MOLECULAR MECHANISMS OF

LEARNING AND MEMORY

Chapter 25Jack Whylings

TYPES OF LEARNING

Declarative Memory: Facts and events

Procedural: Skills, emotional learning

PROCEDURAL LEARNINGNon-associative

Habituation: decreasing response to a repeated stimulusAllows organisms to ignore unimportant stimuli

e.g: Wearing clothesSensitization: increasing response to all stimuli after an intense stimuluse.g.: Loud noises make you more sensitive to everything else

Allows organisms to respond quickly in possibly dangerous situations

AssociativeClassical Conditioning: Associating a “meaningless” stimulus with a meaningful onee.g: Pavlov’s dogs

Instrumental Conditioning: Associating an action with an outcomee.g.: Lever-pressing

INVERTEBRATE LEARNING

Why use invertebrate models?Small Nervous SystemsLarge, identifiable neurons and circuits

Simple genetics

Aplysia (Aplysia californica) is one model species ued in studying neuronal circuits

What types of learning studied?HabituationSensitizationClassical Conditioning

HABITUATION IN APLYSIA

Touching Aplysia’s siphon causes it to retract its gill

Repeated touching causes Aplysia to habituate to thisNo more retraction

http://youtu.be/yLa-cXg8BwM?t=43s

HABITUATION IN APLYSIA

Where in circuitry could habituation occur?Sensory endings in skinSynapse between sensory and motor neuronNeuromuscular junction

Repeated touches don’t change the firing of the sensory neuron

Repeated motor neuron stimulation doesn’t change muscle contraction

Stimulating the presynaptic sensory neuron causes reduced responses from the postsynaptic motor neuron

HABITUATION IN APLYSIA

How could habituation happen at the synapse?Presynaptic MechanismsReduction of NT releasedLess vesiclesLess NT/vesicle

Postsynaptic MechanismReduction in effectiveness of neurotransmitterLess receptorsReceptors less effective

How would you test these?

HABITUATION IN APLYSIA

Habituation is a presynaptic process (in this instance)Repeated action potentials result in less Ca2+ influx into the cell

Less Ca2+ means less vesicle binding

SENSITIZATION IN APLYSIA

When a stimulus causes stronger reactions to other stimuli

Noxious Stimulus: Head shockResponse: exaggerated gill withdrawal in response to siphon touch

Sensory input from head must feed into gill withdrawal circuit

SENSITIZATION IN APLYSIA

L29 is neuron that feeds information into gill circuitUses Serotonin as its neurotransmitter

Serotonin causes strengthening of motor neuron responseSerotonin causes increase of Ca2+ into presynaptic terminal

SENSITIZATION IN APLYSIA

Mechanism of Serotonin Action

Serotonin binds to metabotropic receptor (G-protein coupled)

G-protein activates Adenylyl Cyclase

Adenylyl Cyclase converts ATP to cAMP

cAMP activates Protien Kinase A

Protien Kinase A phosphorylates potassium channels, inhibiting them

Less K+ outflux, longer action potential, more Ca2+ in cell

CONDITIONING IN APLYSIA

Aplysia are also capable of associative learningDifferent from sensitizationTiming is important

Combining tail shock (US) with gentle siphon touch (CS) would condition aplysiaFuture gentle touch would cause gill withdrawalAssociation only there if US and CS were close in time

Mechanism is still through serotonergic input

CONDITIONING IN APLYSIA

Serotonin from L29 causes increase in cAMPSame as in sensitization

If combined with depolarization, causes Ca2+ influx

Ca2+ causes adenylyl cyclase to produce cAMP much faster

Results in more phosphorylated K+ channels

VERTEBRATE LEARNING

Vertebrate learning is more complexChallenging to directly connect behavior with cellular mechanisms

Non-associative learningHappens pre- and post-synaptically

Associative LearningLong-term changes

Hippocampus is involved in learning and memory

Molecular mechanisms best understood in hippocampusEasy anatomy to study

HIPPOCAMPUS

Entorhinal Cortex inputs onto hippocampus through the perforant pathSynapse on Dentate gyrus neurons

Dentate Gyrus axons form mossy fibersSynapse onto CA3 pyramidal cellsCA means cornu Ammonis, or Ammon’s Horn

CA3 axons for Schaeffer CollateralSynapse onto CA1 pyramidal cells

All of these paths are in same plane

ASSOCIATIVE LEARNING

Associative learning causes permanent changes in communication

Are these changes really memory?Removing key players in the system affects memory-based tasks

Two forms of learning in hippocampusLong-term potentiation: A permanent strengthening of a synapse

Long-term depression: A permanent weakening of a synapse

LTP

Neurons that fire together, wire together

Experimental Set-upRecord from postsynaptic neuronCause presynaptic neuron to fire

Give tetanus from pre-synaptic neuronBurst of high-frequency firing

After tetanus, postsynaptic neuron has stronger response to presynaptic input

LTPAssociative LTP: Multiple

synapses firing together strengthen each-otherAnalogous to classical conditioning

A “strong” synapse can fire with a “weak” synapse and turn the weak synapse into a strong one

LTP

LTP uses both AMPA and NMDA receptors

AMPA receptorsGlutamate receptorsAllow Na+ and K+ throughExcitatory

NMDA receptorsGlutamate receptorsVoltage gated: cell must be depolarized

Allow Na+, K+, and Ca2+ into cell

LTP

One release of glutamate opens AMPA channels, but not NMDA channels

Repeated releases of glutamate would open both channels, and allow Ca2+ into cell

Ca2+ causes LTPBlocking calcium prevents LTP

LTP

LTP is mediated by calcium

Ca2+ activates protein kinasesProtien Kinase CCalcium-calmodulin-dependent protein kinase II (CamKII)

Phosphoyrlation of AMPA channels increases their effectiveness

CamKII can increase the number of AMPA channels in the membrane

Ca2+ dependent mechanisms can cause pre-synaptic changes

LTPAre those mechanisms really

permanent?Phosphorylation doesn’t last forever

CamKII can autophosphorylateKeeps it on, even when Ca2+ isn’t present

Molecular Switch Hypothesis: the kinases have been “switched on”

LTP

CREB proteins can change gene expressionPhosphorylation from LTP causes changes in genes transcribed

LTD

Depression weakens synapses that are not driving (or weakly driving) the postsynaptic cell

Same set-up for establishing LTP, but presynaptic input is different

Instead of tetanus, pre- fires at low frequency

After repeated weak inputs, the postsynaptic neuron responds less

LTD

LTD is also caused by Ca2+

Low frequency stimulation doesn’t allow most NMDA receptors to be unblocked (not enough voltage increase)Some still do, and let some Ca2+ in

Low levels of Ca2+ cause depressionActivate phosphatases instead of kinases

Opposite mechanisms from LTP

LONG-TERM PLASTICITY

LTP and LTD discussed in terms of frequency of inputsFaster input = stronger firing = high calcium influx = potentiation

Slow input = weak firing = low calcium influx = depression

Timing of neuronal firing also causes potentiation or depressionPre-synaptic must fire before post-synaptic cell

Changes caused by Ca2+ are permanent (or at least very long-lasting)

QUESTIONS?