Memory and learning

1. Memory and learning LeDoux, chapters 5 and 6

2. Types of memory • There is general agreement that there are several different types of memory, each of which is predominantly in a different part of the brain.

3. Declarative vs. procedural memory • Declarative memory (explicit memory): • facts • dates • events • Hippocampus is critical • Procedural memory (non-declarative/implicit): • how to perform an act (ride a bicycle) • basal ganglia (dorsal striatum / caudate-putamen) is critical

5. Patients with Alzheimer's disease are unable to learn or remember ordinary facts (declarative memory) but are normal or nearly normal at learning and remembering how to do things (procedural memory).

6. Memory experiment • Alzheimer's patients learned and remembered how to read complex words in a mirror as well as normal control subjects • Were unable to recall the training session or the fact that they had acquired this skill.

7. Classical (Pavlovian) conditioning • Another kind of memory is distinct, both behaviorally and anatomically, from declarative or procedural memory. • Pavlovian conditioning is a form of learning based on the tendency of certain natural events (food presentation) to elicit involuntary responses (salivation) with little or no training.

8. Initiating event: Unconditioned stimulus (US) • Response pattern: Unconditioned response (UR) • Another "neutral" stimulus (ringing a bell), besides the US, does not usually elicit the UR.

9. If another "neutral" stimulus (ringing a bell) is presented simultaneously several times with the Unconditioned stimulus (food), the "neutral" will be able to elicit the Unconditioned response (salivation). • The "neutral" stimulus (ringing a bell) is then called the Conditioned stimulus (CS). • The response (salivation) is then called the Conditioned response (CR)

10. This process of learning an association between a CS and a CR is called Pavlovian or classical conditioning, or sometimes "associative learning". • Pavlovian conditioning occurs automatically, with no control, voluntary participation, or (usually) even awareness on the part of the individual to whom it occurs.

11. Evidence in animals and humans indicate that the amygdala is critical for classical conditioning. • The studies indicate that the amygdala mediates expression of conditioned rewarding and approach behaviors as well as conditioned aversive and escape responses (e.g., "freezing" in mice).

12. Fear conditioning • A simple form of associative learning (Pavlovian conditioning) • Animals learn to "fear" a previously neutral stimulus (conditioned stimulus, CS), because the US has been presented at the same time as an aversive stimulus (unconditioned stimulus, US) such as a foot shock. • Conditioned animals, when exposed to the CS, tend to refrain from all movement except breathing ("freezing").

13. Freezing responses can be triggered with two different types of CS, each working via different parts of the brain: • - In "cued conditioning", the CS is simply a tone (e.g., 85 dB, 2800 Hz), and lesions in the amygdala, but not the hippocampus, appear to disrupt this type of conditioning. • - In "contextual conditioning", rodents become conditioned to the "context" in which they were exposed, such as a particular location. Contextual conditioning is thought to depend on both the amygdala and the hippocampus.

14. Memory and the hippocampus • In 1950, a young man, known now by his initials, H.M. underwent brain surgery in Hartford, Connecticut. • H.M. was one of several patients in whom parts of the temporal lobe were removed in an effort to control epilepsy.

15. The temporal lobe is one of the four major divisions (lobes) of the brain, and is often the place in the brain attacked by epilepsy. • In H.M’s case, temporal lobe areas were removed on both sides of his brain. • After the surgery, his epilepsy was better, but he no longer had the ability to acquire new memories.

16. H.M became probably the most famous case in neurological history, and has been the subject of many studies. • Much of the initial work was carried out by Brenda Milner and her colleagues in Montreal.

17. Milner found that, although H.M could recall many of the events of his earlier life, he was unable to form new memories for experiences that occurred after the surgery. • He could remember things for a few seconds (short-term memories) but he couldn’t convert this information into long-term memories.

18. Analysis of H.M.’s lesion, based on the surgical report, indicated that the main temporal lobe areas affected were the hippocampus, amygdala, and parts of the surrounding cortex. • By comparing H.M.’s lesion with those in other patients, it seemed that the hippocampus was the area damaged most consistently in memory deficits.

19. At first, it was thought that H.M. had lost all ability to acquire new memories. • However, it was found that he could learn certain tasks.

20. Brenda Milner asked H.M. to copy a picture of a star viewed through a mirror. • To do this, the movements had to be done in the direction opposite from the way the seemed they should be made. • This task is hard at first, but eventually most people can do it, and H.M. was no exception.

21. H.M. learning the mirror drawing task, and he retained the learning. • But if asked about drawing using the mirror, he had no conscious memory of having done it.

22. Suzanne Corkin of MIT found that H.M. also improved with practice in another manual skill learning task – one in which he was required to keep a stick held in his hand on a dot spinning on a turntable. • As with the mirror drawing task, the more times he did it, the better he got. • His ability to form memories about how to make precise movements (motor skills) seemed intact. • Subsequent work has shown that other regions of the brain (the basal ganglia) are primarily responsible for remembering motor skills.

23. Much is now known about the hippocampus, but we will mention just a few points. • Information about the external world comes into the brain through sensory systems that relay signals to the cortex, where sensory representations of objects and events are created

24. Outputs of each of the cortical sensory systems converge in parahippocampal region (also known as the rhinal cortical areas) which surrounds the hippocampus. • The parahippocampal region integrates information from the different sensory modalities before sending it to the hippocampus proper.

25. The hippocampus and parahippocampal region make up what is now called the medial temporal lobe memory system, which is involved in explicit or declarative memory.

27. The connections between the hippocampus and the neocortex are all more or less reciprocal • The pathways that take information from the neocortex to the rhinal areas and then into the hippocampus are mirrored by pathways going in the opposite direction. • Cortical areas involved in processing a stimulus can thereby also participate in the long-term storage of memories of that stimulus.

28. The rhinal areas serves as convergence zones, brain regions that integrate information across sensory modalities and create representations that are independent of the original modailty. • As a result, sights, sounds, and smells can be put together in the form of a global memory of a situation.

30. Convergence zones allow mental representations to go beyond perceptions to become conceptions. • They make possible abstract representations that are independent of concrete stimulus. • The primate neocortex has several cortical areas, more than in other mammals.

31. Because the hippocampus receives inputs from several convergence zones in the rhinal region, it can be thought of as a superconvergence zone. • It can form explicit memories about many domain-specific systems, such as face- and language-processing systems, allowing us, for example, to form a memory that includes both what someone says and what he looks like.

32. Many researchers believe that explicit memories are stored in the corical systems that were involved in the initial processing of the stimulus, and that the hippocampus is needed to direct the storage process.

33. Early experiments on drug effects on memory • Certain post-training treatments can modulate memory storage in ways that enhance or prevent retention. • First observed with stimulant drugs • strychnine (very low doses) • amphetamine • caffeine

34. Early studies showed that drugs that inhibit protein synthesis also inhibit long-term memory formation. • Several inhibitors of RNA synthesis or protein synthesis block long-term memory, but do not affect short-term memory.

35. Gene transcription, translation, and memory • DNA is transcribed to produce RNA • RNA is translated to produce protein • DNA -> RNA -> protein • Transcription factors are proteins that regulate what genes are transcribed (expressed). • Transcription factors typically bind near the promoter region of a gene (the on/off switch).

36. Amphetamine improves learning • Rats were put into a cage where they could drink water. • After being put in the cage, the rats heard a series of 10 second tones, each terminated with a brief foot shock. • The shock caused the animals to stop moving (freeze). • After several such tone-shock pairings, the rats acquired a conditioned freezing response, which lasted for several minutes each time the tone was presented.

37. The next day, the rats were placed in the drinking cage. • Tone came on when they began to drink. • Animals froze • Duration of freezing was used as a measure of the rats' memory for the tone-freezing association. • Rats that experiences more pairings (12) froze significantly longer than rats that had fewer pairings (2).

38. Some rats got drug injections immediately after their experience of the tone-shock pairings. • Rats that got two pairings followed immediately by a saline injection froze for slightly longer than rats that got two pairings but no injection. • However, rats that got two pairings followed immediately by an amphetamine injection froze for about the same length of time as rats that got 12 pairings (but no drug). • => Amphetamine improves learning if it is given immediately after training

39. Another group of rats got 2 pairings followed by amphetamine injection 2 hours later. • These rats froze for the same length of time as rates that received saline or no injection, • => amphetamine had no effect if it was given 2 hours after the training

40. The results indicate that the immediate amphetamine injections improved the rats' memory for the tone-freezing association. • The fact that the delayed drug injection had no effect is consistent with the idea that the memory was susceptible to modulation only during a consolidation period that lasted less than two hours.

41. How drugs act on synapses • Neurons communicate with each other at synapses using chemical neurotransmitters. • This provides the bases for drugs (and poisons) to affect synaptic transmission. • Drugs with chemical properties similar in some way to those of neurotransmitters can act on synapses to alter behavior and thoughts (psychotropic or psychoactive drugs)

42. Drugs that increase synaptic transmission are "agonists". • Drugs that block or reduce synaptic transmission are "antagonists".

44. About 25 neurotransmitters are known in the mammalian brain. • Most psychoactive drugs act on the synapses of a single neurotransmitter. • These synapses often occur in different, functionally unrelated parts of the brain, controlling many different behaviors • The psychological actions of drugs can be quite complex and difficult to predict

45. To affect the brain, drugs must cross the blood-brain barrier • Access to the brain from the circulatory system is controlled by the blood-brain barrier (BBB). • This barrier is made up of a layer of cell surrounding the blood vessels that supply the brain. • These cells determine the degree to which substances in the blood can enter the brain.

46. Fat-soluble substances (e.g., alcohol) cross the BBB more easily than water –soluble substances. • Drugs and hormones with large molecular weights do not easily pass the BBB. • Some substances, including glucose and insulin, are actively transported into the brain. • The degree to which drugs cross the BBB is critical to their effects on memory.

47. Learning and memory • What is the nature of the neural changes that constitute learning and memory? • Most neuroscientists today believe that alterations in synaptic connectivity underlie learning, and that memory is the stabilization and maintenance of these changes over time. • How does experience change synapses, and what makes changes last?

48. Changes in synapses resulting from the simultaneous (or near simultaneous) activation of neurons is generally thought to be the basis of all learning, including procedural, declarative, and conditioned learning. • We will see that the central role of synaptic changes in learning and memory provides the bases for the action of neurologic drugs.

49. By the early 1950’s, several studies had shown that repeated delivery of a brief electrical stimulus to a nerve pathway could alter synaptic transmission in that pathway – could, in other words, produce synaptic plasticity.

50. Hebbian learning • The most-widely accepted theory of how information is stored in the nervous system is based on a concept first described by D.O. Hebb, now called Hebbian learning. • Start with the idea that each perception evokes a unique set pattern of neural activity. • The set of activated neurons are connected to each other, and reactivate each other for a short period of time.