></ul><ul><li>Amnesia for the meaning of nouns but not verbs and vice versa </li></ul><ul><li>Amnesia for recognizing animals but not people or who become amnesic for human faces but not for other objects </li></ul>3. What is Amnesia?
  15. 15. 3. Patient H.M. <ul><li>Global anterograde amnesia – inability to form new memories </li></ul><ul><li>“ every day is alone in itself, whatever enjoyment I’ve had, and what ever sorrow I’ve had” </li></ul><ul><li>Retrograde amnesia – loss of memories that took place prior to brain damage </li></ul><ul><li>H.M.’s retrograde amnesia is not global – he knows who he is, where he lived, where he went to school etc. </li></ul>
  16. 16. 3. Can Patients Like H.M. Learn Any New Information? <ul><li>Psychologist Edouard Claparède put a pin between his fingers before shaking hands with a woman with Korsakoff’s syndrome (discussed later on), characterized by memory problems </li></ul><ul><li>Several days later, the patient could not remember the event but refused to shake Claparède’s hand saying: “sometimes people hide pins in their hands” </li></ul>OUCH!!
  17. 17. <ul><li>Different Types of Memory Implicit Learning </li></ul><ul><li>H.M. could learn new motor tasks </li></ul><ul><li>Could not remember doing the task before </li></ul><ul><li>Hence he ‘implicitly’ learned but could not ‘explicitly’ remember doing the task </li></ul>Page 495
  18. 18. <ul><li>Pursuit-rotor task </li></ul><ul><li>The Gollin Test </li></ul>Page 495
  19. 19. 4. There Are at Least Two Kinds of Long-Term Memory <ul><li>Explicit – conscious, intentional recollection of previous experience </li></ul><ul><li>Declarative </li></ul><ul><li>Fact </li></ul><ul><li>Memory </li></ul><ul><li>Knowing what </li></ul><ul><li>Examples: knowing what the capital of Germany is. Remembering your first day at the university </li></ul><ul><li>Implicit – unconscious, non-intentional form of memory </li></ul><ul><li>Non-declarative </li></ul><ul><li>Skill </li></ul><ul><li>Habit </li></ul><ul><li>Knowing how </li></ul><ul><li>Examples: knowing how to ride a bicycle. Knowing how to play hockey. </li></ul>Pages 495-8
  20. 20. <ul><li>Different Types of Explicit Memory Interview of G.O. by Dr. Levine </li></ul><ul><li>Do you have a memory of when you had to speak in public? </li></ul><ul><li>Well yes, I’m a call centre trainer with Modern Phone Systems, so I did a lot of speaking because I did a lot, a lot of training all across Canada. I also went to parts of the States. </li></ul><ul><li>Do you remember one time that you were speaking? Can you tell us about one incident? </li></ul><ul><li>Oh yes! Well I trained thousands and thousands of clients on a wide variety of topics including customer service, inbound and outbound telemarketing. Handling difficult customers. </li></ul>
  21. 21. <ul><li>Do you remember one training session that you gave? Something that may have happened, a specific incident? </li></ul><ul><li>Well for example I always recommended that people take customer service first. And I always had people come up with four things about themselves, three that were true and one that was false. Not necessarily in that order. </li></ul><ul><li>But this was something ongoing, so every training session you would tell people this, right? </li></ul><ul><li>Yes </li></ul>
  22. 22. <ul><li>So what we’re looking for is one incident or one time that you gave a training session or any other speech that you want to tell us about. A specific incident. </li></ul><ul><li>Oh well I customized a lot of material for many, many companies. And I also did lots of training at the home office </li></ul><ul><li>OK, so what we’re asking is do you remember one time you gave a talk? </li></ul><ul><li>Oh! Yes I do. </li></ul><ul><li>One specific time not over a series of times, one time, can you tell us about that? </li></ul><ul><li>Oh sure yes, it was at the home office and yes, many many people were there </li></ul>
  23. 23. <ul><li>One occasion. When did it take place? </li></ul><ul><li>When? Well I left Modern voluntarily in 1990. </li></ul><ul><li>But this one occasion when did it take place? </li></ul><ul><li>Ummm, well I started in the Modern home office. </li></ul><ul><li>I’m getting the impression that you have a really good memory for all the training that you’ve done but you don’t seem to be able to come up with a specific talk that maybe stands out in your mind for any reason? Would you agree with that? </li></ul><ul><li>Oh yes well I always trained customer service. </li></ul><ul><li>So there was no talk that maybe something went wrong or something strange happened? </li></ul><ul><li>No, no I was a very good trainer. </li></ul>
  24. 24. <ul><li>Patient K.C. </li></ul><ul><li>Motorcycle accident </li></ul><ul><li>Subdural hematoma (a pool of blood under the dura mater) was surgically removed </li></ul><ul><li>Short-term memory OK </li></ul><ul><li>Retrograde and anterograde amnesia </li></ul><ul><li>All episodic memories have been lost </li></ul>4. Patient K.C. – Loss of All Episodic Memories, Preservation of Semantic Memories
  25. 25. 4. Two Kinds of Explicit Memory <ul><li>Episodic Memory (personal experiences) </li></ul><ul><li>Conscious awareness of past events </li></ul><ul><li>Autobiographical memory </li></ul><ul><li>Example: Recalling your last birthday (who is there, what are you wearing, etc). </li></ul><ul><li>Semantic Memory (facts about the world) </li></ul><ul><li>Examples: Capital of Italy, your mother’s name, distinction between rocks and animals etc. </li></ul><ul><li>No episodic recollection of the specific circumstances surrounding this learning </li></ul>
  26. 26. 4. Korsakoff’s Syndrome <ul><li>Damage to diencephalon (dorsomedial thalamus and mammillary bodies) causes amnesia </li></ul><ul><li>Strokes, tumors, trauma, and metabolic problems (associated with alcoholism) (vitamin B1 deficiency) </li></ul><ul><li>Korsakoff’s syndrome: 1) retrograde amnesia, 2) anterograde amnesia, 3) lack of insight, 4) apathy, 5) meager content in conversation, 6) confabulations. </li></ul><ul><li>Confabulations – the recitation of imaginary experiences to fill gaps in memory </li></ul>
  27. 27. <ul><li>H.M. case led neuropsychologist to focus on the hippocampus </li></ul><ul><li>Remember that H.M. brain resection included several structures making conclusions difficult </li></ul><ul><li>Hippocampus as a storage site for memory? </li></ul><ul><li>Hippocampus consolidates new memories? </li></ul><ul><li>Hippocampus plays the role of librarian for memories? </li></ul><ul><li>Hippocampus is responsible for tagging memories with respect to context – the location and time of their occurrence? </li></ul>4. The Neural Basis of Explicit Memory
  28. 28. 4. Evidence for Consolidation Theory <ul><li>Electroconvulsive shock therapy (ECT) </li></ul><ul><li>Originally used in attempts of treating schizophrenia </li></ul><ul><li>Treatment of major depression </li></ul><ul><li>Hypothesis: Memories are solidified in long-term stores over days, weeks, months and years </li></ul><ul><li>Hippocampal patients have retrograde amnesia (6-24 months) and inability to form new memories </li></ul>
  29. 29. <ul><li>Patient R.B. – memory loss after ischemic episode (reduction of blood to the brain) during heart bypass surgery </li></ul><ul><li>Dense anterograde amnesia </li></ul><ul><li>1 to 2 years retrograde amnesia </li></ul><ul><li>Autopsy – overall hippocampus looked intact </li></ul><ul><li>Histological analysis indicated a loss in CA1 region of the hippocampus </li></ul>4. Evidence for Consolidation Theory
  30. 30. 4. Where Are Memories Located? <ul><li>If memories are distributed throughout the cortex than damage to the cortex will lead amnesia </li></ul><ul><li>Lesions of the lateral cortex of the anterior temporal lobes (entorhinal and parahippocampal cortex also) produce retrograde amnesia </li></ul><ul><li>Patients can form new memories </li></ul><ul><li>Alzheimer’s disease and herpes simplex encephalitis </li></ul><ul><li>Is this where the memory is stored? Possibly – they are probably distributed throughout the brain </li></ul>Alzheimer’s Disease Page 504
  31. 31. 4. The Neural Basis of Explicit Memory Page 508
  32. 32. 4. Episodic Memory
  33. 33. <ul><li>Insight from Parkinson’s Disease patients </li></ul><ul><li>Basal ganglia - dopamine </li></ul><ul><li>Patient J.K. – PD (DA cells in basal ganglia die) </li></ul><ul><li>On one occasion, he stood at the door of his bedroom frustrated by his inability to recall how to turn on the lights. He remarked “I must be crazy. I’ve done this in my life, and now I can’t remember how to do it!” </li></ul><ul><li>Huntington’s Chorea – mirror drawing task </li></ul>4. What About The Neural Basis of Implicit Memories?
  34. 34. 4. The Neural Basis of Implicit Memory <ul><li>Motor-based implicit memory is thought to be mediated by a circuit separate from limbic structures (explicit memories) </li></ul><ul><li>Basal ganglia (caudate nucleus and putamen; dopamine) and cerebellum (classical conditioning; slide 38) </li></ul><ul><li>Huntington’s Chorea (degeneration of cells in basal ganglia) – fail to improve in mirror tracing task. </li></ul>Page 508
  35. 35. Brief Summary For This Section <ul><li>Anterograde amnesia (episodic memory) – damage to the limbic system (medial temporal lobe) and diencephalon (dorsomedial thalamus) </li></ul><ul><li>These structures are not a location of memories – they are important for consolidation </li></ul><ul><li>Damage to temporal lobe associated with retrograde amnesia </li></ul><ul><li>Patients can form new implicit memories </li></ul><ul><li>Motor based implicit memories are mediated by basal ganglia </li></ul>
  36. 36. 5. Modern Search for the Engram Non-human Animal Models <ul><li>Classical Conditioning Models: </li></ul><ul><li>Eye Blink Conditioning </li></ul><ul><li>Fear Conditioning </li></ul><ul><li>Operant Conditioning </li></ul><ul><li>Morris Water Maze </li></ul>
  37. 37. 5. Localized Representation of Memory <ul><li>Ivan Pavlov – classical conditioning </li></ul><ul><li>CS+UCS UCR </li></ul><ul><li>CS CR </li></ul>
  38. 38. 5. Classical Conditioning - Eye-Blink Conditioning <ul><li>Studied in humans and rabbits </li></ul><ul><li>Puff of air is paired with tone </li></ul><ul><li>Consequently tone alone elicits an eye-blink response </li></ul><ul><li>Cerebellum mediates eye-blink conditioning </li></ul>Page 491
  39. 39. 5. Classical Conditioning - Fear Conditioning Threatening Stimuli Natural Threat Conditioned Stimulus Defensive behavior Autonomic arousal Hypoalgesia Reflex potentiation Stress hormones This has been demonstrated in: flies, worms, snails, pigeons, fish, rabbits, cats, rats, dogs, monkeys and humans. Fear Responses
  40. 40. 5. Fear Conditioning in the Laboratory <ul><li>Mild shock (UCS) produces startle/freeze response (UCR) </li></ul><ul><li>Shock (UCS) is paired with tone (CS) </li></ul><ul><li>CS produces CR (freezing) </li></ul><ul><li>Dependent measure is freezing/urination/defecation </li></ul>Page 492
  41. 41. 5. Fear Conditioning – Where is it in the Brain? <ul><li>Techniques: lesions, electrical recording, neural tracing </li></ul><ul><li>Information about the CS and US is transmitted to amygdala (12 regions – lateral amygdala) </li></ul><ul><li>Information is transmitted from amygdala to the behavioral, autonomic, and endocrine response control systems located in the brainstem. </li></ul>
  42. 42. 5. Fear Conditioning – Where is it in the Brain? Auditory Cortex Thalamus Amygdala MGv MGm Behavior ANS HPS CS (10 kHz tone) MGv- ventral medial geniculate nucleus MGm- medial medial geniculate nucleus
  43. 43. Auditory Cortex Thalamus Amygdala MGv MGm 5. Fear Conditioning – What Happens if Amygdala is Lesioned? CS (10 kHz tone)
  44. 44. Auditory Cortex Thalamus Amygdala MGv MGm 5. Fear Conditioning – What Happens if MG of Thalamus is Lesioned? CS (10 kHz tone)
  45. 45. Auditory Cortex Thalamus Amygdala MGv MGm 5. Fear Conditioning – What Happens if Auditory Cortex is Lesioned? CS (10 kHz tone)
  46. 46. 5. What About Context of Conditioning? <ul><li>Rats sometimes exhibit fear responses when they are returned to the chamber in which the tone and shock were paired, or a chamber in which shocks occur alone </li></ul><ul><li>This is an example of contextual fear conditioning </li></ul>
  47. 47. 5. What Structure Mediates Contextual Fear Conditioning? Amygdala Hippocampus Fear Reaction Contextual Stimulus (the look of the room, location, etc.)
  48. 48. 5. Is Hippocampus Important for Spatial Learning and Memory? Operant Conditioning Approach Internalized cognitive map Dependent measure: Latency to find platform Page 494
  49. 49. 5. Hippocampus Spatial Learning and Memory Lesions of the hippocampus cause deficits in spatial learning Animals fail to show improvement over time – “no memory of location in space” Intact rats show rapid improvement over trials Page 494
  50. 50. 5. Hippocampus Spatial Learning and Memory birds that store food in different locations have relatively larger hippocampi Page 506
  51. 51. 6. Cellular Basis of Learning and Memory <ul><li>Donald Hebb </li></ul><ul><li>Hebbian synapse and cell assemblies </li></ul><ul><li>Learning and memory are based on modification of synaptic strength among neurons that are simultaneously active </li></ul><ul><li>Axon A excites cell B slightly, and axon C excites B more strongly. If A and C fire together, their combined effect on B may produce an action potential </li></ul><ul><li>“ neurons that fire together wire together” </li></ul>
  52. 52. 6. Cellular Basis of Learning and Memory
  53. 53. <ul><li>LTP is an experimental model of Hebbian synapse </li></ul><ul><li>Long Term Potentiation or Enhacement (LTE) – a change in the amplitude of an excitatory postsynaptic potential that lasts for hours to days in response to stimulation of a synapse </li></ul><ul><li>Most often studied in hippocampus </li></ul><ul><li>Neurons that have previously been activated simultaneously, are more easily activated </li></ul><ul><li>Why are they more easily activated? </li></ul><ul><li>Changes in synapse? Changes inside neurons? </li></ul>6. Cellular Basis of Learning and Memory Hebbian Synapse – Long Term Potentiation (LTP) Pages 181-182
  54. 54. <ul><li>Protein synthesis is important – Cycloxemide (protein synthesis inhibitor) blocks memory formation </li></ul><ul><li>Glutamate plays an important role in LTP </li></ul><ul><li>Two glutamate receptors: NMDA and AMPA </li></ul><ul><li>Postsynaptic neuron more “sensitive” </li></ul>6. Cellular Basis of Learning and Memory LTP Changes in The Synapse Pages 181-182
  55. 55. If NMDA receptors are important, could organisms learn faster and have better memory if they have more NMDA receptors? How can we increase the number of NMDA receptors? 6. Cellular Basis of Learning and Memory
  56. 56. <ul><li>Neurotransmitter receptors are proteins </li></ul><ul><li>These proteins are encoded in DNA </li></ul><ul><li>Can we alter DNA so that more NMDA receptors are produced? YES </li></ul><ul><li>TRANSGENIC animals refers to animals in which new or altered genes have been deliberately introduced into the genome </li></ul><ul><li>Transgenic mice can be made to produce more NMDA receptors </li></ul><ul><li>KNOCKOUT animals refers to animals in which particular gene has been disabled by the experimenter </li></ul>7. Genes and Learning and Memory Genes for NMDA Receptors
  57. 57. <ul><li>Transgenics’ rate of learning in the water-maze is faster </li></ul>7. Genes and Learning and Memory Genes for NMDA Receptors [WT – wild type (control)] Tang et al., 1999
  58. 58. <ul><li>Are NMDA Transgenic Mice Smarter? </li></ul><ul><li>YES </li></ul><ul><li>Transgenic mice learn fear conditioning faster and remember it longer </li></ul>7. Genes and Learning and Memory Genes for NMDA Receptors
  59. 59. <ul><li>Is Transgenic Mice Intelligence Unadaptive? </li></ul><ul><li>Rain Man effect? </li></ul><ul><li>NO </li></ul><ul><li>Transgenic mice have a faster extinction of fear </li></ul><ul><li>Transgenic mice unlearn faster </li></ul><ul><li>It is adaptive to unlearn irrelevant things faster </li></ul>7. Genes and Learning and Memory Genes for NMDA Receptors
  60. 60. <ul><li>NMDA knockout mice </li></ul><ul><li>Unable to induce LTP </li></ul><ul><li>Learning deficits </li></ul><ul><li>Can these deficits be reversed? </li></ul><ul><li>Enriched environment significantly improved the performance of knockouts </li></ul>7. Genes and Learning and Memory Genes for NMDA Receptors Rampon et al, 2000
  61. 61. 7. Genes and Learning and Memory Genetic Models of Alzheimer’s Disease <ul><li>AD is characterized by memory deficits </li></ul><ul><li>Memory deficits are believed to be due to brain atrophy associated with beta-amyloid plaques (they lead to reduced number of dendrites and cell death) </li></ul><ul><li>Transgenic mice (PDAPP) contain genes that lead to increased number of beta-amyloid plaques </li></ul><ul><li>PDAPP show memory deficits in the water-maze </li></ul>
  62. 62. 7. Genes and Learning and Memory Drosophila Models <ul><li>Conditioning – choice between two tubes with two different odors </li></ul><ul><li>One tube associated with shock, the other no shock – most learned rapidly to avoid the shock side </li></ul><ul><li>Dunce (genetic mutant) could not learn this </li></ul><ul><li>Amnesiac (genetic mutant) could learn this but would forget it rapidly </li></ul>
  63. 63. 7. Genes and Learning and Memory Are there any problems with the use of transgenics and knockouts? <ul><li>“broken” animals </li></ul><ul><li>Grow up, from conception, with missing genes </li></ul><ul><li>Other genes might have different function in the absence of knocked-out genes </li></ul>
  64. 64. 7. Genes and Learning and Memory The Role of CREB (protein) in Memory <ul><li>Is CREB important for LTM? </li></ul><ul><li>IF yes, would increased CREB produced better memory? </li></ul>
  65. 65. DNA changed - “CREB” inserted – herpes virus becomes a viral vector
  66. 66. Increased CREB in the Amygdala Produced Enhanced Fear Conditioning and Memory Josselyn et al., 2001 Rats injected with Herpes vector carrying CREB show much better memory