Hmb300 h1f 2013final lecture

HMB300 - Neuroscience

Try not to be afraid of CREB
The CREB and flow of memory
Season and Series Finale

HMB300H1 - Dr. JU - Bye Class!

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It’s something to be afraid of
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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


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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

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So what is next?
• Can we merge what we know about memory,
different areas of the brain and behavioural tests
Local tag? Arc?

PKMzeta?


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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


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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

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Back to the old model - context


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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?


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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

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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.

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Let’s take stock for a moment


• 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

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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

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Memory consolidation molecules?
Inject only in lateral amygdala

loxP

AD

loxP

All cells have inactive Rosa


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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

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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


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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

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Why do my Profs suck at teaching?
Almost The End


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What do you think?
This family is:
A) Sad
B) Angry
C) Happy
D) Calm
I agree
A) Yes
B) No

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Can you pick up on his vibe?
This man is:
A) Sad
B) Angry
C) Happy
D) Calm
I agree
A) Yes
B) No

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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

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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


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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


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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


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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


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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?


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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)

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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


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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

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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!

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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

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Mirror neurons – so cool!


• 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


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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%


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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

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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

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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.

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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

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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


37


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,


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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


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Left SMA


Medial temporal lobe
right entorhinal cortex


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• 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)

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Review of autism
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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


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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


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HMB300H1S:
Keep Calm – It’sThe END
Dr. Bill Ju
105C Wetmore Hall
wmyh.ju@utoronto.ca
theprofessor.bill@gmail.com

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Useful or useless?


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This was all that I knew


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Nowadays

Spinning disc lasers


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Even more mind-blowing


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I feel like I’m living in a Sci-Fi story

THG microscopy

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In living animals


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New developments all the time


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What my students picked
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Stem cell therapy
Brain machine interfaces
Imaging studies (human and research)
Machine and artificial intelligence
Beyond fMRI
RNAi technology
Nanotechnology including brain nanotechnology


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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


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Content Comprehensiveness


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Visual Appeal


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Best Linked


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Student’s Choice



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Most Nominated (Other)
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Alison Boven
Shana Kim
Bahar Amani
Xiao Yu
Arya Abdool
Cynthia Xu


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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


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Hmb300 h1f 2013final lecture

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