Hmb300 h1f 2013final lecture

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Hmb300 h1f 2013final lecture

  1. 1. HMB300 - Neuroscience Try not to be afraid of CREB The CREB and flow of memory Season and Series Finale HMB300H1 - Dr. JU - Bye Class! 1
  2. 2. It’s something to be afraid of • • • • • HMB300 - Neuroscience As we last left off in the world of neuroscience CREB – another synaptic tag? Molecules, transport and cargo Fear memory – similar to other forms of memory Altering fear memory – cool story bro’ but you have to pay attention HMB300H1 - Dr. JU - Bye Class! 2
  3. 3. HMB300 - Neuroscience Be afraid, very, very afraid • Electrical stimulation of the amygdala in humans elicits fear and anxiety (Gloor et al., 1981) • Reward system from dopaminergic fibres that project from amygdala to the hippocampus? (Blum et al., 1996) • Panic attacks and aggression? Herman et al., 1992 reported that ictal fear predominant in amygdala- shows prominent EEG activity •Classic paper by Mesulam 1981 shows abnormal EEG activity with panic attacks, fear and paranormal delusions in amygdala HMB300H1 - Dr. JU - Bye Class! 3
  4. 4. HMB300 - Neuroscience So what is next? • Can we merge what we know about memory, different areas of the brain and behavioural tests Local tag? Arc? PKMzeta? HMB300H1 - Dr. JU - Bye Class! 4
  5. 5. HMB300 - Neuroscience Understanding memory (again) • One of the major tenets of memory theory, any type of memory is that groups of neurons have to be involved (a memory trace) • These neuron ensembles (groups) are very sparse however – so it makes the detection of a memory trace very challenging • Good correlation between certain neurons and memory encoding or expression but no definitive or direct proof HMB300H1 - Dr. JU - Bye Class! 5
  6. 6. HMB300 - Neuroscience Technical challenges part II • Must find a discrete area that is easily targeted that has been associated with a memory • Must be able to selectively eliminate these neurons and not others • Must also show directly, that by eliminating these neurons, you have selectively ablated those memories • Optogenetics is one approach but this is yet another very useful technique HMB300H1 - Dr. JU - Bye Class! 6
  7. 7. HMB300 - Neuroscience Back to the old model - context HMB300H1 - Dr. JU - Bye Class! 7
  8. 8. HMB300 - Neuroscience A new molecule in our repertoire • Previous work had established that a group of neurons within the lateral amygdala (LA) increased levels of CREB following auditory fear training • Have neurons in this area overexpressing CREB (both active and dominant negative as control) • Ones expressing CREB much more likely to be activated during a contextual fear training model • So within this area, can we lesion these CREB overexpressing neurons? HMB300H1 - Dr. JU - Bye Class! 8
  9. 9. HMB300 - Neuroscience CREB a central player • Know certain things about fear memory in the lateral amygdala • It is protein synthesis dependent – cycloheximide and actinomycin D • It requires GluA1 – also known as GluR1 • Other downstream molecules seem to be very important – BDNF, Arc/Arg3.1, cytoskeletal proteins, IEGs zif268,Homer1a and PKM HMB300H1 - Dr. JU - Bye Class! 9
  10. 10. HMB300 - Neuroscience Just a quick review of molecules • Activated synapses increase signaling of CaMKII AD etc. that lead to activation of MAPK (mitogen activated protein kinase) – among others... • MAPK can translocate to the nucleus to cause the increased phosphorylation of CREB • phosphoCREB is the activated transcription factor that binds to nuclear DNA sequences that contain cyclic AMP response elements (CRE) • Also binds to CREB Binding Protein (CBP) which acts to enhance activity to cause transcription of factors such as c-fos, zif268, BDNF, etc. HMB300H1 - Dr. JU - Bye Class! 10
  11. 11. Let’s take stock for a moment HMB300 - Neuroscience • Use a contextual fear response to evoke a fear memory • Neurons that are involved in LTP-like responses are express more CREB • Have a unique mouse that expresses iDTR in every cell in every part of the body including the amygdala (DTR is not normally found in mice) • Create a specific vector that incorporates both things CREB-Cre and put it into a viral vector that infects specific neurons HMB300H1 - Dr. JU - Bye Class! 11
  12. 12. HMB300 - Neuroscience Amazing specificity intraperitoneal • Mice must be made to express DT Receptor • Stereotactically nject a vector that targets LA neurons, and activates the DT Receptor but only in ones that are made to express CREB • Inject DT and the toxin works into the area and destroy selective neurons by apoptosis HMB300H1 - Dr. JU - Bye Class! 12
  13. 13. HMB300 - Neuroscience Memory consolidation molecules? Inject only in lateral amygdala loxP AD loxP All cells have inactive Rosa All cells have inactive Rosa HMB300H1 - Dr. JU - Bye Class! All cells have inactive Rosa 13
  14. 14. HMB300 - Neuroscience Sometimes napping does help Talk promotors here CaMKII Synapsin I GFAP GAD65 Specific effect, since random ablation of small number of inactive neurons (i.e. those without high levels of CREB) didn’t erase the fear memory HMB300H1 - Dr. JU - Bye Class! 14
  15. 15. HMB300 - Neuroscience Incredible effect • Rosa mouse allows specific ablation of neurons that overexpress CREB that has become associated with a learned fear response • Effects were specific and offer a different route for being able to manipulate discrete group of neurons – in this case ablation of neurons associated with a memory • Still cited as a classic paper and variations are still being published today HMB300H1 - Dr. JU - Bye Class! 15
  16. 16. HMB300 - Neuroscience For your information (FYI only) • If you want to learn more on this technique and some of the challenges associated with it check out the following paper • Han J-H, Kushner SA, Yiu AP, Cole CA, Matynia A, Brown RA, Neve RL, Guzowski JF, Silva AJ, Josselyn SA. (2007) Neuronal competition and selection during memory formation. Science 316:457-460. • Han J-H, Kushner SA, Hsiang HL, Yiu AP, Buch T, Waisman A, Bontempi B, Neve RL, Frankland PW, Josselyn SA. (2009) Selective erasure of a fear memory. Science 323:1492-1496 HMB300H1 - Dr. JU - Bye Class! 16
  17. 17. Why do my Profs suck at teaching? Almost The End HMB300H1 - Dr. JU - Bye Class! 17
  18. 18. HMB300 - Neuroscience What do you think? This family is: A) Sad B) Angry C) Happy D) Calm I agree A) Yes B) No HMB300H1 - Dr. JU - Bye Class! 18
  19. 19. HMB300 - Neuroscience Can you pick up on his vibe? This man is: A) Sad B) Angry C) Happy D) Calm I agree A) Yes B) No HMB300H1 - Dr. JU - Bye Class! 19
  20. 20. HMB300 - Neuroscience The beginnings of a theory How did you come to understand the context? • Different theories to try and understand what happens when you observe things in others • You have basically taken on the perspective of someone else • How did this occur? How did you understand the other person’s perspective? • Intuitive learning model • Theory of Mind model HMB300H1 - Dr. JU - Bye Class! 20
  21. 21. HMB300 - Neuroscience Great theory but controversial • How do we understand what is going on? • How do we process what we perceive? • Is this a simple model such as sensory perception (what we see), cognition (processing) and then turn this into action? • In many ways this process resembles what is known as the Theory of Mind HMB300H1 - Dr. JU - Bye Class! 21
  22. 22. HMB300 - Neuroscience Does your Prof understand? • Theory of Mind allows an individual to understand the mental states and belief systems of others (that may be different from their own) • Very closely associated with empathy • This may be what allows us to understand those pictures without any other clues or guidance • Our ability to understand or take on the viewpoint of others may allow us to imitate them better HMB300H1 - Dr. JU - Bye Class! 22
  23. 23. HMB300 - Neuroscience Profs unlearn this ability? • Are we born with this ability to understand others? • Do we have the innate ability to understand the intention of others? • Most researchers believe that we have to develop or learn a theory of mind • It turns out that children are incapable of truly understanding others until they reach a critical age HMB300H1 - Dr. JU - Bye Class! 23
  24. 24. HMB300 - Neuroscience Beginning of a new theory • Famous research on what is known as the falsebelief system (other individuals may have an inappropriate understanding) Wimmer, H., & Perner, J. (1983) Beliefs about beliefs: Representation and constraining function of wrong beliefs in young children's understanding of deception. Cognition, 13, 103-128 HMB300H1 - Dr. JU - Bye Class! 24
  25. 25. HMB300 - Neuroscience A simple test • One of the tests originally used to understand false beliefs in the theory of mind was known as the Sally-Anne task • There are 2 containers, 2 characters and children are asked whether one character will have a false belief or not • Can the child predict behaviour correctly? HMB300H1 - Dr. JU - Bye Class! 25
  26. 26. HMB300 - Neuroscience Playing with dolls http://www.youtube.com/watch?v=57bYqiRYxyg • Children over a certain age pass • Children with developmental problems fail (such as Autism or Asperger’s Syndrome) HMB300H1 - Dr. JU - Bye Class! 26
  27. 27. HMB300 - Neuroscience How do we account for this? • One of our central tenets in this course is that behaviour can be explained by examining the brain • How can we account for our ability to understand others, and to show empathy? • There must be a structure or structures in the brain that accounts for this • 1970s through to the 1990s HMB300H1 - Dr. JU - Bye Class! 27
  28. 28. HMB300 - Neuroscience Great mistakes – great findings • Italian neuroscientists Giacomo Rizzolatti, Vittorio Gallese, Leonardo Fogassi and colleagues studying brain and motor activity • Using electrodes, measured activity of single neurons in macaque brains in the premotor cortex • In monkeys, this area had been shown to be active during the times where monkey grasps or manipulates objects • i.e. neurons are active when monkey picks up a peanut or cracks the shell HMB300H1 - Dr. JU - Bye Class! 28
  29. 29. HMB300 - Neuroscience Strange results • Activity within the monkey premotor cortex triggers movements • In humans, stimulation of premotor cortex results in patients reporting urge to perform actions • In other words, it is part of our ability to trigger voluntary movement • Key finding came while recording in monkey brain, that when the experimenter picked up the peanut that the same neuron fired • Why should this neuron fire? • It shouldn’t! HMB300H1 - Dr. JU - Bye Class! 29
  30. 30. HMB300 - Neuroscience If you see it, you feel it • Very specific activation patterns • Not food alone • Not hand alone • Need to be performing same task and see the same task being performed • Gallese V, Fadiga L, Fogassi L, Rizzolatti G. 1996. Action recognition in the premotor cortex. Brain 119:593-609 HMB300H1 - Dr. JU - Bye Class! 30
  31. 31. Mirror neurons – so cool! HMB300 - Neuroscience • As the activity that was elicited was so specific, it was hypothesized to be an actual finding • Interestingly, only specific to a point • Later it was determined that these types of neurons – now known as mirror neurons – were activated by sound as well (Christian Keysers) • The experimenters proposed that these specific cells within the monkey’s brain could transform what they were seeing into motor programs HMB300H1 - Dr. JU - Bye Class! 31
  32. 32. HMB300 - Neuroscience Is your whole brain full of these? • Originally these mirror neurons that are activated by the actions of others were found in the area F5 (the ventral premotor cortex) • Later also found in the inferior parietal lobe What percent? Superior temporal sulcus Biological motion perception RIPL (multimodal sensory processing) Estimated around 10% HMB300H1 - Dr. JU - Bye Class! 32
  33. 33. HMB300 - Neuroscience Actions speak louder than words • Originally thought to be important for action understanding • In other words, these mirror neurons allow us to truly understand actions that we couldn’t understand just by seeing them alone (i.e. holding that cup of coffee – beyond just seeing cup and a hand) • As part of this, these neurons are also likely important for imitation and imitation learning (big proponent being the Iacoboni group HMB300H1 - Dr. JU - Bye Class! 33
  34. 34. HMB300 - Neuroscience We’re better than supercomputers • Beyond merely associating and understanding motor activities well these mirror neurons have also been proposed to be involved in intention understanding Iacoboni M., Molnar-Szakacs I., Gallese V., Buccino G., Mazziotta J.C., Rizzolatti G. 2005 Grasping the intentions of others with one's own mirror neuron system. PLoS biology, 3, e79 HMB300H1 - Dr. JU - Bye Class! 34
  35. 35. HMB300 - Neuroscience Even more complex actions? • Watch someone cut their finger? Your response? • Are mirror neurons responsible for empathy? • There is a parieto-premotor circuit that seems to be activated in response to emotions • Exposure to disgusting odours activates the insula and the anterior cingulate cortex • Interestingly watching people who showed disgust also activated the insula • Wicker B., Keysers C, Plailly J, Royet JP, Gallese V, Rizzolatti G.. (2003) Both of us disgusted in my insula: The common neural basis of seeing and feeling disgust. Neuron 40, 655-664. HMB300H1 - Dr. JU - Bye Class! 35
  36. 36. HMB300 - Neuroscience I was once a groupie • Meeting up with a Rock Star • V.S. Ramachandaran • Single-handedly proposed that these neurons are the coolest things of all time • Called them the most important discovery of the last decade • "mirror neurons will do for psychology what DNA did for biology". http://www.ted.com/talks/vs_ramachandran_the_neurons_that_shaped_civilization.html HMB300H1 - Dr. JU - Bye Class! 36
  37. 37. HMB300 - Neuroscience But can they slice and dice? • Mirror neurons have been proposed to be what allowed humans to develop language (originally proposed back in 1998) • Morality? If I can feel your pain, if I can see your point of view – it would mean that I would have to change my value systems • Still a matter of great debate HMB300H1 - Dr. JU - Bye Class! 37
  38. 38. HMB300 - Neuroscience The search for UFOs in the brain • The big question – not sure • Likely yes, but no one has yet recorded electrically from neurons in the proposed areas of the HUMAN brain • All of the studies to date have been using EEG, MEG and fMRI • Lingnau, Angelika; Gesierich, Benno; Caramazza, Alfonso (2009), "Asymmetric fMRI adaptation reveals no evidence for mirror neurons in humans", PNAS 106 (24): 9925–9930, HMB300H1 - Dr. JU - Bye Class! 38
  39. 39. HMB300 - Neuroscience And they lived happily ever after • Until this year down in UCLA • Mukamel et al. Single-Neuron Responses in Humans during Execution and Observation of Actions. Current Biology, 2010 • 1177 cells in 21 patients human medial frontal and temporal cortices (seizure patients) • patients executed or observed hand grasping actions and facial emotional expressions HMB300H1 - Dr. JU - Bye Class! 39
  40. 40. HMB300 - Neuroscience Left SMA And they lived happily ever after Medial temporal lobe right entorhinal cortex HMB300H1 - Dr. JU - Bye Class! 40
  41. 41. HMB300 - Neuroscience And they lived happily ever after • Cells in SMA respond during execution and observation of actions • Cells in medial temporal lobe respond during observation and execution of actions • Some respond with excitation during execution and inhibition during observation • Did not find evidence of such cells in the ACC, amygdala or in the pre-SMA • Did not record from F5 but SMA (lateral vs medial) HMB300H1 - Dr. JU - Bye Class! 41
  42. 42. HMB300 - Neuroscience Review of autism • • • • • • • • Developmental issues within brain Typical symptoms occur by the age of 2-3 years Poor social interactions Lack of communication/speech difficulties Repetitive almost obsessive behaviour Often exhibit echolalia Deficits in motor skills also tightly linked Genetic causes not fully established HMB300H1 - Dr. JU - Bye Class! 42
  43. 43. HMB300 - Neuroscience Super controversial • In autism, there are very poor social skills, and an inability to imitate and understand the intent of others • Could this be due to problems with mirror neurons • Anatomic evidence showing that the areas where mirror neurons are supposed to be localized are thinner or smaller in autistic patients • fMRI studies suggest that these areas are also less active during imitation in autistic children HMB300H1 - Dr. JU - Bye Class! 43
  44. 44. HMB300H1S: Keep Calm – It’sThe END Dr. Bill Ju 105C Wetmore Hall wmyh.ju@utoronto.ca theprofessor.bill@gmail.com HMB300H1 - Dr. JU - Bye Class! 44
  45. 45. HMB300 - Neuroscience Useful or useless? HMB300H1 - Dr. JU - Bye Class! 45
  46. 46. HMB300 - Neuroscience This was all that I knew HMB300H1 - Dr. JU - Bye Class! 46
  47. 47. HMB300 - Neuroscience Nowadays Spinning disc lasers HMB300H1 - Dr. JU - Bye Class! 47
  48. 48. HMB300 - Neuroscience Even more mind-blowing HMB300H1 - Dr. JU - Bye Class! 48
  49. 49. HMB300 - Neuroscience I feel like I’m living in a Sci-Fi story THG microscopy HMB300H1 - Dr. JU - Bye Class! 49
  50. 50. HMB300 - Neuroscience In living animals HMB300H1 - Dr. JU - Bye Class! 50
  51. 51. HMB300 - Neuroscience New developments all the time HMB300H1 - Dr. JU - Bye Class! 51
  52. 52. HMB300 - Neuroscience What my students picked • • • • • • • Stem cell therapy Brain machine interfaces Imaging studies (human and research) Machine and artificial intelligence Beyond fMRI RNAi technology Nanotechnology including brain nanotechnology HMB300H1 - Dr. JU - Bye Class! 52
  53. 53. HMB300 - Neuroscience And now for the Glogster Awards • Thanks for your continued excellence • Amazing material – best I’ve seen and amazing! • Very creative and I’m glad I didn’t have to choose • All of you did so well but your peers have nominated: • Then off to Project Impact HMB300H1 - Dr. JU - Bye Class! 53
  54. 54. HMB300 - Neuroscience Content Comprehensiveness HMB300H1 - Dr. JU - Bye Class! 54
  55. 55. HMB300 - Neuroscience Visual Appeal HMB300H1 - Dr. JU - Bye Class! 55
  56. 56. HMB300 - Neuroscience Best Linked HMB300H1 - Dr. JU - Bye Class! 56
  57. 57. Student’s Choice HMB300H1 - Dr. JU - Bye Class! HMB300 - Neuroscience 57
  58. 58. HMB300 - Neuroscience Most Nominated (Other) • • • • • • Alison Boven Shana Kim Bahar Amani Xiao Yu Arya Abdool Cynthia Xu HMB300H1 - Dr. JU - Bye Class! 58
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  67. 67. Your final exam • 20 MCQs – more on this online • 4 SA (with parts – longer – the current online assignment) • 2 hours long – you will need the time • Tutorial scheduled for 11th and 12th • Sample questions will be posted Dec. 9th HMB300H1 - Dr. JU - Bye Class! 67
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