Post on 31-Mar-2015
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?