Molecular Mechanisms of Learning and Memory

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Molecular Mechanisms of Learning and Memory
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Procedural Learning

• Learning a motor response (procedure) in relation
  to a sensory input
• Two types
• Nonassociative learning
• Associative learning

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Contrast to Declarative Memory

• Declarative Memory
• Easily formed and easily forgotten
• Created by small modifications of synapses
• Widely distributed in the brain
• Difficult to study
• Procedural Memory
• Is robust (not easily lost)
• Can be formed along simple reflex pathways
• Easier to study

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Nonassociative Learning

• A change in behavior over time in response to a
  single type of stimulus
• Two types
• Habituation
• Learning to ignore a stimulus that lacks meaning
• The response to a repeated stimulus decreases
• Sensitization
• A strong sensory stimulus can intensify your
  response to all stimuli
• The response to a given stimulus increases

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Associative Learning

• Formation of associations between two events
• Two Types
• Classical conditioning
• associating an effective, response-evoking
  stimulus with a second, normally ineffective
  stimulus
• Pavlovs dogs
• Instrumental conditioning
• associating a motor action with a stimulus
• pressing a lever produces a food pellet

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Invertebrate Systems

• Provide models to study learning behavior
• Small nervous systems
• perhaps 1000 neurons, 107 fewer than humans
• Large neurons
• easy to study electro-physiologically
• Identifiable neurons
• can be identified from animal to animal
• Identifiable circuits
• identifiable neurons make the same connections
  with one another from animal to animal
• Simple genetics
• small genomes and short life cycles

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Aplysia as a Model for Learning

• The sea slug Aplysis californica, is used for
  studies in neurobiology
• Exhibits simple forms of learning, including
  habituation, sensitization, and classical
  conditioning

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Aplysia Nonassociative Learning

• Gill withdrawal reflex
• A jet of water squirted on a portion of the slug
  (the siphon) causes withdrawal of the siphon
  the gill
• Habituation
• After repeated trials, effect is diminished

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What Causes Habituation?

• Motor neuron, L7, receives direct sensory input
  from the siphon innervates muscles used for
  gill withdrawal
• Showed that habituation occurs at the synapse
  between sensory motor neuron
• Progressive decrease in the size of excitatory
  postsynaptic potentials (EPSP's)
• Mechanism
• less calcium enters presynaptic terminal
• so fewer transmitter molecules are released
• Therfore presynaptic modification

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Neurons in Habituation
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Gill Withdrawal Reflex Sensitization

• Shock to head associated with stimulation of
  siphon increases gill withdrawal reflex
  sensitization
• How does this work?
• Neuron from head (L29) synapses on the axon
  terminal of the sensory neuron
• Releases serotonin
• Causes molecular cascade that sensitizes sensory
  axon terminal

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Neurons in Sensitization
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Sensitization Cascade

• Serotonin receptor on the sensory axon terminal
  is a G-protein coupled receptor
• Binding activates adenylyl cyclase enzyme
• Which produces cyclic AMP (2nd messenger)
• Which activates protein kinase A (PKA)
• Which phosphorylates a protein forming the
  potassium channel
• Which causes it to close
• Prolonging the presynaptic action potential
• So more calcium enters
• Thus more neurotransmitters are released

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Associative Learning in Aplysia

• Classical conditioning
• Unconditioned stimulus shock to tail
• Conditioned stimulus siphon stimulation
• If the 2 stimuli were paired, subsequent gill
  withdrawal response to siphon stimulation alone
  was greater
• Uses same neuron as sensitization, through an
  interneuron

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Molecular Mechanism

• CS response (gill withdrawal) results from influx
  of calcium ions
• US (tail shock) causes G-protein coupled
  activation of adenylyl cyclase
• Elevated Ca causes adenylyl cyclase to make
  more cAMP
• This increases total cascade, resulting in more
  neurotransmitter release
• Learning occurs when presynaptic Ca release
  coincides with G-protein activation of adenylyl
  cyclase producing abundant cAMP
• Memory occurs when K channels are phosporylated
  increasing transmittere release

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Molecular Changes Memory

• One synapse affects another synapse.
• Short term memory can be produced when a weak
  stimulus causes phosphorylation of ion channels,
  leading to release of an increased amount of
  transmitter.
• Long term memory requires a stronger and more
  long-lasting stimulus causing increased cAMP,
  which causes further activation of protein
  kinases.

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Visualizing Memory Changes

• Short-term memory
• thin arrows in the left lower part of the figure
• Long-term memory
• bold arrows

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Lessons Learned

• Learning and memory can result from modification
  of synaptic transmission
• Synaptic modifications can be triggered by
  conversion of neural activity to 2nd messengers
• Memories can result from alterations in existing
  synaptic proteins

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Vertebrate Models of Learning

• The cerebellum, because of its role in motor
  control, is a model system to study synaptic
  basis of learning in higher organisms
• Site of motor learning
• Place where corrections of movement are made

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Anatomy of the Cerebellar Cortex

• 2 layers of neuronal cell bodies
• Purkinje cell layer
• Granule cell layer
• Purkinje cells
• modify the output of the cerebellum
• Use GABA so influence is inhibitory
• Fibers
• Climbing fibers
• innervate Purkinje cell from inferior olive
• Mossy fibers
• innervate granule cells from pons 11
• Parallel fibers from granule cells
• innervate Purkinje cell 100,0001

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Layers of Cerebellar Cortex
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Long Term Depression (LTD)

• Occurs when climbing fibers and parallel fibers
  are active together
• Molecular mechanism
• Climbing fiber activation causes surge of Ca
  into Purkinje cell
• Glutamate from parallel fiber activates AMPA
  receptor (glutamate receptor that mediates
  excitatory transmission)
• Na increases
• But this process employs a second receptor . . .

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Mechanism of LTD (cont.)

• There is a second glutamate receptor postsynaptic
  to the parallel fibers metabotropic glutamate
  receptor
• G-protein-coupled to enzyme phospholipase C.
  (PLC)
• Which catalyzes formation of a second messenger,
  diacylglycerol (DAG)
• Which activates protein kinase C (PKC)
• Analogous to what happens in classical
  conditioning in Aplysia

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Molecular Changes in Learning Memory

• Learning occurs when the three things happen
  together
• Elevated Ca due to climbing fiber activation
• Elevated Na due to AMPA receptor activation
• Activated PKC due to metabotropic receptor
  activation
• Memory results from changes in AMPA receptor due
  to PKC - decrease AMPA openings

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Declarative Memory the Hippocampus

• Declarative memory relies on the neocortex and
  structures in the medial temporal lobe, including
  the hippocampus
• Long-term potentiation (LTP)
• Brief high-frequency electrical stimulation of a
  pathway to the hippocampus produces long lasting
  increase in strength of stimulated synapses
• LTD also found in the hippocampus
• LTP LDP may be the basis of how declarative
  memories form in the brain

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Anatomy of the Hippocampus

• Two thin sheets of neurons folded on each other
• Dentate gyrus
• Ammons horn
• Has 4 divisions
• CA3 CA1 are important here

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Connections in the Hippocampus

• Entorhinal cortex connects to the hippocampus via
  axons called the perforant path
• Mossy fibers from the dentate gyrus synapses on
  CA3
• CA3 cells synapse via Schaffer collateral on
  cells in CA1 region
• Both CA3 and CA1 cells have output fibers to the
  fornix

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Hippocampus Structure
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Long Term Potentiation (LTP)

• LTP occurs in CA1 when multiple synapses are
  active at the same time that the CA1 cell is
  depolarized
• Recall that glutamate receptors are responsible
  for excitatory transmission in the hippocampus

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Mechanism of LTP

• Glutamate released from synapse
• Na ions pass through the AMPA receptor causing
  EPSPs
• CA1 neurons also have post synaptic
  N-methyl-D-aspartate (NMDA) receptors
• These conduct Ca ions when cell is depolarized
• Thus Ca entering the NMDA receptor indicates
  that presynaptic postsynaptic elements are
  active at the same time

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Induction of LTP

• Rise in postsynaptic Ca linked to LTP
• LTP induction is prevented if NMDA receptors are
  inhibited
• Rise in Ca activates 2 protein kinases
• Protein kinase C
• Clacium-calmodulin-dependent protein kinase II
  (CaMKII)
• Inhibition of either of these blocks long term
  potentiation
• Following LTP a single axon may form multiple new
  synapses on a single postsynaptic neuron

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Long Term Depression (LTD)

• LTD occurs in CA1 when it is only weakly
  depolarized by other inputs
• Inward calcium levels are lower, activating a
  different enzymatic response
• Thus, LTP and LTD are two responses of the same
  system

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LTD, LTP, Memory

• LTP LDP are mechanisms of synaptic plasticity
• They may contribute to the formation of
  declarative memory
• Recordings from inferotemporal cortex slices from
  humans shows the same kind of interplay of LTP
  and LTD
• Rats with damage to the hippocampus show reduced
  learning in Morris water maze
• Injecting an NMDA-blocker into rats produces the
  same reduction of learning

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Molecular Basis of Long-term Memory

• Molecular mechanisms all involve the
  phosphorylation of something
• Phosphorylation is not permanent
• phosphate groups get removed, erasing memory
• Proteins themselves are not permanent, but get
  replaced

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Persistently Active Protein Kinases

• Maybe memory is a turned on protein kinase
• For LTP in CA1 in the hippocampus, an enzyme
  activating CaMKII may autophosphorylate and then
  just stay on
• Molecular switch hypothesis - autophosphorylating
  kinase could store information at the synapse

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Protein Synthesis Memory Consolidation

• Inhibitors of protein synthesis block
  consolidation in experimental animals, both
  mammals and Aplysia
• Suggests some new protein must arrive to make
  short-term changes permanent

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CREB Memory

• (CREB)   cAMP response element binding protein
• CREB regulates gene expression on DNA
• CREB regulated gene expression is essential for
  consolidation in the fruit fly
• Similar results have been shown in Aplysia
• CREB may be able to regulate the strength of a
  memory

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Structural Plasticity Memory

• In Aplysia long-term learning involves the
  addition of synapses
• forgetting is the deletion of synapses
• Some indication that such changes occur in
  mammals, despite being past the critical period
  for developmental plasticity