1. Molecular Mechanisms of Learning and Memory
Chapter 25
Jack Whylings

2. Types of Learning Declarative Memory: Facts and events
Procedural: Skills, emotional learning

3. Procedural Learning Non-associative
Habituation: decreasing response to a repeated stimulus
Allows organisms to ignore unimportant stimuli
e.g: Wearing clothes
Sensitization: increasing response to all stimuli after an intense stimulus
e.g.: Loud noises make you more sensitive to everything else
Allows organisms to respond quickly in possibly dangerous situations
Associative
Classical Conditioning: Associating a “meaningless” stimulus with a meaningful one
e.g: Pavlov’s dogs
Instrumental Conditioning: Associating an action with an outcome
e.g.: Lever-pressing

4. Invertebrate Learning
Why use invertebrate models?
Small Nervous Systems
Large, identifiable neurons and circuits
Simple genetics
Aplysia (Aplysia californica) is one model species ued in studying neuronal circuits
What types of learning studied?
Habituation
Sensitization
Classical Conditioning

5. Habituation in Aplysia
Touching Aplysia’s siphon causes it to retract its gill
Repeated touching causes Aplysia to habituate to this
No more retraction

6. Habituation in Aplysia
Where in circuitry could habituation occur?
Sensory endings in skin
Synapse between sensory and motor neuron
Neuromuscular 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

8. Habituation in Aplysia
How could habituation happen at the synapse?
Presynaptic Mechanisms
Reduction of NT released
Less vesicles
Less NT/vesicle
Postsynaptic Mechanism
Reduction in effectiveness of neurotransmitter
Less receptors
Receptors less effective
How would you test these?

9. 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

10. Sensitization in Aplysia
When a stimulus causes stronger reactions to other stimuli
Noxious Stimulus: Head shock
Response: exaggerated gill withdrawal in response to siphon touch
Sensory input from head must feed into gill withdrawal circuit

11. Sensitization in Aplysia
L29 is neuron that feeds information into gill circuit
Uses Serotonin as its neurotransmitter
Serotonin causes strengthening of motor neuron response
Serotonin causes increase of Ca2+ into presynaptic terminal

12. 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

14. Conditioning in Aplysia
Aplysia are also capable of associative learning
Different from sensitization
Timing is important
Combining tail shock (US) with gentle siphon touch (CS) would condition aplysia
Future gentle touch would cause gill withdrawal
Association only there if US and CS were close in time
Mechanism is still through serotonergic input

16. Conditioning in Aplysia
Serotonin from L29 causes increase in cAMP
Same 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

18. Vertebrate Learning Vertebrate learning is more complex
Challenging to directly connect behavior with cellular mechanisms
Non-associative learning
Happens pre- and post-synaptically
Associative Learning
Long-term changes
Hippocampus is involved in learning and memory
Molecular mechanisms best understood in hippocampus
Easy anatomy to study

19. Hippocampus
Entorhinal Cortex inputs onto hippocampus through the perforant path
Synapse on Dentate gyrus neurons
Dentate Gyrus axons form mossy fibers
Synapse onto CA3 pyramidal cells
CA means cornu Ammonis, or Ammon’s Horn
CA3 axons for Schaeffer Collateral
Synapse onto CA1 pyramidal cells
All of these paths are in same plane

20. 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 hippocampus
Long-term potentiation: A permanent strengthening of a synapse
Long-term depression: A permanent weakening of a synapse

21. LTP Neurons that fire together, wire together Experimental Set-up
Record from postsynaptic neuron
Cause presynaptic neuron to fire
Give tetanus from pre-synaptic neuron
Burst of high-frequency firing
After tetanus, postsynaptic neuron has stronger response to presynaptic input

23. LTP
Associative LTP: Multiple synapses firing together strengthen each-other
Analogous to classical conditioning
A “strong” synapse can fire with a “weak” synapse and turn the weak synapse into a strong one

24. LTP LTP uses both AMPA and NMDA receptors AMPA receptors
Glutamate receptors
Allow Na+ and K+ through
Excitatory
NMDA receptors
Voltage gated: cell must be depolarized
Allow Na+, K+, and Ca2+ into cell

25. 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 LTP
Blocking calcium prevents LTP

27. LTP LTP is mediated by calcium Ca2+ activates protein kinases
Protien Kinase C
Calcium-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

29. LTP Are those mechanisms really permanent?
Phosphorylation doesn’t last forever
CamKII can autophosphorylate
Keeps it on, even when Ca2+ isn’t present
Molecular Switch Hypothesis: the kinases have been “switched on”

30. LTP CREB proteins can change gene expression
Phosphorylation from LTP causes changes in genes transcribed

31. 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

33. 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 depression
Activate phosphatases instead of kinases
Opposite mechanisms from LTP

34. Long-Term plasticity
LTP and LTD discussed in terms of frequency of inputs
Faster input = stronger firing = high calcium influx = potentiation
Slow input = weak firing = low calcium influx = depression
Timing of neuronal firing also causes potentiation or depression
Pre-synaptic must fire before post-synaptic cell
Changes caused by Ca2+ are permanent (or at least very long- lasting)

35. Questions?