1. Learning and Memory

2. Learning relatively permanent change in behavior as a function of training, practice or experience excludes behavioral changes resulting from sensory adaptation or fatigue

3. memory is implicit in the definition of learning “relatively permanent” implies a lasting alteration of nervous system structure and/or function Learning and Memory

4. Two aspects of learning 1. acquisition of a response in presence of a stimulus 2. suppression of responses in its absence

5. Two fundamental questions 1. What are the neural mechanisms of learning? (cellular level) 2. What is learned? (where in the brain; organizational level)

6. To answer the first question, simplified systems have been studied. Simple forms of learning Simple systems e.g. invertebrates, simplified mammalian preparations

7. Non-associative –Habituation, sensitization –perceptual in nature –recognition of objects and situations Associative –Classical conditioning S-S learning – Operant Conditioning R-S learning Types of Learning

8. Associative learning may involve acquisition of new motor behaviors acquisition of associations between new stimuli and existing behaviors acquisition of new associations between familiar stimuli and existing responses.

9. Non-associative learning habituation repeated exposure to a stimulus results in reduced responding to that stimulus generally neutral, non-noxious stimuli sensitization repeated exposure to a stimulus results in increased responding to that stimulus generally biologically relevant, strong hedonic valence (+ or -) also refers to augmentation of responding following exposure to a second stimulus

10. Associative learning classical conditioning; Pavlovian conditioning; respondent conditioning A neutral stimulus is paired with a stimulus that reliably elicits a response. Conditioning is indicated when the previously neutral stimulus elicits a response. CS  US  UR US CS UR CR

11. Associative learning operant conditioning; instrumental learning repeated presentation of a stimulus after emission of a designated response increases (reinforces) or decreases (punishes) the likelihood of that response CR  US  UR

12. Modeling, latent learning Usually defined as learning in the absence of a reinforcer (US or conditioned reinforcer such as money) Problem: One can always posit a “hidden reinforcer,” a negative hypothesis that cannot be disproven. The burden of proof therefore falls on those to make hidden reinforcers evident. The existence of mirror neurons seems to provide a neurobiological basis for imitative learning.

13. Eric Kandel and his collaborators used Aplysia to unravel synaptic mechanisms for short- and long-term habituation, short- and long-term sensitization, and classical conditioning. Eric Kandel won the 2000 Nobel Prize for Physiology and Medicine for this work. Research on neural mechanisms has focused on non-associative learning and classical conditioning. Aplysia

14. Habituation in Aplysia

15. Sensitization in Aplysia Kandel termed the neural mechanisms that underlie behavioral sensitization, “heterosynaptic facilitation,” which is produced by a second (usually strong) stimulus

17. heterosynaptic facilitation 5-HT released onto presynaptic terminal (metabotropic synapse) c-AMP mediated closure of K+ channels Prolongation of depolarization at the terminal greater Ca 2+ influx more neurotransmitter released onto target neuron

18. Memory in Aplysia also involves structural changes in the presynaptic terminal groupactive zonesactive zone area vesicles/ active zone vesicles/ neuron naïve100%.16 um132250 habituated28.114500 sensitized183.28206300

19. LTP in the hippocampus: A mammalian model for learning Hippocampus most studied because of it's organization-- complete circuitry represented in thin slices (100-400um thick) can be placed in a dish for in vitro electrophysiological experiments also thought to be important for memory consolidation in vivo

20. 20 Copyright © 2004 Allyn and Bacon

21. LTP in the hippocampus: A mammalian model for learning typical LTP experiment 1.stimulate neuron A, record PSP from neuron B 2.stimulate neuron A tetanically (e.g. burst of stimuli @ 100 Hz) 3.record PSP from B w/test pulses at varying intervals 4.PSP augmented for several days or even up to months 5.this augmentation is what is called LTP

24. LTP in the hippocampus: A mammalian model for learning

27. CaMKII: Calcium/calmodulin dependent kinase II PKA, PKC: Protein kinase A, C CREB: cAMP-responsive element-binding protein Low-frequency stimulation results in small increases in [Ca 2+ ] in the postsynaptic cell, which in turn results in fewer AMPA channels opening in response to glutamate. This is called low-frequency depression and is a mechanism for weakening synaptic strength.

28. http:// www.sumanasinc.com/webcontent/anisamples/neurobiology/receptors.htmlhttp:// www.sumanasinc.com/webcontent/anisamples/neurobiology/receptors.html

29. Organizational Aspects of Learning and Memory Three gross stages of learning and memory Acquisition Storage Retrieval

31. Organizational Aspects of Learning and Memory There are also qualitatively different kinds of learning Declarative episodic semantic Procedural or non-declarative skill learning priming conditioning

33. Organizational Aspects of Learning and Memory Memory can be categorized according to its duration or persistence Sensory traces e.g. iconic (visual) and echoic (auditory) at most a few seconds in duration

34. Organizational Aspects of Learning and Memory Memory can be categorized according to its duration or persistence Sensory traces Short-term memory (STM) or working memory information held in “consciousness” phonological loop (sub-vocal rehearsal) visual imagery episodic buffer can be initiated by current event or by recall from LTM controlled by “central executive”

35. Organizational Aspects of Learning and Memory Memory can be categorized according to its duration or persistence Sensory traces Short-term memory (STM) or working memory Intermediate-term memory distinguishable from STM and LTM? up to a few days in duration

36. Organizational Aspects of Learning and Memory Memory can be categorized according to its duration or persistence Sensory traces Short-term memory (STM) or working memory Intermediate term memory Long-term memory indefinite duration, up to days

37. Organizational Aspects of Learning and Memory Memory can be characterized by its underlying physical bases Sensory traces persistent activity in sensory pathways

38. Organizational Aspects of Learning and Memory Memory can be characterized by its underlying physical bases Sensory traces Short-term memory (STM) or working memory reverberating circuits electrical basis limited capacity can be disrupted by intrusion of other activity displays both primacy and recency effects

39. Organizational Aspects of Learning and Memory Memory can be characterized by its underlying physical bases Sensory traces Short-term memory (STM) or working memory Intermediate term memory biochemical basis? accessible by working memory eventually irretrievable (storage or retrieval failure?)

40. Organizational Aspects of Learning and Memory Memory can be characterized by its underlying physical bases Sensory traces Short-term memory (STM) or working memory Intermediate term memory Long-term memory structural or anatomical basis protein synthesis essential unlimited(?) capacity

41. Organizational Aspects of Learning and Memory Memory can be characterized by its underlying physical bases Sensory traces Short-term memory (STM) or working memory Intermediate term memory Long-term memory

42. The case of Henry Molaison (H.M.) H.M. suffered from epilepsy, with epileptic foci in both temporal lobes. It did not respond to drugs available at the time and was life-threatening. Therefore, it was decided to remove the tissue in which the epileptiform activity originated. H.M.’s surgery removed the amygdala, the hippocampus, and some of temporal lobe cortex.

43. Patient H.M. EC: Entorhinal cortex H: Hippocampus Cer: Cerebellum PH: Parahippocampal cortex

44. Following surgery, H.M.’s memory of events prior to the surgery was intact (no retrograde amnesia). But, he did display anterograde amnesia, the inability to form declarative memories after the surgery. H.M.’s memory deficit was confined to verbal tasks, with motor learning (non-declarative memory) unaffected. However, H.M. DID display anterograde amnesia for spatial tasks, e.g. navigating new environments

45. There Are Several Kinds of Memory and Learning Studies in animals and other humans with brain damage showed that the H.M.s deficits were unlikely due solely to hippocampal damage. Other temporal lobe structures and the thalamus form a larger functional circuit necessary for consolidation of declarative memories.

48. Damage to other areas can also cause memory loss. Patient N.A. has amnesia due to accidental damage to the dorsomedial thalamus, which is part of the same memory circuit affected by H.M.’s surgery. Like Henry Molaison, he has short-term memory but cannot form declarative long- term memories.

49. Patient N.A. damage of the dorsomedial thalamus damage to floor of third ventricle, mammillary bodies

50. Korsakoff’s syndrome is a memory deficiency caused by lack of thiamine (vitamin B6)–often seen in chronic alcoholism. Brain damage occurs in mammillary bodies and basal frontal lobes, which produces anterograde amnesia. Patients often confabulate–fill in a gap in memory with a false memory that they fully believe to be true. Korsakoff’s Syndrome

52. Organizational Aspects of Learning and Memory Three gross stages of learning and memory Acquisition Storage Retrieval

53. STM is susceptible to disruption prior to consolidation electroconvulsive shock (or ECT in clinical settings) can disrupt long-term memory by pulling those memories back into working memory at the time of ECT, which prevents re-consolidation head trauma generally results in retrograde amnesia, whose magnitude is inversely related to the age of the memory, by disturbing ongoing electrical activity traumatic events may also induce amnesia similar to head trauma or ECS e.g. placing rats in ice water immediately after training trial results in forgetting, or amnesia may be a model for the loss of memory following psychological trauma (e.g. rape) in humans

54. LTM can be prevented by interfering with protein synthesis Protein synthesis inhibitors block LTP and formation of memories in behavioral tasks. The role of protein synthesis in response to environmental stimulation is very evident in the phenomenon of environmental enrichment

56. “Enrichment” studies are really studies of varying degrees of impoverishment. Rats living outdoors in natural envronmental enclosures exceed “enriched” rats on all measures