Integrative Functions of the Nervous System

1. Integrative Functions of the Nervous System Topic 5a

2. Lecture Overview • Learning and Memory Introduction • Sensitization and Habituation in Aplysia • Long-term Potentiation and Depression

3. Learning • 50+ years ago • Donald Hebb proposed that learning is mediated by changes in synaptic strength • As an animal learned a response, some synapses became stronger

4. Why are learning and memory important? • To be able to adapt to changes in the environment • Learning • Acquire and process information from the environment • Changes the nervous system • Memory • Ability to retain this information

5. Learning vs Memory • Learning: process that will modify a subsequent behaviour • Memory: ability to remember past experiences • Memory essential to learning—storage and retrieval of records left by learning • Learning depends on memory

6. Memory

8.  Performance Retrieval Incoming information Working memory Long-term storage Sight   Sound Short-term storage Sensory buffers Consolidation Encoding Smell Touch Loss of information Hypothesized Memory Processes Adapted from Rozenzeig, 2002

9. Sensory memory • Large capacity, but rapid decay • Sensory association areas involved • Example: Your mother is lecturing you and you aren’t paying attention, however, if asked, you can repeat the last sentence she said. High Low Input

10. Short-term memory(Working memory) • Lasts for seconds to minutes • Severely limited capacity • magical 7 ± 2 – hold for digits, letters, etc. • Available to conscious awareness • Prefrontal cortex involved • Example: remember a phone number between looking it up and dialing High Low Input

11. Intermediate-term Memory • Lasts for hours and days • May be transferred to LTM through rehearsal • Example: remembering where you parked your car High Low Input

12. Declarative Memory • Involves hippocampus and medial temporal lobes • Neurons in hippocampus register information about the space surrounding an animal (rat studies) • Hippocampus contains a cognitive map of the external environment

13. HM, the man with no memory • Henry Molaison • Epileptic patient • Hippocampus removed in 1957 (age 27) • Global amnesia

14. HM • Could not “learn” anything after the surgery • Some retrograde memory loss • Likely not due to loss of hippocampus • Mentioned in 12,000 research articles • First studied by Brenda Milner at the Montreal Neurological Institute • Participated in research studies for 55 years

17. Synaptic Plasticity • Change in synaptic function in response to patterns of use • Synaptic facilitation/sensitization • Repeated APs result in increased Ca2+ in terminal • Increased neurotransmitter release • Synaptic depression/habituation • Repeated APs deplete neurotransmitter in terminal • Decreased neurotransmitter release

18. A reductionist model • Eric Kandel (Nobel Prize 2000) • Use a simple model to delineate the basic mechanisms of memory and learning • Use those findings to address memory & learning in vertebrates • Model of choice: Aplysia californica

19. http://employees.csbsju.edu/ltennison/PSYC340/KandelAplysia.jpghttp://employees.csbsju.edu/ltennison/PSYC340/KandelAplysia.jpg

20. Aplysia californica http://biomedme.com/wp-content/uploads/2010/02/aplysia23.jpg

21. Why Aplysia? • Aplysia have: • A relatively small number of neurons (~20,000) • Relatively large neurons (up to 1 mm in diameter) • Culturable neurons that form circuits in vitro • Responses are visible and measurable • Response triggered by several electrical synapses firing simultaneously

22. Nervous system • No brain • Number of ganglia • Control sensory and motor behaviour in nearby region • Also contain interneurons • Allow connections between ganglia

24. Abdominal ganglion http://aplysia.miami.edu/images/abdominal-1.jpg

25. http://aplysia.miami.edu/images/abdominal-2-large.jpg

26. Gill withdrawal reflex • On dorsal surface • Gill and siphon located under mantle • Normally gill and siphon extend out from mantle • Touch or threat • Gill and siphon pulled back under mantle • Discrete number of cells involved • All have been identified

27. Gill withdrawal reflex • Depends on ~100 neurons • ~50 are sensory • ~40 are motor • ~10 are interneuron • Stimulation excites sensory neuron to fire an AP • Directly activates motor neuron • Indirectly activates motor neuron via polysynaptic connections via the interneurons

29. Kandel & Aplysia • http://www.hhmi.org/biointeractive/media/Aplysia_reflex2-lg.mov

30. Habituation & Sensitization • Habituation • Repeated stimulus leads to “ignore” • “negative” memory (i.e., not stored) • Sensitization • Noxious shock results in response • Results in consolidated memory • “kept” memory

31. Short & Long Term Synaptic Plasticity • Gill withdrawal reflex • One training trial • Short-term memory lasting minutes • Repeated, spaced training • Long-term memory lasting days to weeks

32. Habituation • Simplest formation of implicit learning • Novel stimulus • Pay attention first time • Repeated exposure • If neither beneficial or harmful--ignore

33. Habituation • Size of EPSP by sensory neuron on motor neuron decreases in amplitude • Inactivation of calcium channels • Less Ca2+ entering nerve terminal of pre-synaptic membrane • Less neurotransmitter released

36. Sensitization • Large increase in amplitude of EPSP • Increase in amount of NT released • Amplification due to interneurons

38. Sensitization http://www.cidpusa.org/I10-86-Aplysia.jpg

39. Signalling by the Interneurons • Excitatory interneurons release serotonin (5-HT) • 2 serotonin receptors • 5-HT2-like receptor • PLC pathway • 5-Ht4/6/7-like receptor • Adenylate cyclase pathway

40. Short-term Sensitization http://people.usd.edu/~cliff/Courses/Behavioral%20Neuroscience/Aplysia/Apfigs/Apshortfacil.jpg

42. http://employees.csbsju.edu/ltennison/PSYC340/LTP.jpg

43. Structural Changes • Storage of long-term memory results in physical changes in the pre-synaptic termini • Habituation • Retraction of pre-synaptic termini • In Aplysia, 35 fewer connections with motor neurons and interneurons • Sensitization • Increase in number of connections • In Aplysia, 2fold increase

44. Normal Aplysia showed 1300 axon terminals on sensory neurons. Aplysia experiencing sensitization had 2800 terminals. Aplysia experiencing habituation had 800 terminals. Long-term Changes in Habituation and Sensitization

45. Long-term sensitization http://people.usd.edu/~cliff/Courses/Behavioral%20Neuroscience/Aplysia/Apfigs/ApLTS.gif

46. Long-term Memory • cAMP binds to and activates CREB • cAMP response element binding protein • MAPK may also be involved • CREB translocates to nucleus and increases gene expression of specific gene • Changes protein profile of synapse—changes in size etc

47. Feedback loop • One gene synthesized in response to CREB is ubiquitin hydroxylase • Degrades regulatory domain of PKA • Results in continuous activity of PKA • Ks is continuously phosphorylated • AP prolonged • Ca influx almost permanent • Continued release of NT

48. BDNF • Brain-derived neutrophic factor • Activated by NMDA receptor • In Aplysia, blocking BDNF—no long-term memory • Corticosteroids decrease BDNF • Role? • Activates growth of dendritic spines • Role in generation/localization of new receptors

50. Learning Pathways in Vertebrates • Uses glutamate receptors • Requires an influx of Ca2+ into the post-synaptic cleft • Ca2+ activates (directly or indirectly) three protein kinases • Calcium/calmodulin kinase II • Protein kinase C • Tryosine kinase fyn