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Presentation on theme: "MOLECULAR MECHANISMS OF LEARNING AND MEMORY Chapter 25 Jack Whylings."— Presentation transcript:


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 Ca 2+ influx into the cell  Less Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ influx  Ca 2+ 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  Glutamate receptors  Voltage gated: cell must be depolarized  Allow Na +, K +, and Ca 2+ 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 Ca 2+ are permanent (or at least very long- lasting)


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