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Molecular Mechanisms of Learning and Memory

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Presentation on theme: "Molecular Mechanisms of Learning and Memory"— Presentation transcript:

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?

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