1. Learning and Memory Chapter 12
Learning as the storage of memories
Brain changes in learning
Learning deficiencies and disorders

2. Learning as the Storage of Memories
At the age of 27, Henry Molaison had most of both temporal lobes removed to reduce seizures.
The surgery destroyed the hippocampus and the rest of the hippocampal formation and the amygdala.
As a result, he experienced anterograde amnesia.
For the next 55 years, he was able to form very few new memories.
Within minutes, a new memory would disappear.
He could, however, remember well rehearsed information, such as the layout of the family home. ◊

3. Learning as the Storage of Memories
Henry also experienced retrograde amnesia.
He had few memories from the decade before his surgery.
He didn’t remember his high school graduation or the end of World War II.
However, memories before that time were intact.
He participated in a hundred scientific studies.
His preserved brain is being digitized and will be available online so scientists can continue studying it. ◊

4. HM’s Brain and the Hippocampal Area Figure 12.1
HM’s brain (top left) is missing some of the structures labeled in the normal brain (below).

5. Learning as the Storage of Memories
During consolidation, the brain forms a more or less permanent physical representation of a memory.
This involves three stages: short-term memory, long-term memory, and long-lasting memory.
Figure 12.2

6. Learning as the Storage of Memories
Retrieval is the process of accessing stored memories.
Glutamate is required both for consolidation and for retrieval.
Blocking glutamate receptors for 7 days following learning prevents the memory from being consolidated.
Blocking them during testing interferes with retrieval.
The prefrontal area is believed to direct the search strategy required for retrieval. ◊

7. Learning as the Storage of Memories
The brain apparently stores information temporarily in the hippocampal formation.
Then, over time a memory is progressively transferred to cortical areas.
All memories are not stored in a single area, nor is each memory distributed throughout the brain.
Memories appear to be located where the information they are based on was processed.
For example, verbal memories are stored in the left frontal lobe.

8. Learning as the Storage of Memories
Place cells are another example of localized storage.
Place memory depends on cells in the hippocampus, which increase their firing when the individual is in a specific location in the environment.
The place fields of these cells form a “spatial map” of an environment, which is then adjusted upon entering a new environment and restored on return to the original location.
The fields depend on cues in the environment.
Humans have place cells too, that are so precise that the investigators could determine the subject’s “location” in a virtual environment.

9. Learning as the Storage of Memories
In spite of his impairments, HM:
improved over time on the mirror drawing task;
learned to solve the Tower of Hanoi problem.
Figure 12.8: Tower of Hanoi

10. Learning as the Storage of Memories
But he could not remember ever seeing either of these tasks. His problem was declarative memory.
Declarative memory involves learning that results in memories of facts, people, and events, which a person can verbalize.
The tasks he could do are examples of nondeclarative memory.
Nondeclarative memories are memories for behaviors.
They result from procedural (skill) learning, emotional learning, and stimulus-response conditioning. ◊

11. Learning as the Storage of Memories
Testing rats in the radial arm maze, researchers were able to determine which brain areas distinguished between these two types of
learning. ◊

12. Learning as the Storage of Memories
Rats with damage to both hippocampi could learn the simple conditioning task of going to any lighted arm for food—a nondeclarative memory task.
But if every arm was baited with food,
the rats could not remember which arms they had visited;
they repeatedly returned to arms where the food had already been eaten. This was a declarative memory task.
Conversely, rats with damage to the striatum could remember which arms they had visited, but could not learn to enter lighted arms.

13. Learning as the Storage of Memories
The amygdala has a significant role in nondeclarative emotional learning.
This could explain why a person might have an emotional response resulting from an unremembered experience.
The amygdala also strengthens declarative memories about emotional events.
In rats, stimulation of the amygdala activates the hippocampus, which improves performance on a choice maze.
In humans, memory for both pleasant and aversive stimuli is related to the amount of activity in the amygdala while viewing the material.

14. Learning as the Storage of Memories
Working memory provides a temporary “register” for information while it is being used.
It holds a phone number in memory while you dial the number.
It also integrates information from long-term memory with other information for use in problem solving and decision making. ◊

15. Learning as the Storage of Memories
The delayed match-to-sample task requires the individual to hold information in temporary memory during a delay period; it is a good example of working memory.
Cells in the prefrontal cortex serve this role, continuing to fire during a delay, even in spite of a distracting stimulus.
The prefrontal cortex also acts as a working memory central executive.
It manages behavioral strategies and decision making.
It directs the neural traffic in working memory.
It coordinates activity involved in perception and response.

16. Brain Changes in Learning
According to the Hebb rule, if the axon of a presynaptic neuron is active while the postsynaptic neuron is firing, the synapse will be strengthened.
This describes how neurons are selected for survival during development, and is the likely basis of changes during learning.
It also describes long-term potentiation (LTP).
LTP is the increase in synaptic strength that occurs when presynaptic and postsynaptic neurons are both activated.
It lasts for hours in tissue culture and months in lab animals.
It has been studied most in the hippocampus, but it appears to be characteristic of much of neural tissue.

17. Brain Changes in Learning
Long-term depression (LTD) is a decrease in the strength of synapses that occurs when stimulation of presynaptic neurons is insufficient to activate postsynaptic cells.
This may be the way the brain modifies or clears memories to make room for new information.
LTP and LTD are usually induced by stimulating the presynaptic neurons with pulses of electricity for several seconds.
Trains of high frequency stimulation produce LTP.
Trains of low frequency stimulation produce LTD.

18. LTP and LTD in the Human Brain Figure 12.10
Repeated 100-Hz stimulation produces LTP.
Repeated 1-Hz stimulation produces LTD, blocking the earlier potentiation.

19. Brain Changes in Learning
Associative LTP occurs when a weak synapse and a strong synapse on the same postsynaptic neuron are active simultaneously, resulting in strengthening of the weak synapse.
Fig 12.11

20. Brain Changes in Learning
Researchers believe that associative LTP underlies classical conditioning.
LTP is usually studied in isolated tissue, but it has also been demonstrated in rats.
After an auditory stimulus was presented with electric shock, the auditory stimulus produced activation of the amygdala, along with fear behavior.
The phrase “cells that fire together wire together” is a good summary of LTP, LTD, and associative LTP. ◊

21. Brain Changes in Learning
LTP and LTD are most likely triggered in the brain by theta activity, with a frequency range of 4 to 7 Hz.
Theta activity occurs in the hippocampus during novel situations.
Hippocampal stimulation that coincides with the peaks of theta waves produces LTP.
Stimulation that coincides with the troughs of theta waves suppresses LTP. ◊

22. Brain Changes in Learning Figure 12.12
LTP requires a sequence of events.
Initially, glutamate activates
AMPA receptors, but NMDA
receptors are blocked by
magnesium ions.
The first few pulses of stimulation partially depolarize the membrane and dislodge the magnesium ions.
Further stimulation activates the NMDA receptor, depolarizing the membrane;
calcium influx activates CaMKII, an enzyme required for strengthening the synapse. ◊

23. Brain Changes in Learning
LTP induction is followed by gene activation and silencing, which affect the synthesis of proteins.
The postsynaptic cell releases nitric oxide, which causes the presynaptic cell to release more neurotransmitter.
Structural changes include:
increased numbers of dendritic spines;
enlargement or splitting of existing spines;
transport of additional AMPA receptors into the spines. ◊

24. Increase in Dendritic Spines After LTP Figure 12.13

25. Brain Changes in Learning
Additional changes during learning:
Dopamine release unmasks previously silent synapses and initiates growth of new synapses.
Neurogenesis increases in the hippocampus.
The significance of new neurons is that they are more likely to participate in learning. ◊

26. Brain Changes in Learning
Does all this growth affect the volume of the brain areas that are involved in LTP?
Yes! London taxi drivers must navigate the complex streets from memory; typically two years of training are required for a license.
MRI scans of 16 drivers showed that the posterior part of the hippocampus—known to be involved in navigation—was larger than in males of a similar age.
This difference was greater for cabbies who had been driving for the longest time. ◊

27. Brain Changes in Learning
The process of consolidation involves two enzymes:
CaMKII, which is critical for the establishment of LTP;
protein kinase M zeta, which helps maintain long-term memory.
Transfer of information from hippocampus to cortex may take place during sleep, when the brain is “off-line”.
During sleep, neurons in the rats’ hippocampus and involved cortical areas repeat the pattern of firing sequences that occurred during learning while they were awake.
Many genes turned on during sleep play a role in protein synthesis, synaptic modification, and memory consolidation.

28. Brain Changes in Learning
A memory needs to be stable to be useful, but at the same time it must remain malleable, or modifiable.
Extinction eliminates useless memories.
Extinction involves new learning.
Like LTP, it requires activation of NMDA receptors; blocking these receptors eliminates extinction.
Forgetting is an active biological process, which appears to be adaptive.
The enzyme PP1 and the protein Rac produce memory loss after learning.
Forgetting may prevent the saturation of synapses.

29. Brain Changes in Learning
A third mechanism for modifying memories is reconsolidation.
When a memory is retrieved, it must be reconsolidated.
During that time, electroshock and drugs that interfere with protein synthesis can disrupt the memory.
However, reconsolidation also is an opportunity to refine memories and correct errors.
Thus, reconsolidation can be adaptive; for example, it is being used in therapy for PTSD for example.
On the other hand, it can result in memory reconstruction and the “recall” of false memories.

30. Learning Deficiencies and Disorders
Researchers long believed that memory deficits in the elderly were inevitable, and that they were due to substantial loss of neurons.
Many elders show little or no memory loss; often apparent deficits reflect motivation on memory tests.
In rats, there is no loss of hippocampal neurons and cortical cell loss is minimal.
There is evidence that an active lifestyle may promote “successful aging.” ◊

31. Learning Deficiencies and Disorders
Deficits that do occur:
Loss of synapses and NMDA receptors in some hippocampal circuits, leading to LTP impairment and slower learning.
Myelin loss and metabolism decrease in the entorhinal cortex.
Substantial cell loss in the basal forebrain region.
Prefrontal deficits, as seen in the gambling task. ◊

32. Learning Deficiencies and Disorders
The most common cause of dementia is Alzheimer’s disease.
Its most characteristic symptoms are progressive brain deterioration and (declarative) memory loss.
Most behaviors suffer, including language, visual-spatial functioning, and reasoning.
There are often behavioral problems, such as aggressiveness and wandering away from home.
The incidence of Alzheimer’s disease increases with age, affecting 10% of people over 65 and 50% of individuals over 85. ◊

33. Projected Increases in Alzheimer’s Disease Figure 12.18
The Alzheimer’s Association estimates that the number of people with Alzheimer’s disease will increase by 350% by 2050 (14.3 million people).
This represents huge medical costs, along with tremendous emotional pain.

34. Learning Deficiencies and Disorders
There are two notable characteristics of the Alzheimer’s brain, though they are not unique to the disease.
Plaques are clumps of amyloid, a type of protein, that cluster among axon terminals and interfere with neural transmission.
Neurofibrillary tangles, which are abnormal accumulations of the protein tau inside neurons.
Tangles are associated with the death of brain cells. ◊

35. Plaques and Tangles in Alzheimer’s Disease Figure 12.16

36. Learning Deficiencies and Disorders
However, the number of amyloid plaques is only moderately related to cognitive impairment.
Focus is shifting to ADDL, a soluble form of amyloid.
ADDL causes memory and LTP failure in mice.
ADDL is 70% higher in the brains of Alzheimer’s patients.
There is considerable cell loss as well.
Loss is greatest in the temporal and frontal lobes.
Gyri are reduced in size; sulci and ventricles are enlarged.
The hippocampus is effectively isolated from the rest of the brain. ◊

37. Alzheimer’s Brain and Normal Brain Figure 12.17

38. Learning Deficiencies and Disorders
Only four genes have been confirmed in Alzheimer’s disease; they all affect amyloid production or deposit.
Three genes are involved in early onset Alzheimer’s disease; they account for about 2% of cases.
The APP (amyloid precursor protein) gene is best known.
Individuals with Down syndrome also have plaques and tangles, which led researchers to chromosome 21.
The 4th gene (ApoE4) plays a role in over 50% of cases.
This form of Alzheimer’s is “late-onset” (over age 60).
It is likely the number of genes will turn out to be large, and gene activation/silencing will be important as well.

39. Learning Deficiencies and Disorders
Four drugs are typically used for treating Alzheimer’s.
Three are acetylcholinesterase inhibitors.
The fourth, memantine, is the first approved for use in patients with moderate to severe symptoms.
This drug limits neurons’ sensitivity to glutamate. (Excess glutamate can kill cells by excitotoxicity.)
Another approach is to induce an immune response to amyloid.
Injecting amyloid cleared plaques but did not affect cognition.
Injecting immunoglobulin removed plaques and produced mental improvement.

40. Learning Deficiencies and Disorders
Implanting genes for nerve growth factor:
in aged monkeys increased density of acetylcholine-producing axons;
and in humans increased brain metabolism and reduced cognitive loss by 84%.
Manipulation of Alzheimer’s genes is not possible yet.
Genetic counseling is an option. Choices are to forego having children or to screen eggs and sperm for the genes. ◊

41. Effect of Nerve Growth Factor on ACh Cells Figure 12.19
Acetylcholine-producing neurons in (a) a young monkey, (b) an aged monkey, and (c) an aged monkey treated with the nerve growth factor gene.

42. Learning Deficiencies and Disorders
Current means of diagnosing Alzheimer’s disease:
Batteries of physical, neurological, and cognitive tests;
Brain scans to detect structural abnormalities.
PET scans using tracers to detect plaques, which may allow diagnosis two years earlier.
Markers in skin, blood, and cerebrospinal fluid promise diagnosis 5-6 years in advance, with 90%-100% accuracy. ◊

43. Learning Deficiencies and Disorders
In a study of elderly Catholic nuns:
Differences in writing 5 decades earlier distinguished which ones would develop Alzheimers.
Some had plaques and tangles but were unimpaired.
Resistant nuns had larger hippocampal cells, which could have been a reaction to plaques and tangles or protection against dementia. ◊

44. Learning Deficiencies and Disorders
Another form of dementia is Korsakoff’s syndrome, brain deterioration that is almost always caused by chronic alcoholism.
The deterioration results from a deficiency in thiamine (vitamin B1), which has two causes:
The alcoholic consumes large quantities of calories in the form of alcohol in place of an adequate diet.
The alcohol reduces absorption of thiamine in the stomach.
The most pronounced symptom is anterograde amnesia, but retrograde amnesia is also severe.
The amnesia is for declarative memories; nondeclarative memory remains intact.

45. Learning Deficiencies and Disorders
Damage includes:
size reductions in the mammillary bodies and the medial thalamus;
structural and functional abnormalities in the frontal lobes.
Thiamine therapy can relieve the symptoms somewhat, but the damage is irreversible. ◊

46. Learning Deficiencies and Disorders
Some Korsakoff’s patients show a particularly interesting characteristic in their behavior, called confabulation.
They fabricate stories and facts to make up for those missing from their memories.
Confabulation apparently depends on abnormal activity in the frontal lobes, and confabulating patients usually have lesions there.
Confabulating amnesic patients have more trouble than nonconfabulating patients in suppressing irrelevant information they have learned earlier.
It has been suggested that confabulation is due to an inability to distinguish between current reality and earlier memories.