Memory, Learning and Amnesia

1. Memory, Learning and Amnesia

2. Memory, Learning and Amnesia • Memory = site and/or process where knowledge and experiences are stored. • Learning = the process of committing new knowledge and experiences into (semi-) permanent storage. • Classical conditioning • Operant conditioning • Other neural mechanisms • Amnesia = the inability to form or recall memories.

3. Memory, Learning and Amnesia • Types of memory and amnesia • Brain areas involved in memory • Sensory and working short-term memory • Procedural memories • Declarative memories • Neural mechanisms of learning

4. History of Memory Studies • The study of memory • 1885 Ebbinghaus publishes first studies on memory. • 1889 Korsakoff describes severe anterograde amnesia. • 1915 Karl Lashley begins a long-term study of memory. • 1950 Lashley states “… the engram is represented throughout the region.” • 1953 Dr. William Scoville removes the bilateral medial temporal lobes of H. M. to stop epileptic seizures and inadvertently discovers the role of the hippocampus.

5. Areas of Memory • Lashley was wrong. Memories are not evenly distributed over the cortex. • Memories are not all stored in the same place. Different types of memory are found in different areas, but all rely on synaptic connections. • There is no “grandma” neuron. • All parts of the nervous system can learn and remember. • Multimodal information is remembered better.

6. Types of Memory - Data • Declarative or explicit (conscious) • Facts & events • Easily formed, and easily forgotten • Nondeclarative or implicit (unconscious) • a.k.a. procedural memory • Skills, habits and conditioning • Skeletal muscle practiced movements. • Emotional responses • Requires repetition, but rarely forgotten

7. Types of Memory - Data

8. Types of Memory - Time • Short-term • Only good for seconds to hours • Easily disruptable • Long-term • Lasts for days, months or years • Permanent

9. Short-term Memory • Average capacity is 7 +/- 2 chunks, generally proportional to intelligence. • Kept in right orbital cortex (frontal lobe). • Data only remains there for a few seconds without rehearsal. Modulated by attention. • Easily disrupted. • Unrelated to long-term memory.

10. Short-term Memory • Short-term sensory memory • The senses have independent short-term storage. • Kept in the cortical area of the sense. • Temporal lobe for audio data, etc. • The lateral intraparietal cortex (LIP) seems to hold short-term visual memories in monkeys. • If there is sufficient attention, the sensory information can be moved to short-term working memory areas. If not, the information will be lost.

11. Types of Memory Sensory Information Attention Sensory Register Declarative Implicit Short-term Memory Consolidation Long-term Memory

12. Loss of Memory • Amnesia = The loss of (declarative) memory • Retrograde • Can’t recall previously available information. • Sometimes very old memories are still available. • Anterograde amnesia • Can’t learn new information. • Can affect short-term, long-term, or both. • Usually accompanied by retrograde amnesia. • Specific deficits • Prosopagnosia, anomia, etc.

13. Procedural Memory Areas • The striatum seems to be strongly involved in procedural memories and conditioning. • Huntington’s and Parkinson’s patients have difficulties learning procedural tasks because of damage to the striatum. • The cerebellum is the primary site of coordinated movement learning.

14. Declarative Memory Areas • Amnesia, lobectomy and stimulation studies point to the temporal lobe as the primary site for declarative memories, or at least their recall. • Stimulation of the temporal cortex produces more complex memories and hallucinations than any other brain area. • Anomia and prosopagnosia tied to temporal lobe.

15. Declarative Memory Areas – H.M. • Case study: H. M. (1953, M, 27 y.o.) • Dr. Scoville removed both medial temporal lobes to alleviate untreatable epileptic seizures. • Seizures were greatly reduced, BUT… • H. M. had severe post-op anterograde amnesia which never improved, but little retrograde or motor amnesia or short-term memory problems. • From previous understanding (distributed memory), this could not occur. • Research changed from place to process.

16. Declarative Memory Areas • Medial temporal lobe • Removed in H.M. • Hippocampus is directly below the amygdala (highlighted in pink).

17. Implicit Memory Areas • H.M.’s working memory is intact. • H.M. can still learn habits and trained tasks. • This shows that lack of the hippocampus impairs consolidation required for conscious recall, but not for implicit memories. • Priming • Exposure to a stimulus makes it easier to recognize that stimulus again (it is remembered). • H. M. shows very limited signs of recognizing prior stimuli without cognitively realizing it.

18. Declarative Memory Areas • 8 other psychotic patients were examined • Only those who had a hippocampusectomy had anterograde amnesia. • They deduced the hippocampus is necessary for new memory formation, but not recall. • It is not necessary for short-term memory. • Modern procedures call for only one hippocampus to be removed, and it is now tested for functionality before the operation.

19. Declarative Memory Areas • Alzheimer’s disease • A progressive disease causing loss of cells and deterioration in the association cortex. • Marked by anterograde amnesia and later also by retrograde amnesia. • Damage begins in medial temporal cortex and spreads to other areas. • This is evidence that anterograde amnesia is related to the medial temporal cortex.

20. Declarative Memory Areas • Korsakoff’s Syndrome • Symptoms • Severe anterograde amnesia • Confabulation • Make up stories based on fragments of recent occurrences • Caused by thiamine (vitamin B1) deficiency • Alcoholism • Malnutrition • Damages the mammillary bodies, which relay information from the hippocampus to the thalamus via the fornix.

21. Declarative Memory Areas • Patient R. B. • Permanent anterograde amnesia caused by anoxic ischemia of the hippocampus. • On autopsy, it was found that the CA1 region of the hippocampus was gone. • The CA1 region is especially rich in NMDA receptors (involved in learning). • If only CA1 damaged: anterograde amnesia only. • Anoxia causes NMDA receptors to allow excessive Ca++ influx, damaging cells.

22. Declarative Memory Areas • Further evidence of NMDA-Hippocampus connection: • Mice with NMDA receptor knock out learn very slowly, if at all. • Mice with excess NMDA receptor genes learn quicker than normal.

23. Declarative Memory Areas • Neuromodulation in the hippocampus • 5-HT inhibits memory formation. • NE, E, D, cocaine enhance memory formation. • Cholinergic theta rhythms (5-8 Hz) from medial septum seem to be necessary. • In rats, theta activity is correlated with exploratory behaviors. • Info sampled into dentate gyrus and CA3 on theta. • Info moved to CA1 when theta waves subside.

24. Declarative Memory Areas • Anatomical structures: • Thalamus, sensory relay • Amygdala, emotional memory • Hippocampus, spatial memory • Rat radial maze performance: evidence of place neurons • Rhinal cortex, object & recognition memory • Fornix and mammilary bodies • Prefrontal cortex • Surrounding limbic structures

26. Neural Mechanisms

27. Classical Conditioning • A form of learning where an otherwise unimportant stimulus acquires the properties of an important stimulus. • Forms an association between two stimuli, one which would normally cause a behavior and one which would not. • Implicit memory

28. Classical Conditioning • Ex. Rabbit eye blink • A puff of air directed at a rabbit’s eye causes the rabbit to blink, an unconditioned response. • A 1000 Hz tone is played independently and causes no eye blink response. • A tone is played and shortly followed by an air puff and this sequence is repeated. • The rabbit quickly learns to blink as soon as the tone is sounded, a conditioned response.

29. Hebb’s Rule • 1949 Donald Hebb proposes that a synaptic connection will be strengthened if a synapse repeatedly becomes active at the same time or just after the postsynaptic nerve fires (he could not verify his own theory).

30. Operant Conditioning • Similar to classical conditioning, except that it involves an association between a learned behavior and a response (instead of an automatic behavior and another stimulus). • Permits an organism to adjust its behavior according to the consequences. • Reinforcing stimuli increase the likelihood of the response, punishing stimuli decrease it.

31. Operant Conditioning Dr. Skinner and his famous box

32. Operant Conditioning • Ex. Skinner Box - Training • A hungry rat is placed in a box with a lever. • It has no particular reason to press the lever. • By random interaction, the rat learns that it will get a food reward for pressing the lever. • This will increase the likelihood that the rat will press the lever to get more food (reinforcing stimulus).

33. Operant Conditioning • Ex. Skinner Box - Extinction • Once trained, the rat is then also shocked (a punishing stimulus) when the lever is pressed, decreasing the likelihood of further lever presses. • The lever pressing behavior is extinguished. • Recent research suggests 2 mechanisms: • Immediate: The new synaptic connection destroyed. • Delayed: A separate learned inhibitory pathway forms. • Consolidation seems to be required.

34. Neural Mechanisms • The basis of all learning is plasticity, the ability of the nervous system to change its neural connections by: • Forming or destroying neural connections. • Forming or destroying receptors. • Activating or deactivating receptors.

35. Learning • Two major plasticity mechanisms • Long-term potentiation (LTP) • Creates associations by synaptic enhancement • Long-term depression (LTD) • Loosens associations by synaptic degradation

36. Anatomy Review • Hippocampus (a.k.a. Ammon’s Horn = cornu ammonis) is heavily involved in new memory formation. • Neurons enter through the entorhinal cortex, relay through the granule cells of the dentate gyrus, and project to pyramidal cells of CA3 (30,000+ spines per dendrite). • Output is from CA1.

39. Long-term Potentiation • Glutamate is the predominant interneuronal neurotransmitter in the CNS. • Two major glutamate receptor types: • AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) • Na+ ion channels • NMDA (n-methyl-D-aspartate) • Voltage and glutamate controlled Ca++ ion channel • The channel is normally blocked by a Mg++ ion, which is expelled when the cell becomes depolarized.

41. Long-term Potentiation • “Silent synapse” theory - new dendritic spines only contain NMDA receptors (no AMPA receptors). • If the new synapse receives stimulation at the same time as the nerve fires, AMPA receptors will be created, unsilencing the synapse.

42. Long-term Potentiation • The NMDA receptors are assumed to be responsible for LTP. • AP5 (2-amino-5-nopentanoate) blocks NMDA channels and temporarily inhibits learning, but not recall. • Ca++ acts as a 2nd messenger, regulating the creation of new AMPA receptors. • EGTA, which binds to Ca++ and makes it insoluble, also blocks learning.

43. Long-term Potentiation • Ca++ influx • Activates type II calcium-calmodulin kinase (CaM-KII). • Converts arginine to nitrous oxide (NO). Which signals presynaptic neuron to release Glu. • CaM-KII self-phosphorylates, allowing continued action after Ca++ influx. • CaM-KII controls synthesis of receptors, protein kinases and cytoskeleton, and phosphorylates the AMPA receptors.

44. LTP Summary • Initially only NMDA channels. • Simultaneous presynaptic glutamate and postsynaptic depolarization let Ca++ enter NMDA channels. • AMPA receptors are synthesized and strengthen the synaptic connection.

45. LTP • CaM-KII effects: • Self-phos-phorylation • Creation of new AMPA receptors • Arginine to nitrous oxide conversion

46. Long-term Potentiation • NO release by the postsynaptic cell has retrograde causes further presynaptic glutamate release.

47. Long-term Potentiation • Recent evidence also shows that the presynaptic terminal button projects a finger-like extension into the postsynaptic dendritic spine. • The projection divides the spine and causes a split into two buttons and two spines.

48. Long-term Potentiation

49. Long-term Potentiation • Protein synthesis in LTP • Proteins (i.e. AMPA receptors) don’t last long, but memories do. • Something else must make memories permanent. • Protein synthesis inhibitors have been found to interfere with the formation of long-term memories.

50. Long-term Potentiation • Protein synthesis experiments • Experiments with Drosophila identified two proteins involved with long term learning, cAMP Response Element Binding proteins CREB-1 and CREB-2. • CREB2 repressed memory formation. • CREB1 gave super-memory. • CREB formation is governed by protein kinases that results from varying Ca++ influx.