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Biopsychology of Memory

Biopsychology of Memory. What is Memory?. The storage of information about our experiences. Major Research Questions. What is the biological substrate(s) of memory? Where are memories stored in the brain? How are memories accessed during recall? What is the mechanism of forgetting?.

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Biopsychology of Memory

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  1. Biopsychology of Memory

  2. What is Memory? The storage of information about our experiences

  3. Major Research Questions • What is the biological substrate(s) of memory? • Where are memories stored in the brain? • How are memories accessed during recall? • What is the mechanism of forgetting?

  4. Early Hypotheses about the Brain Substrates of Memory • Two prominent psychologists - Karl Lashley - Donald Hebb

  5. Karl Lashley • Studied memory of complex maze learning in rats • Design: -train lesions of the cortex test their memory • Results: - only large lesions of the cortex produced deficits - similar deficits were obtained no matter where the cortical lesion was located

  6. Lashley’s Two Principles 1. Principle of Mass Action ~ Memories for complex tasks are stored diffusely throughout the neocortex. 2. Principle of Equipotentiality ~ All parts of the neocortex play an equal role in the storage of memories for complex tasks. IMPORTANT POINT: Lashley’s research discouraged thinking about localized regions important for memory

  7. Donald Hebb - 1949ff • Two memory systems - short-term storage system - long-term storage system • Short-term storage = reverberatory activity • Long term storage = structural change • Different substrates for short- vs. long-term storage • Transfer from short- to long-term storage = CONSOLIDATION OF MEMORY

  8. The Evidence for Hebb’s Consolidation Theory • RETROGRADE AMNESIA Russell and Nathan - 1949 - World War II concussions - Short-term or recent memory was vulnerable - Long-term or older memory was resistant

  9. CONSOLIDATION MODEL OF MEMORY Long-term (older) memory (resistant) Short-term (recent) memory (vulnerable) Consolidation process

  10. Experimental Evidence for Consolidation Theory Pinel (1969) Water bottle niche

  11. Pinel (1969) • Design: Days 1-5 Exploration of Box, no water present Day 6 1. Water present, rats drink 2. Electroconvulsive shock (ECS) given at various times after drinking Day 7 Retention Test - count niche explorations

  12. Squire etal. 1975 • ECS treatments in depressed humans • Two memory tests - one before, one after ECS treatments - pick from a list of T.V. shows those that played for only one season - some shows were from 1-3 years before ECS, some from 4-5, 6-7, 8-9, and 10-17 years previously. • RESULTS: - Retrograde amnesia for events that occurred from 1-3 years prior to ECS - consolidation of memory can continue for a long time period

  13. The Case of H.M. • Epileptic seizures • William Scoville, 1953 – Neurosurgeon • Bilateral medial temporal lobectomy • Brenda Milner – Neuropsychologist

  14. H.M.’s Memory Deficit Retrograde Amnesia - Loss of some memories for information learned before (3 years) the surgery Anterograde Amnesia – Inability to form enduring memories for events occurring after the surgery Intact short-term memory

  15. H.M. - Formal Testing for LTM Long-term Memory Tests – Deficient • Digit Span + 1 test • Matching to Sample • Maze Learning Perceptual Tests -Normal • Gollin Incomplete Pictures Test • Mooney Face Perception Test Long-term Memory Tests –Normal • Mirror drawing • Rotary pursuit • Pavlovian trace eyeblink conditioning • Gollin incomplete pictures • Tower of Hanoi Puzzle

  16. Digit Span + 1 Test • 1,3,2,7,9 • 1,3,2,7,9,6, • 1,3,2,7,9,6,4 • etc.

  17. Explicit Memory(Declarative) • Memory that is directly accessible to conscious recollection • Memory of facts, events - “knowing that” something happened • Memory with record • Impaired with medial temporal lobe damage

  18. Implicit Memory(Procedural) • Memory not accessible as specific facts or data • Memory that is contained within learned skills or cognitive operations -“knowing how” • Expressed only in performance - motor skill learning - cognitive skill learning • Not impaired with medial temporal lobe damage

  19. What has H.M. taught us about the neural substrates of memory? • The importance of the medial temporal lobes • There is localization of function for memory • Different brain structures for short- and long-term memory • Medial temporal lobes contribute to memory consolidation • Memories are not permanently stored in the medial temporal lobes • Different brain structures for “explicit” vs. “implicit” memory

  20. H.M.’s MRI Scans

  21. The Contribution of the Hippocampus • Corsi – 1970 • Case R.B. - 1986

  22. Zola-Morgan etal. (1986) • Case R. B. • Severe ischemic episode hypoxia • Extensive memory tests - Story recall - Paired associates recall ~ 10 pairs of words Dog – Umbrella Car – Face Mask - Pencil - Diagram recall

  23. Zola-Morgan etal. - cont • R.B. died in 1983 • Obtained brain 4 hours after death • Brain Pathology - Hippocampus 1. CA1 subfield gone 2. 4.6 million neurons missing • Little, if any, damage to other brain areas

  24. HIPPOCAMPAL ANATOMY

  25. Rempel-Clower etal. (1996) • Three additional cases • GD, LM, WH • All suffered from cardiovascular problems - hypotension - ischemia during surgery - seizures with respiratory distress

  26. Patient GD • Bilateral cell loss in hippocampal CA1 subfield • Other hippocampal subfields intact • Extra-hippocampal cell loss - small region of the left amygdala - small region of the left fornix - region in the right globus pallidus

  27. Patient LM • Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields and dentate gyrus • Extra-hippocampal cell loss - Entorhinal cortex (layers II and III) – major source of input to hippocampus - minor cell loss in areas of cortex and cerebellum

  28. Patient WH • Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields, dentate gyrus • Extra-hippocampal cell loss - entorhinal cortex - subiculum - fornix, striatum, pons

  29. Important implications for the effects of cardiac arrest and cardiovascular disease on brain integrity

  30. Two Questions • How does ischemia/hypoxia damage the hippocampus? • Why the selective damage (e.g., CA1 damage) in some cases?

  31. Animal Models of Ischemia • Davis – 1986 - Radial arm maze to assess spatial memory in rats - Design: 1. 30 min. ischemic period (carotid artery clamp) 2. 30 day recovery period 3. Maze training - Results: 1. ischemic rats demonstrate memory impairments 2. cell loss in hippocampal CA1 subfield

  32. How Does Ischemia/Hypoxia Cause Hippocampal Damage? • Microdialysis: - ischemia elevates glutamate in the hippocampus • How? ischemia/hypoxia anoxic depolarization of glutamate bouton 1. Excessive glutamate release 2. Reversal of the glutamate reuptake system additional glutamate release

  33. Two Effects of Excess Glutamate on the Postsynaptic Hippocampal Neuron • Early, immediate effect • Delayed effect over a 24 hour period

  34. Early, Immediate Effect of Glutamate Excess glutamate release Extended period of depolarization in postsynaptic cell Excessive Na+ influx Water pulled osmotically into neuron Neurons swell and burst

  35. Delayed Effect of Glutamate • Neurons demonstrate morphological and biochemical signs of disintegration over 24 hour period • Dependent on the presence of CA++ in the extracellular fluid • Glutamate receptors: Kainate receptor AMPA “ NMDA “ mGlu “ class

  36. The Glutamate NMDA Receptor(N-methyl-D-aspartate) • Associated with Ca++ ion channel • At rest, Ca++ channel blocked by magnesium ion • Sufficient depolarization from Na+ influx thru’ kainate and AMPA receptor Na+ channels ejects magnesium ion permits Ca++ flow into soma activation of numerous enzymes, 2nd messengers

  37. The NMDA Receptor – cont. Abnormally excessive glutamate release Prolonged period of Ca++ influx Excessive activation of enzymes Delayed cellular disintegration

  38. What Evidence Points to the NMDA Receptor in Ischemia? • Gill etal. (1987) 1. ischemia elevates glutamate in hippocampus 2. lesion of perforant pathway (major glutamate input pathway to hippocampus) prevents ischemia cell death in CA1 region 3. MK – 801, a glutamate receptor antagonist Protects against ischemic cell death in CA1 region

  39. HIPPOCAMPAL ANATOMY

  40. Why the selective damage to the CA1 region in some humans? • Probable Answer(?) The CA1 region has the highest concentration of glutamate receptors in the brain.

  41. Animal Models of Medial Temporal Lobe Amnesia • Tests of Memory Monkey: - Nonrecurring-Items Delayed Nonmatching-to- Sample Test (DNMS) - Explicit memory - Delayed Response Task - Explicit memory - Barrier Motor-Skill Task - Implicit memory - Lifesaver Motor-Skill Task – Implicit memory Rats: - Mumby Box - Explicit memory

  42. Characteristics of Human Amnesia Produced by MTL lesions in Monkeys • Memory impaired on several tasks including ones identical to those failed by human patients. • Memory impairment exacerbated by increasing the retention delay. • Memory impairment is not limited to one sensory modality. • Memory impairment is enduring. • Skill-based memory is spared. • Immediate memory is spared.

  43. What Areas in the Temporal Lobe Contribute to Memory Consolidation? • Hippocampus • Neocortex • Amygdala

  44. Zola-Morgan etal. (1980s-1990s) • Is the hippocampus the only medial temporal lobe structure important for memory consolidation? • Compared DNMS scores across experiments: -Hippocampal plus surrounding cortex lesions (H+) -Hippocampal plus amygdala plus all surrounding cortex lesions (H+A+) 1. The medial temporal lobectomy monkey Result: The H+A+ lesion produces the greatest deficit.

  45. Why does H+A+ lesion produce more memory impairment than the H+ lesion? • Possibilities: 1. The amygdala contributes to explicit memory OR 2. The cortex surrounding the amygdala contributes to explicit memory

  46. Zola-Morgan etal. • Five groups of monkeys 1. Group A amygdala lesion, spared the cortex 2. Group H+ hippo. lesion plus surrounding cortex 3. Group H+A hippo. lesion plus surrounding cortex plus amygdala lesion 4. Group H+A+ Hippo. plus surrounding cortex plus amygdala plus surrounding cortex lesion 5. Group N Unoperated Control

  47. Zola-Morgan etal. • Results: Group A no deficit Group H+A Group H+ Group H+A+worse than all other groups Conclude: 1. Amygdala doesn’t contribute to explicit memory 2. Cortex surrounding the amygdala may contribute similar deficits

  48. A Dissociation of Hippocampal vs. Amygdala Memory Function in Humans Declarative (Explicit Memory) (Hippocampal Function) versus Emotional Memory (Amygdala Function)

  49. Bechara etal. (1995) Three patients: - one with bilateral hippocampal damage (H+) - one with bilateral amygdala damage due to Urbach-Wiethe Disease (A) - one with bilateral medial temporal lobe damage (H+A+) Normal control group: no brain damage (n=4)

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