Learning and Memory

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Learning and Memory
Memory is not a single phenomenon-- several
related mechanisms exist associative memory is
learning which links a stimulus to a response
Classical (Pavlovian)- links a neutral stimulus
to a noxious one conditioned stimulus (neutral)
and unconditioned (noxious) one operant
(instrumental)- links an innate behavior to a
consequence ie. reinforcing stimulus generates
some desired consequence Pavlov linked a bell
ringing to food cats coming when cat food is
opened cars stopping at red lights to avoid a
ticket
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Learning and Memory
non-associative learning changes a normal
behavior into something else habituation loss
of response to a normally bad stimulus by
repetition dishabituation recovery of a
habituated response using another
stimulus sensitization augmentation of some
response to a strong stimulus
sensitization
habituation
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Aplysia Sea Slugs Teach Us About Learning
Aplysia have a simple nervous system with
identifiable neurons have several behaviors
which can be modified by learning behavioral
modifications can be short or long term depending
upon the length of the training period 3
parts of sensitization 1) induction-- initial
triggering events 2) expression-- how is the
modified behavior shown 3) maintenance-- how
behavior is changed to last over time
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Aplysia Sea Slugs Teach Us About Learning
short term sensitization lasts for minutes and
requires a short induction heterosynaptic
facilitation release of modulatory
neurotransmitters from different interneurons
regulating sensory neuron connections to other
neurons (interneurons as well as motor
neurons) metabotropic serotonin receptors
linked to cAMP, activating PKA PKA
phosphorylates K channels, reducing their
activity and causing neurons to slowly
depolarize PKA also mobilizes more vesicles to
be released at synapses, increasing their
ability to release transmitter
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Aplysia Sea Slugs Teach Us About Learning
DAG is also activated by serotonin DAG
activates protein kinase C, changing K and Ca
channels to broaden action potentials key
common step one transmitter activates several
second messengers short term sensitization only
lasts as long as the kinases are active and
target proteins are phosphorylated
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Aplysia Sea Slugs Teach Us About Learning
long term sensitization requires extended
training to initiate- at least 1 hr long term
sensitization happens AFTER short term
sensitization-- must change for a short time
before it can last longer-- uses same
proteins requires new RNA transcription and
new protein translation CREB (cAMP response
element binding protein) is phosphorylated
and binds DNA, aiding transcription MAP kinase
also activated by 5-HT3 10 genes required for
activation required to convert short term to
long term memories-- consolodation
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Aplysia Sea Slugs Teach Us About Learning
long term changes become permanent by changing
synaptic structure ApCAM cell adhesion molecule
is reduced at transcriptional and cell surface
level (endocytosis of receptor) BMP-like
protein receptor work together to stimulate new
axon growth along with TGF-b family
factors short and long term changes may have
several intermediates
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Aplysia Sea Slugs Teach Us About Learning
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Aplysia Sea Slugs Teach Us About Learning
gill withdrawal is another mechanism which has
shown learning behavior unconditioned stimuli
(US) are paired with conditioned stimuli
(CS) when the 2 stimuli are paired, the
conditioned response is enhanced by the
unconditioned stimulus 2 synapses on
postsynaptic cell must be coactive-- mediated by
NMDA receptors and initiates retrograde signals
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Long Term Potentiation
LTP persistent increase in synaptic strength
caused by a train of presynaptic action
potentials (can last weeks-months in
vivo) originally studied in the hippocampus, but
occurs in many regions stimulate CA3 axons with
a tetanus, or train of action potentials
response in CA1neurons can also activate
Schaeffer collaterals onto CA1 neurons
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Long Term Potentiation
LTP is cooperative, associative, and
specific associative requires stimulation of a
'strong' pathway to induce LTP in the 'weak'
one cooperative stronger the stimulation, the
more likely LTP is to be induced specific
only inputs receiving a tetanus form LTP
other synapses NOT potentiated tetanus work
together stimulating a neuron in a Hebbian
fashion, strengthening synapses not all forms of
LTP seem to be Hebbian
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Long Term Potentiation
LTP requires a pre- or post-synaptic calcium ion
increase both NMDA receptors and voltage gated
Ca channels can cause LTP depending upon the
system studied AP-5 or MK-801 blockers of the
NMDA receptor prevents LTP
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Long Term Potentiation
non-NMDA dependent LTP uses voltage gated calcium
channels occurs over a longer time (20-30
minutes to onset) can coexist at the same
synapses as NMDA dependent LTP longer term LTP
requires new gene transcription and protein
translation just like Aplysia also requires MAP
kinase and CREB activation as well many genes
are activity regulated in mammals
neurotensin knockout mice generate easier LTP
in the amygdala
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Long Term Potentiation
LTP at CA3-CA1 synapses is mediated by of AMPA
receptors more transmitter receptors gives
more depolarization phosphorylation also
increases AMPA receptor conductance initial LTP
requires kinases and phosphatases- PKC and
CaMK2 seem particularly important late LTP
requires new proteins several dozen genes are
induced including transcription factors,
cytoskeletal proteins, kinases, receptors, and
signaling molecules
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Long Term Potentiation
synaptic tagging marking a synapse to be
potentiated and recruiting newly synthesized
proteins to the correct site a weak tetanus
which by itself may not generate LTP can
mark a synapse for potentiation IF a
different input activates transcription
must happen in a limited time window (approx.
1 hr)
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Long Term Potentiation
LTP has been difficult to link directly to
learning-- technically difficult synaptic
changes linked directly to a learned behavior
are simply too small to detect in a complex
nervous system drug changes may affect systems
outside of the targetted synapse memory is
likely to be distributed over multiple
coactive synapses distribution allows partial
activation to effectively mimic the output
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Long Term Depression
just as synapses can be strengthened, low
frequency stimulation over time causes
synapses to be weakened dephosphorylation and
endocytosis of AMPA receptors mediates LTD both
LTP and LTP require calcium signaling in
dendrites as well as second messenger
activation LTD and LTP are complimentary and
contradictory- potentiated synapses can be
depresssed and vice versa