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Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
Memory2
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Memory2
Memory2
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Memory2

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  • 1. Molecular Mechanisms of Learning and Memory
  • 2. Procedural Learning
    • Learning a motor response (procedure) in relation to a sensory input
    • Two types:
      • Nonassociative learning
      • Associative learning
  • 3. 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
  • 4. 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
  • 5. Associative Learning
    • Formation of associations between two events
    • Two Types:
    • Classical conditioning
      • associating an effective, response-evoking stimulus with a second, normally ineffective stimulus
      • Pavlov’s dogs
    • Instrumental conditioning
      • associating a motor action with a stimulus
      • pressing a lever produces a food pellet
  • 6. Invertebrate Systems
    • Provide models to study learning & behavior:
    • Small nervous systems
      • perhaps 1000 neurons, 10 7 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
  • 7. 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
  • 8. 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
  • 9. 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
  • 10. Neurons in Habituation
  • 11. 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
  • 12. Neurons in Sensitization
  • 13. Sensitization Cascade
    • Serotonin receptor on the sensory axon terminal is a G-protein coupled receptor
    • Binding activates adenylyl cyclase enzyme
    • Which produces cyclic AMP (2 nd 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
  • 14. 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
  • 15. 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
  • 16. 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.
  • 17. Visualizing Memory Changes
    • Short-term memory
      • thin arrows in the left lower part of the figure
    • Long-term memory
      • bold arrows
  • 18. Lessons Learned
    • Learning and memory can result from modification of synaptic transmission
    • Synaptic modifications can be triggered by conversion of neural activity to 2 nd messengers
    • Memories can result from alterations in existing synaptic proteins
  • 19. 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
  • 20. 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 1:1
    • Parallel fibers from granule cells
      • innervate Purkinje cell 100,000:1
  • 21. Layers of Cerebellar Cortex
  • 22. 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 . . .
  • 23. 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
  • 24. 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
  • 25. 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
  • 26. Anatomy of the Hippocampus
    • Two thin sheets of neurons folded on each other:
    • Dentate gyrus
    • Ammon’s horn
      • Has 4 divisions
      • CA3 & CA1 are important here
  • 27. 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
  • 28. Hippocampus Structure
  • 29. 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
  • 30. 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
  • 31. 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
  • 32. 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
  • 33. 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
  • 34. 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
  • 35. 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
  • 36. 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
  • 37. 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
  • 38. 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

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