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1、Outline1. The basic concepts of learning&memory classification of learning&memory brain structures hosting learning&memory learning&memory in behavioral study learning&memory and neural plasticity2. The molecular basis of learning& memory studies in Aplysia studies in mouse, LTP, LTD and long term m
2、emoryAplysia： habituation sensitization associative learningVertebrates: LTP and LTDMolecular mechanism of LTMInvertebrate Nervous Systems Show Plasticity-AplysiaHabituation in Aplysia:Squirts of water on its siphon causes it to retract its gill.After repeated squirts, the animal retracts the gills
3、less it has learned that the water poses no danger.at the sensory nerve endings in the skin, making them less sensitive to the squirt of water; at the muscle, making it less responsive to synaptic stimulation by the motor neuron; at the synapse between the sensory neuron and the motor neuron.Repeate
4、d electrical stimulation of a sensory Neuron leads to a progressively smaller EPSPin the postsynaptic motor neuron.Where the change underlying habituation occurWhere does the synaptic modification happen?less neurotransmitter release by the presynaptic axon? -there are fewer quanta released per acti
5、on potential after habituation. decreased postsynaptic responsiveness to the transmitter? -The sensitivity of the postsynaptic cell to neurotransmitter did not change Habituation of the gill-withdrawal reflex is associated with a presynaptic modification.Why is neurotransmitter release reduced after
6、 repeated stimulation of the sensory nerve terminal? A critical step is the entry of Ca2+ into the terminal, which is mediated by voltage-gated calcium channels. In the nerve terminal of the sensory neuron, these channels become progressively and persistently less effective following habituation. De
7、spite the apparent simplicity of this type of learning, how this change occurs is still unknown.Sensitization of the Gill-Withdrawal Reflex -a brief electrical shock applied to the head of Aplysia results in exaggerated gill withdrawal in response to stimulation of the siphon.The molecular mechanism
8、 of sensitizationL29 release 5-HT in response to head shock 5-HT bind 5-HT receptor and activate G-protein coupled adenylyl cyclase in sensory axon terminal. Cyclic AMP production activates protein kinase A (PKA). PKA phosphorylate potassium channel, causing it to close(Contd)-Closure of K+ channels
9、 lead to prolongation of presynaptic action potential-More Ca2+ entry through voltage gated calcium channels and more quanta of neurotransmitters are released-More postsynaptic glutamate receptors can also add to the explanation of sensitizationConditioning occurred only if the CSpreceded the US by
10、0.5 second. Associative Learning in Aplysia Classical conditioning: US: a strong shock to the tail. CS: gentle stimulation of the siphon that does not cause a response. Response: the withdrawal of the gill. (a) The US alone leads to activation of the motor neuron (via an interneuron, not shown) and
11、to sensitization of the sensory input. (b) Pairing the CS and the US causes greater activation of adenylyl cyclase than either stimulus does by itself because the CS admits Ca2+ into the presynaptic terminal. The Ca2+ (by interacting with a protein called calmodulin) increases the response of adenyl
12、yl cyclase to G-proteins.Aplysia：Vertebrates: LTP and LTDMolecular mechanism of LTMsynaptic plasticity in cerebellar cortex-Anatomy of the Cerebellar Cortex-Long-Term Depression in the Cerebellar Cortex-Mechanisms of Cerebellar LTDsynaptic plasticity in hippocampus -Anatomy of the Hippocampus-Proper
13、ties of LTP in CA1-Mechanisms of LTP in CA1 Learning and memory in vertebratesLong-Term Depression in the Cerebellar CortexLTD- after pairing stimulation of parallel fiber and climbingfiber, activation of the parallel fibers alone resulted in a smaller,long-lasting postsynaptic response in the Purki
14、nje cellinferior olive and muscle proprioceptorsThe structure of the cerebellar cortexpontine nuclei andcerebral neocortexMechanisms of cerebellar LTDClimbing fiber activation depolarizes the Purkinje cell dendrite, and then activate voltage-gated calcium channels to allow influx of Ca2+Parallel fib
15、er release glutamate to activate postsynaptic AMPA receptor and allow Na+ influx in Purkinje cell dendriteThere is postsynaptic metabotropic glutamate receptor that is coupled via G protein to phospholipase C which can produce DAG to activate PKCPKC phosphorylate GluR2, and decrease postsynaptic AMP
16、A receptorsLTD is caused when three intracellular signals occur at the same time: (1) a rise in Ca2i due to climbing fiber activation, (2) a rise in Nai due to AMPA receptor activation (3) activation of protein kinase C due to metabotropic receptor activation.LTD certainly involves the phosphorylati
17、on of proteins, including an AMPA receptor subunit called GluR2, by protein kinase C. The end result is a decrease in the number of AMPA receptor channels in the postsynaptic membrane.LTP in Hippocampal CircuitsLong-term potentiation (LTP) a stable and enduring increase in the effectiveness of synap
18、ses.Some microcircuits of the hippocampus. Information flows from the entorhinalcortex via the perforant path to the dentate gyrus. The dentate gyrus granule cells emit axons called mossy fibers that synapse on pyramidal neurons in area CA3. Axons from the CA3 neurons, called Schaffer collaterals, s
19、ynapse on pyramidal neurons in area CA1. LTP are performed on the Schaffer collateral synapses on the CA1 pyramidal neurons.Long-term potentiation in CA1. (a)The response of a CA1 neuron is monitored as two inputs are alternately stimulated. LTP is induced in input 1 by giving this input a tetanus.(
20、b) The graph shows a record of the experiment. The tetanus to input 1 (arrow) yields apotentiated response to stimulation of this input. (c) LTP is input specific, so there is nochange in the response to input 2 after a tetanus to input 1.Induction of LTP in CA1Usually, a test stimulation is given e
21、very minute or so for 1530 minutes to ensure that the baseline response is stable. Then, the same axons are given a tetanus, a brief burst of high-frequency stimulation (typically 50100 stimuli at a rate of 100/sec). Subsequent test stimulation evokes an EPSP that is much greater than it was during
22、the initial baseline period. Induction of LTP in CA1Requirement of LTP inductionSynapses must be active at the same time that the postsynaptic CA1 neuron is strongly depolarized. (Hebbs Law)Synapses must be stimulated at frequencies high enough to cause temporal summation of the EPSPsEnough synapses
23、 must be active simultaneously to cause significant spatial summation of EPSPs. The CA1 region has both NMDA and AMPA receptors.Glutamate first activates AMPA receptors. NMDA receptors do not respond until enough AMPA receptors are stimulated and the neuron is partially depolarized.NMDA receptors at
24、 rest have a magnesium ion (Mg2+) block on their calcium (Ca2+) channels.Molecular mechanism of LTPAfter partial depolarization, the block is removed and the NMDA receptor allows Ca2+ to enter in response to glutamate.The large Ca2+ influx activates certain protein kinases.CaMKII affects AMPA recept
25、ors in several ways:1. Causes more AMPA receptors to be produced and inserted in the postsynaptic membrane.2. Moves existing nearby AMPA receptors into the active synapse.3. Increases conductance of Na+ and K+ ions.The activated protein kinases also activate CREB.CREB changes the transcription rate
26、of genes. The regulated genes then produce proteins that affect synaptic function and contribute to LTP.Strong stimulation of a postsynaptic cell releases a retrograde messenger that travels across the synapse and alters function in the presynaptic neuron. More glutamate is released and the synapse
27、is strengthened.LTP may be one part of learning and memory formationTime course of LTP is similar to that of memory formation.Pharmacological treatments that block LTP impair learning.Training an animal in a memory task can induce LTP.Vertebrate Models of LearningLearning and memory can result from
28、modifications of synaptic transmissionSynaptic modifications can be triggered by conversion of neural activity into intracellular second messengersMemories can result from alterations in existing synaptic proteins Neural and molecular basis of learning and memory-knowledge from lab animalsAplysia：Ve
29、rtebrates: LTP and LTDMolecular mechanism of LTMThe Molecular Basis of Long-Term Memory Phosphorylation as a long term mechanism: Persistently Active Protein KinasesPhosphorylation maintained: Kinases stay “on” CaMKII and LTPMolecular switch hypothesisThe regulation of CaMKII (a)The hingelike subuni
30、t of CaMKII is normally “off ” when the catalytic region is covered by the regulatory region. (b) The hinge opens on activation of the molecule by Ca2+-bound calmodulin, freeing the catalytic region to add phosphate groups (P) to other proteins.(c) A large elevation of Ca2+ can cause phosphorylation
31、 of one subunit by another, which enables the catalytic region to stay “on” permanently.The Molecular Basis of Long-Term MemoryProtein SynthesisProtein synthesis required for formation of long-term memoryProtein synthesis inhibitorsCREB: Cyclic AMP response element binding proteinStructural Plastici
32、ty and MemoryLong-term memory associated with transcription and formation of new synapsesThe regulation of gene expression by CREB. (a)CREB-2 functions as a repressor of gene expression. (b)CREB-1, an activator of gene expression, can displace CREB-2. (c)When CREB-1 is phosphorylated by protein kinase A (and other kinases), transcription can ensue.Thanks！
