Memory2

Molecular Mechanisms of Learning and Memory

Procedural Learning

• Learning a motor response (procedure) in relation to a sensory input

• Two types:– Nonassociative learning– Associative learning

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

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

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

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

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

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

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

Neurons in Habituation

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

Neurons in Sensitization

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

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

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

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.

Visualizing Memory Changes

• Short-term memory– thin arrows in the

left lower part of the figure

• Long-term memory– bold arrows

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

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

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

Layers of Cerebellar Cortex

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 . . .

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

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

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

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

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

Hippocampus Structure

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

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

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

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

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

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

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

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

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

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