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 Long-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 Priming 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.

51. Long-term Potentiation
CREB-2 does not permit synthesis
CREB-1 readily replaces CREB-2, but does not permit synthesis either.
Phosphorylated CREB-1 does permit synthesis.

52. Long-term Depression CPP, an NMDA antagonist blocks LTP but not LTD.
This suggests at least two subtypes of NMDA receptors.
AMPA receptors are dephosphorylated, decreasing their sensitivity to glutamate.
AMPA receptors also decrease in number.

53. Long-term Potentiation

54. Hebb’s Rule
After 50 years and many new tools (cellular recording, drugs, electron microscopy) we now have solid evidence for at least one mechanism of learning predicted by Hebb.
Other mechanisms also exist, but they are not yet well understood.