CHAPTER 12

1. CHAPTER 12 Learning and Memory Brain Changes in Learning

2. Brain Changes in Learning • Over 50 years ago Donald Hebb (1940) stated what has become known as the Hebb rule: • If an axon of a presynaptic neuron is active while the postsynaptic neuron is firing, the synapse between them will be strengthened. • Note: Hebb made this statement in the absence of much knowledge regarding neural architecture or decent anatomical evidence!

3. Changes in the structure of the synapse during Learning • Long-term potentiation (LTP): • increase in synaptic strength following repeated high-frequency stimulation • Increase in dendritic growth • Changes in receptor sites in synapse • Long-term depression (LTD): • decrease in synaptic strength when an axon of a neuron is active while the postsynaptic neuron is not depolarized. • May result in decreased dendritic growth • Also changes in receptor sites in synapse

4. Changes in the structure of the synapse during Learning • Associative long-term potentiation: • occurs if a synapse is stimulated weakly while another synapse on the same postsynaptic neuron is being stimulated strongly • the “weak” synapse as well as the “strong” synapse will be potentiated • Helps build generalization or secondary associations • Associative long-term depression • weakening of a synapse that is active when the postsynaptic neuron is not depolarized, • is inactive when the postsynaptic neuron is depolarized. • LTP, LTD, associative LTP, and associative LTD can all be summed up in the expression, “Cells that fire together wire together.”

5. The graphs show excitatory postsynaptic potentials in response to a test stimulus before and after repeated stimulation. (a) 100-Hz stimulation produced long-term potentiation that was evident 25 minutes later. (b) 5-Hz stimulation produced long-term depression that blocked potentiation established earlier.

6. How does LTP and LTD happen? • In most locations the neurotransmitter involved in LTP is glutamate. • There are two types of glutamate receptors: • The AMPA receptor • The NMDA receptor

7. Brain Changes in Learning • During initial trials: • Glutamate activates AMPA receptors but not NMDA receptors, • NMDA receptors NOT activated because they are blocked by magnesium (Mg) ions. • During LTP induction: • activation of the AMPA receptors by the first few pulses of stimulation partially depolarizes the membrane • This dislodges the magnesium ions • Dislodging of magnesium ions allows NMDA receptors to begin being activated. • .

8. Brain Changes in Learning • Thus: critical NMDA receptor can then be activated • This NMDA activation result = influx of sodium (Na+) and calcium (Ca+) ions. • Action of Ca+ ions allows release of Mg • Release of Mg ions and thus stimulation of NMDA receptor: • Influx of Na+ and Ca+ further depolarizes the neuron AND • Calcium activates CaMKII. • CaMKII: is an enzyme that is necessary for LTP; • acts as a binary switch to change the strength of a synapse. • Allows growth at the synapse of dendrite

9. (a) Initially, glutamate activates the AMPA receptors but not the NMDA receptors, (blocked by magnesium ions) (b) IF activation is strong enough to partially depolarize the postsynaptic membrane- magnesium ions are ejected. The NMDA receptor can then be activated, allowing sodium and calcium ions to enter.

10. Brain Changes in Learning • The final stage of LTP: • involves alteration of gene activity • and the synthesis of proteins. • Changes responsible for structural modifications in the dendrites • These changes produce longer-lasting increases in synaptic strength: • Neurons develop increased numbers of dendritic spines: • partially bridge the synaptic cleft • make the synapse more sensitive. • Later, additional AMPA receptors are transported from the dendrites into the spines.

12. Brain Changes in Learning • Recent research supports hypothesis that LTP plays fundamental role in learning. • Decreasing number of NMDA receptors in mice results in: • reduced LTP in the hippocampus • impaired learning. • Learning improved by chemically increasing LTP • Humans may possess genes related to various proteins involved in LTP. • Also supports data suggesting that what “works” to remember: • repetition • massed trials • Or other similar practice/rehearsal strategies • Mastery learning: Practice makes perfect • Practice grows your brain!

13. Brain Changes in Learning • Hippocampus has ability to acquire learning “on the fly” • That is, while the event is in progress • Why would this be important? • In contrast, longer time needed for long-term storage of declarative memories in the cortex. • Hippocampus appears to transfers information to the cortex during times when the hippocampus is less occupied, • for example, during sleep • May be function of dreaming.

14. Brain Changes during sleep • Neurons in rat hippocampus and involved cortical areas repeat pattern of firing sequences that occurred during learning while awake. • Presumably: “offline” replay provides cortex opportunity to undergo long-term potentiation • Cortex requires more time to develop LTP, perhaps due to complexity • Takes time for changes in synapse; dendrites • Hippocampus = STM store; cortex is your hard drive

15. Forgetting? Brain Changes in Learning • A memory must be both • stable to be useful • Malleable to be adaptable • Need to remember new information • But must also be able to forget irrelevant/worthless information • Several ways the brain accomplishes this: • Extinction • Forgetting

16. Forgetting? Brain Changes in Learning • Extinction • involves new learning • Like LTP, extinction requires activation of NMDA receptors; • blocking these receptors eliminates extinction. • Forgetting is a problem, but is also adaptive • Prevents saturation of synapses with information that is not used regularly • Eliminates information that not made connections with other stored memories • Thus importance of elaborative rehearsal. • A number of studies indicate: Any time memory is retrieved it must be reconsolidated • During that time the memory becomes vulnerable again to disruption. • Bottom line: • Use it or lose it • Use it and risk losing it!

17. Memory loss and aging • For many years • researchers believed deficits in the elderly caused by a substantial loss of neurons • especially from the cortex and the hippocampus. • More recent investigations • the number of hippocampal neurons was not diminished in aged rats • Even rats with memory deficits show little neuronal loss • What neuronal loss occurs from cortical areas was relatively minor. • BUT: certain circuits in the hippocampus do lose synapses and NMDA receptors as animals age. • Probably as a result of these changes, LTP is impaired in aged rats.

18. dementias • Dementia • substantial loss of memory and other cognitive abilities • Typically in elderly • 50% of those over 80 show some signs of dementia • Alzheimer’s disease • most common cause of dementia is • characterized by progressive brain deterioration, impaired memory, loss of other mental abilities. • earliest and most severe symptom = impaired declarative memory. • Language, visual-spatial functioning, and reasoning are particularly affected • Behavioral problems such as aggressiveness and wandering away from home. • Alzheimer’saffects nearly 10% of people over 65 years of age, and nearly half of those over 85. • Other dementias: • Frontal-temporal dementia • Vascular dementias • Dementias from illness such as stroke/heart attack

19. dementias

20. Brain changes in dementia • There are two notable characteristics of the Alzheimer’s brain, though they are not unique to the disease. • Plaques • Neurofibrillary tangles • Plaques = clumps of amyloid, • a type of protein • cluster among axon terminals • interfere with neural transmission. • neurofibrillary tangles • Abnormal accumulations of the protein tau • form inside neurons. • Tangles are associated with the death of brain cells.

21. Figure 12.14 Neural abnormalities in the brain of an Alzheimer’s patient (a) The round clumps in the photo are plaques. (b) The dark twisted features are neurofibrillary tangles.

22. Dementia and brain changes • In the Alzheimer’s brain, • gyri are smaller • sulci are wider than in the normal brain. • In the diseased brain, many of the lesions are located in the temporal lobe. • Because of their location, they effectively isolate the hippocampus from its inputs and outputs, • this partially explains the early memory loss. • Plaques and tangles in the frontal lobes account for • additional memory problems • attention and motor difficulties.

23. Figure 12.15 Alzheimer’s brain (left) and a normal brain The illustrations show the most obvious differences, the reduced size of gyri and increased size of sulci produced by cell loss in the diseased brain.

24. Ach and memory • Acetylcholine: • Neural systems in various parts of the brain that produce acetylcholine are critical for cognitive functions • including attention and learning. • Acetylcholine-releasing neurons are among the victims of degeneration in Alzheimer’s disease. • The majority of treatment efforts have focused on restoring acetylcholine functioning. • E.g., cognex, aricept, exelon

25. Drugs for dementia • Currently five drugs approved by the FDA for the treatment of Alzheimer’s. • Four of them improve acetylcholine neurotransmission by preventing the breakdown of acetylcholine at the synapses. • drugs provide only modest relief for both memory and behavioral symptoms in mild cases of Alzheimer’s • little or no help when degeneration is advanced. • Other drug treatment • Psychotropic drugs to control behavioral symptoms, reduce hallucinations • Antiseizure medications to control onset of seizures • tranqulizers

26. Newer dementia drug • Memantine • The fifth dementia drug • first approved for use in patients with moderate and severe symptoms. • Some neuron loss in Alzheimer’s occurs when dying neurons trigger the release of the excitatory transmitter glutamate. • The excess glutamate overstimulates NMDA receptors and kills neurons, a phenomenon known as excitotoxicity. • Memantine limits the neuron’s sensitivity to glutamate, reducing further cell death. • Studies indicate moderate slowing of deterioration and improvement in symptoms.

27. Korsakoff’s syndrome • Korsakoff’s syndrome • Another form of dementia is, brain deterioration • almost always caused by chronic alcoholism. • The deterioration results from a deficiency in the vitamin thiamine (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.

28. Korsakoff’s syndrome • The most pronounced symptom : anterograde amnesia • retrograde amnesia is also severe. • Impairment is to declarative memory, while nondeclarative memory remains intact. • Several brain changes: • hippocampus and temporal lobes are unaffected. • mammillary bodies and the medial part of the thalamus are reduced in size • structural and functional abnormalities occur in the frontal lobes. • Thiamine therapy can relieve the symptoms if the disorder is not too advanced, • Brain damage itself it irreversible.

29. Korsakoff’s symptoms • confabulation • Some Korsakoff’s patients show a particularly interesting characteristic in their behavior • Many other dementia patients, particularly frontal-temporal lobe also show this • They fabricate stories and facts to make up for those missing from their memories. • Confabulation : • depends on abnormal activity in the frontal lobes • confabulating patients usually have lesions there. • Confabulating amnesic patients • more trouble than nonconfabulating amnesiacs in suppressing irrelevant information they have learned earlier. • Why? confabulation is due to an inability to distinguish between current reality and earlier memories.