Lecture 5 - Learning & Memory

Lecture 5 - Learning & Memory

1. Processes

   • Learning = strengthening of responses or the formation of new responses to stimuli due to repetition or practice
   • Memory = the storage and retrieval of knowledge gained through learning

2. Different forms of L & M

   • Declarative or explicit
     • Knowledge about facts and their meaning (recalled consciously)
   • Non-declarative or implicit
     • Knowledge about how to perform something (recalled unconsciously)
     • Implicit learning and memory can be associative or non-associative
       • Non-associative
         • Habituation = the decrease in response to a benign stimulus through repeated presentation of the stimulus
         • Sensitisation = an enhanced response to multiple different stimuli after presentation with a noxious or intense stimulus
       • Associative = the association between two stimuli is learned
         • Classical conditioning

3. Neuromodulation studies in invertebrates

   • Evidence shows that forms of implicit memory involve experience-dependent modulation of synaptic strength and structure (synaptic plasticity)
     • Conserved in mammals
   • Short term memory
     • Lasts minutes and involves covalent modifications of pre-existing proteins at the synapse by kinases
   • Intermediate term memory
     • Lasts hours and involves new protein synthesis (but not mRNA synthesis)
   • Long term memory
     • Lasts days, weeks or more and requires CREB-mediated gene expression and new mRNA and protein synthesis (CREB = TF)
   • Aplysia = sea snail
     • Natural predator of sea snail = spiny lobster
       • Responds to attack by closing gill and syphon + ejecting a cloud of ink containing a mixture of chemicals that repel and confuse the lobster
         • After attack --> sea snail sensitized to future attacks --> involves modulation of synapses at sensory neurons
     • Nervous system
       • Contains ~20,000 large, identifiable nerve cells - there electrical activity can be recorded
       • Neural circuits controlling behaviours have been defined
       • Behaviour most studied is gill and syphon-withdrawal reflex
     • Cellular mechanisms of short and intermediate memory formation
       • 1. Serotonin released in vivo/applied directly to cultured neurons - binds to cell surface receptors of sensory neurons
         • 2. This binding activates adenyl cyclase --> causes cAMP to be produced
           • 3. Increased [cAMP] = short term sensitisation - increase in synaptic strength of sensory to motor neuron connection = short-term facilitation
             • Short-term facilitation is partly due to enhanced release of glutamate (neurotransmitter) by the sensory neuron
               • 4. Short-term facilitation is accompanied by an increase in sensory neuron excitability due to the depression of specific sets of K+ channels
                 • 5. Changes in cAMP and Ca levels regulate the activity of kinases and phosphatases to control the duration & strength of the synaptic efficiency changes
       • Short and intermediate-term synaptic plasticity for leaning in Aplysia involves different combinations of pre and postsynaptic molecules including...
         • ...presynaptic PKA
         • ...presynaptic calcium and CamKII
         • ...presynaptic PKC
         • ...postsyaptic calcium and CamKII
         • ...recruitment of pre and possibly postsynaptic molecules to new sites
         • Results in enhanced neurotransmitter release from sensory neurons
       • Watch lecture video back for better explanation with diagram
     • Cellular mechanisms of long-term memory formation
       • L-T synaptic plasticity (L-T facilitation/potentiation) contributing to learning involves a sequence of cellular and molecular mechanisms including...
         • ...neurotransmitter release and S-T strengthening of synaptic connections (1)
         • ...equilibrium between kinase and phosphatase activities at the synapse (2)
         • ...retrograde transport from the synapse to the nucleus (3)
         • ...activation of nuclear TFs (4...)
         • ...activity-dependent induction of gene expression
         • ...chromatin alteration and epigenetic changed in gene expression
         • ...synaptic capture of newly synthesized gene products
         • ...local protein synthesis at active synapses
         • ...synaptic growth and formation of new synapses
         • ...activation of pre-existing silent synapses
         • Location of these events moves from the synapse to the nucleus and then back to the synapse
       • Need repeated stimulus for LTM

4. Classical (associative) olfactory L&M in Drosophila

   • Conditioning requires activity of molecules that can integrate an odour (conditioned stimulus) with an aversive/appertitive stimulus (unconditioned stimulus)
     • Form of adenyl cyclase performs this integrative function in the mushroom body (MB) neurons of the fly brain
       • Dopaminergic neurons carry information about aversive stimuli
         • 1. CS information is presented to the MB neurons by the PNs
           • 2. Projection neurons (PNs) release ACh at synapses with MB cells causing voltage-gated Ca channels to open
             • 3. Increase in intraceullar [Ca2+] produces more calmodulin (CaM) bound with Ca2+
               • 4. This activates adenyl cyclase (AC) producing an elevation in cAMP
                 • 5. The US info is presented to the MB neurons by PPL1/PPL2ab neurons --> releases DA onto MB neurons
                   • 6. Activation of DA receptors also increases cAMP levels through the activation of heterotrimeric G protein coupled to AC
                     • 7. With the coincident activation of the CS and US pathways during conditioning a synergistic increase in cAMP occurs providing the necessary info in the MB neurons for encoding the CS/US temporal coincidence
       • Octopaminergic neurons carry information about appetitive stimuli to the MB neurons
         • The same CS pathway is induced in the MB neurons as with the aversive stimuli
         • The US information may be represented by octopamine (OA) release onto the MB neurons that also stimulated AC
         • DA neurons appear to also have a role in appetitive conditioning but their role is not clear
         • The coincident application of CS and US (OA) produces a subadditive increase in postsynaptic cAMP
       • GABAergic neurons control the ability to learn via inhibitory inputs