Memory2
- 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
- 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
- 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
- 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