Neuroscience: Exploring the
Brain, 3e
Chapter 25: Molecular Mechanisms of Learning and
Memory
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Introduction
• Neurobiology of memory
– Identifying where and how different types of
information are stored
• Hebb
– Memory results from synaptic modification
• Study of simple invertebrates
– Synaptic alterations underlie memories
(procedural)
• Electrical stimulation of brain
– Experimentally produce measurable synaptic
alterations - dissect mechanisms
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Procedural Learning
• Procedural memories amenable
to investigation
• Nonassociative Learning
– Habituation
• Learning to ignore
stimulus that lacks
meaning
– Sensitization
• Learning to intensify
response to stimuli
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Procedural Learning
• Associative Learning
– Classical Conditioning: Pair an unconditional stimulus
(UC) with a conditional stimulus (CS) to get a
conditioned response (CR)
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Procedural Learning
• Associative Learning (Cont’d)
– Instrumental Conditioning
• Learn to associate a response with a meaningful
stimulus, e.g., reward lever pressing for food
• Complex neural circuits related to role played by
motivation
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Simple Systems: Invertebrate Models of
Learning
• Experimental advantages in using invertebrate nervous
systems
– Small nervous systems
– Large neurons
– Identifiable neurons
– Identifiable circuits
– Simple genetics
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Simple Systems: Invertebrate
Models of Learning
• Nonassociative Learning in Aplysia
– Gill-withdrawal reflex
– Habituation
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Simple Systems: Invertebrate Models of Learning
• Nonassociative Learning in Aplysia (Cont’d)
– Habituation results from presynaptic modification at L7
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Simple Systems: Invertebrate Models of Learning
• Nonassociative Learning in Aplysia (Cont’d)
– Repeated electrical stimulation of a sensory neuron leads
to a progressively smaller EPSP in the postsynaptic motor
neuron
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Simple Systems: Invertebrate Models of Learning
• Nonassociative Learning in Aplysia (Cont’d)
– Sensitization of the Gill-Withdrawal Reflex involves L29
axoaxonic synapse
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Simple Systems: Invertebrate Models of Learning
• Nonassociative Learning in
Aplysia (Cont’d)
– 5-HT released by L29 in
response to head shock
leads to G-protein coupled
activation of adenylyl
cyclase in sensory axon
terminal.
– Cyclic AMP production
activates protein kinase A.
– Phosphate groups attach to
a potassium channel,
causing it to close
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Simple Systems: Invertebrate Models of Learning
• Nonassociative Learning in
Aplysia (Cont’d)
– Effect of decreased
potassium conductance in
sensory axon terminal
– More calcium ions admitted
into terminal and more
transmitter release
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Simple Systems: Invertebrate Models of Learning
• Associative Learning in Aplysia
–
Classical conditioning: CS
initially produces no response
but after pairing with US,
causes withdrawal
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Simple Systems: Invertebrate Models of Learning
• The molecular basis for classical conditioning in Aplysia
–
Pairing CS and US causes greater activation of adenylyl cyclase
because CS admits Ca2+ into the presynaptic terminal
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Vertebrate Models of Learning
• Neural basis of memory: principles learned from
invertebrate studies
– Learning and memory can result from modifications
of synaptic transmission
– Synaptic modifications can be triggered by
conversion of neural activity into intracellular second
messengers
– Memories can result from alterations in existing
synaptic proteins
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Vertebrate Models of Learning
• Synaptic Plasticity in the Cerebellar Cortex
– Cerebellum: Important site for motor learning
– Anatomy of the Cerebellar Cortex
• Features of Purkinje cells
• Dendrites extend only into molecular layer
• Cell axons synapse on deep cerebellar nuclei
neurons
• GABA as a neurotransmitter
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Vertebrate Models of Learning
• The structure of the cerebellar cortex
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Vertebrate Models of Learning
• Cancellation of expected reafference in the electrosensory
cerebellum of skates- synaptic plasticity at parallel fiber
synapses.
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Vertebrate Models of Learning
• Synaptic Plasticity in the Cerebellar Cortex
– Long-Term Depression in the Cerebellar Cortex
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Vertebrate Models of Learning
• Synaptic Plasticity in the Cerebellar Cortex (Cont’d)
– Mechanisms of cerebellar LTD
• Learning
• Rise in [Ca2+]i and [Na+]i and the activation of
protein kinase C
• Memory
• Internalized AMPA channels and depressed
excitatory postsynaptic currents
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Vertebrate Models of Learning
• Synaptic Plasticity in the Cerebellar Cortex (Cont’d)
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Vertebrate Models of Learning
• Synaptic Plasticity in the Cerebellar Cortex (Cont’d)
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Vertebrate Models of Learning
• Synaptic Plasticity in the Hippocampus
– LTP and LTD
• Key to forming declarative memories in the brain
– Bliss and Lomo
• High frequency electrical stimulation of excitatory
pathway
– Anatomy of Hippocampus
• Brain slice preparation: Study of LTD and LTP
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Vertebrate Models of Learning
• Synaptic Plasticity in the Hippocampus (Cont’d)
– Anatomy of the Hippocampus
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Vertebrate Models of Learning
• Synaptic Plasticity in the Hippocampus (Cont’d)
– Properties of LTP in CA1
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Vertebrate Models of
Learning
• Synaptic Plasticity in the
Hippocampus (Cont’d)
– Mechanisms of LTP in CA1
• Glutamate receptors
mediate excitatory
synaptic transmission
• NMDA receptors and
AMPA receptors
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Vertebrate Models of Learning
• Synaptic Plasticity in the Hippocampus (Cont’d)
– Long-Term Depression in CA1
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Vertebrate Models of Learning
• Synaptic Plasticity in the
Hippocampus (Cont’d)
– BCM theory
• When the postsynaptic cell is
weakly depolarized by other
inputs: Active synapses
undergo LTD instead of LTP
• Accounts for bidirectional
synaptic changes (up or
down)
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Vertebrate Models of Learning
• Synaptic Plasticity in the Hippocampus (Cont’d)
– LTP, LTD, and Glutamate Receptor Trafficking
• Stable synaptic transmission: AMPA receptors are
replaced maintaining the same number
• LTD and LTP disrupt equilibrium
• Bidirectional regulation of phosphorylation
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Vertebrate Models of Learning
• LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)
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Vertebrate Models of Learning
• LTP, LTD, and Glutamate Receptor Trafficking (Cont’d)
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Vertebrate Models of Learning
• Synaptic Plasticity in the Hippocampus (Cont’d)
– LTP, LTD, and Memory
• Tonegawa, Silva, and colleagues
• Genetic “knockout” mice
• Consequences of genetic deletions (e.g., CaMK11
subunit)
• Advances (temporal and spatial control)
• Limitations of using genetic mutants to study
LTP/learning: secondary consequences
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The Molecular Basis of
Long-Term Memory
• Phosphorylation as a long term
mechanism:Persistently Active
Protein Kinases
– Phosphorylation maintained:
Kinases stay “on”
• CaMKII and LTP
• Molecular switch
hypothesis
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The Molecular Basis of Long-Term Memory
• Protein Synthesis
– Protein synthesis required for formation of long-term
memory
• Protein synthesis inhibitors
• Deficits in learning and memory
– CREB and Memory
• CREB: Cyclic AMP response element binding
protein
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The Molecular Basis of Long-Term Memory
• Protein Synthesis (Cont’d)
– Structural Plasticity and Memory
• Long-term memory associated with transcription
and formation of new synapses
• Rat in complex environment: Shows increase in
number of neuron synapses by about 25%
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Concluding Remarks
• Learning and memory
–
Occur at synapses
• Unique features of Ca2+
– Critical for neurotransmitter secretion and muscle
contraction, every form of synaptic plasticity
– Charge-carrying ion plus a potent second messenger
• Can couple electrical activity with long-term
changes in brain
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End of Presentation
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Simple Systems: Invertebrate Models of Learning
• The molecular basis for classical conditioning in Aplysia
– Pairing CS and US causes greater activation of
adenylyl cyclase because CS admits Ca2+ into the
presynaptic terminal
Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins
Simple Systems: Invertebrate Models of Learning
• Associative Learning in Aplysia
–
Classical conditioning: CS initially produces no
response but after pairing with US, causes withdrawal
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Vertebrate Models of Learning
• Synaptic Plasticity in Human area IT
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