Chapter 25-Molecular Mechanisms PDF

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Professor Julia Peterman...

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Chapter 25- Molecular Mechanisms of Learning and Memory Learning and memory  This chapter looks into HOW info can be stored  Memories are stored from subtle alterations in synapses  They can be widely distributed across the brain Working memory vs short term memory  In order to differentiate between acquisition and consolidation, we have to understand the different types of memory  We are now looking at memory AFTER working memory  Working memory o Keeping neural activity going o Keeping neurons active and in your mind with rehearsal o Does not require any lasing physical changes in the brain o Does not survive distraction o Has a limited capacity  Memory acquisition o Converting something into short term memory  Short term memory o Survives distraction o Large capacity o Can be held for minutes to hours without rehearsal  Memory consolidation o Converting something from short term memory to long term memory  Long term memory

Memory acquisition  First step of learning  Occurs due to physical modification in the brain  Happens as a result of incoming sensory information  Different from working memory o No physical modification for working memory  Mechanisms responsible for initial acquisition: o Modification of synaptic transmission between two neurons Memory consolidation  The process by which some experiences or events that are held temporarily by these temporary synaptic modifications get selected for permanent longer term storage in the brain  Not all memories are created equal o Brain has a system for choosing which memories to hold onto

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Mechanisms responsible for consolidation: o Synaptic consolidation requires modifying synaptic transmission between neurons AND new gene expression and protein synthesis ! o Essential for consolidation that doesn’t happen in acquisition  Test: what is different for acquisition vs consolidation ??  AND how are these both different from working memory? Research question  Declarative memories are in cerebral cortex  Neurons across the entire brain are involved in memory  Visual information and discriminating between and recognizing similar pieces is the first step to creating a memory o Where is this stored? o If you use only ONE sense (seeing a pic, not hearing their voice) , we can look at which neurons are firing o Should see it in the visual cortex only  This is TRUE  Just using one piece of info- found in synapses in that area only Inferotemporal cortex  Can train monkeys to discriminate between visual objects  If this is damaged, they can no longer do this  This area contains higher order vision neurons involved in visual perception  After lesions to this area, monkeys are unable to recognize objects that should be familiar to them, even though visual capacities are intact  They can see the object; they can’t identify that they’ve seen it before Prosopagnosia  Selective amnesia for familiar faces o Even including your own face  Results from damage to this area, even in humans o Could be born with it also  Visual agnosia o Visual difficulty recognizing objects  Prosopagnosia o Can recognize objects, but NOT faces o Cannot recognize that a face belongs to one person and not the other  Includes own face, or faces you see every day o Can describe the individual characteristics and can describe it, but they can’t understand the face as a whole o Patients use other cues to identify people  Oliver sacks o Famous author with prosopagnosia o “the man who mistook his wife for a hat” o Important because it shows that area is important in processing visual info, faces, and memory

o Both recognition and memory storage Inferotemporal cortex  Stimulus selectivity o Neurons fire to one or two stimuli they are selected for o Often selective for faces in this area o Specific neurons respond to faces – can be similar, but they are very selective Distributed memory storage  After repeated exposure, the neurons of the network acquire selectivity  When they first see them, all neurons respond slightly to presentations of A B and C o Occurs before learning  After showing these faces multiple times, certain cells responds more to certain faces  Each cell becomes selective for one face  On a network level, there are alterations in the cells in addition to the one cell selected for the face o Not just one neuron to one face o Network of neurons that all respond a certain amount o If we lost one neuron, we would lose all memory for that person o Because it’s a network, we can train neurons that already recognize a face to recognize it better  After learning, there is a unique pattern or ratio of activity in the three neurons for each face o This is called distributed memory  The physical change that leads to mem in the brain can be the modification of synaptic weight that changes the input-output relationship of neurons  Over time, these neurons that were all responding the same amount, now respond differently  Output becomes different after learning  The synapses are what store memories  Important because neurons die every day o A part of aging  Important because we can retain all of our memories regardless of how many neurons, we lose  Memory diseases – slow, gradual deterioration rather than something happening all at once Studying this in invertebrates  Nobel prize winner- Eric Kandel  Most important and foundational neuroscientists of the last several years  Used a marine snail o Have very vastly different nervous system than humans o But it does have advantages o Have small nervous systems with large neurons o Able to study them easier than smaller neurons o Well established what neurons and what connections exist

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o Have very simple genetics o Able to understand the neural basis of behavior Research o Showed there is a synaptic basis for the formation of memories o Synaptic changes lead to memory storage o Underlying mechanism for humans as well o If you apply water to one part of the snail, they will retract their gill  Simple reflex of a two-neuron relay  One sensory neurons acts on one motor neuron o FINDING #1- Habituation of the gill withdrawal reflex  Water sprayed continuously in the same spot  Animal would keep retracting the gill  Over time, the animal stopped retracting the gill  Became habituated to the water on that one piece of skin o Mechanism behind how this happens – NOBEL PRIZE WINNER  What happens on a synaptic level  Still exact same amount of action potentials that travel down the axon of the sensory neuron (presynaptic neuron)  No change over time in the recordings of the presynaptic neurons  There IS change in the postsynaptic neuron  Less action potentials  Was getting diminished information o WHY? - Less calcium was let into the axon terminal of the presynaptic neuron o Leads to decreased neurotransmitter release onto the postsynaptic neuron o Ultimate net result was long term depression and can lead to a decrease in synapses o HABITUATION occurs using SHORT TERM MEMORY o FINDING #2 - Sensitization of the gill withdrawal reflex  If you give them a small shock on a different part of the skin, you will cause a more pronounced reflex  Interneuron synapses on sensory neuron that is getting information from the water  Axo-axonic synapse  Where does learning occur?  Short term – with a serotonergic GPCR  Review of how g protein coupled receptors work  GPCR activates Adenylyl Cyclase  AC leads to the production of cAMP  cAMP activates PKA  PKA increases membrane resistance to K+  This makes the membrane more excitable

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This^ all happens when the interneuron synapses on the sensory neuron  Repeated activation of serotonergic neurons case long term sensitization that will then cause new gene expression and protein synthesis  If you keep having activation here, you will end up with longer term activation o Called long term potentiation How does sensitization learning occur?  Short term memory results from a transient strengthening of preexisting synaptic connections o Ex: increasing the amount of NT release  Long term memory results from a persistent strengthening of synaptic connections o Includes  Alterations in gene expression  Synthesis of new proteins  Growth of new synaptic connections Short term learning  Transient strengthen in NT release by the sensory neuron onto the motor neuron that controls the gill muscle  Increase occurs as a result of activation of serotonergic (inter) neuron  Serotonin increases strength of connection between interneurons and sensory neurons  Increases o Permeability of potassium on the membrane o Concentration of cAMP o Production of PKA Long term learning  Occurs because there is a persistent strengthening of these connections  Includes o Alterations in gene expression o Synthesis of new proteins o Growth of new synaptic connections  Another result of the GPCR activation is that CREB binds to CRE o Leads to an increase in number of synapses and protein synthesisLeads to long term changes Sensitization learning in snail  Serotonin from interneuron L29 binds GPCR on sensory neuron  Short term learning  Increases AC  cAMP  PKA o More Glu release  Long term learning  CREB binding CRE leads to protein synthesis and new synapses Classical conditioning in Aplysia snail

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Associative learning can also take place here Instead of not activating a sensory neuron, you have the activation at the same time as an interneuron  Pairing CS and US (or just touch and shock) leads to a greater activation of AC than either by itself because the CS leads to letting calcium into the presynaptic terminal  Leads to amplification of GPCR response (using AC)  AC is called the coincidence detector Implications  Showed the neural or biological basis of learning o Have since talked about brain areas involved in memory, etc. o But had never shown before HOW it happened o Memory was just an abstract concept and nobody had looked into it at the synaptic level  Habituation and sensitization is non-associative learning and classical conditioning is associative learning and they both have biological bases o Infer that this likely extends to many types of memory o Research has rapidly advanced since this discovery What did we learn from the snail?  Memories can reside in synaptic alterations  Identified some of the molecular mechanisms that lead to this synaptic plasticity o What is it about this shock and touch that leads to an exaggerated response?  The synapse is an important part of memory storage o It’s not just distributed brain regions or one memory area o It’s at the individual synapse area that it can be stored Hippocampus  Is an area important in memory  Regions of the hippocampus/pathway: 1. Entorhinal cortex  dentate gyrus synapses 2. Dentate gyrus  CA3 (mossy fiber) synapses 3. CA3  CA1 (Schaffer collateral) synapses  Pathway in more detail: o Major input to hippocampus from entorhinal cortex  Sends info to the dentate gyrus o Then dentate gyrus gives rise to axons that will synapse onto neurons of CA3 o Then CA3 give rise to axons that branch  One branch (the Schaffer collateral) leaves the hippocampus via the fornix  Then synapses on CA1 Properties of LTP (long term potentiation) in CA1  Most excitatory (and many inhibitory) synapses support LTP o Means that via same mechanism or another, there can be changes to that synapse that can allow for memory  The mechanisms can vary from one synapse type to another

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The most sophisticated understanding of the LTP has come from studying the Schaffer collateral synapses on the CA1 pyramidal neurons in brain slice preparations  Input specificity o Researchers give stimulation to the neuron every minute or so to get baseline responses  Makes sure the neurons are responding, and in the same way o Neurons are then given tetanus (a brief burst of high frequency stimulation)  Usually induces LTP  Subsequent or follow up tests evoke EPSPs greater than those in the baseline period  Tetanus has caused modification of the synapses so that they are more effective  What if this is just a result of the baseline responses?  Neurons that didn’t receive the tetanus did not have LTP  Only active inputs show synaptic plasticity  Called input specificity  Longevity o EPSPs stimulated in hippocampus by electricity to neurons that had already received a tetanus stimulation o How long does this last? o Even after a year later, there is still evidence of the LTP being present a year later  High frequency stimulation is not an absolute requirement for LTP  What is a requirement is that synapses be active at the same time that the postsynaptic CA1 neuron is strongly depolarized o In order to achieve the necessary depolarization:  Synapses must be stimulated at frequencies high enough to cause temporal summation of the EPSPs  Enough synapses must be active simultaneously to cause significant spatial summation of EPSPs  This requirement is called cooperativity because coactive synapses (multiple synapses, synapsing at the same time on the same neuron) must cooperate to produce enough depolarization to cause LTP  “Neurons that fire together, wire together” Properties of LTP in CA1  Imagine a hippocampal neuron receiving 3 synaptic inputs: o Initially, no single input is strong enough to evoke an action potential o If inputs 1 and 2 repeatedly fire at the same time, spatial summation will occur, and they can evoke APs in the postsynaptic neurons and may cause LTP  Inputs 1 and 2 become associated due to this potentiation o Now either input 1 or input 2 can fire the postsynaptic neuron  We are talking about the pathway from CA3 to CA1 o Called the Schaffer collateral)

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Excitatory synapse transmission is mediated by glutamate receptors There are multiple types Important subtypes o AMPA receptors o NMDA receptors o Often are on the same postsynaptic neuron When a NT binds to an AMPA receptor, sodium will be allowed to go through and into the cell o AMPA receptor = sodium channel When a NT binds to an NMDA receptor, sodium will be allowed to go through and into the cell o Ligand gated AND voltage gates o Requires binding of glutamate (ligand gated component) AND a voltage change/EPSP in the membrane (voltage gated component) to move the magnesium block out of the way In LTP, we have activation of the AMPA channel following the release of glutamate from the presynaptic neuron o Sodium enters the cell o Causes an EPSP at the CA1 cell synapse of the Shaffer collateral o What happens is the calcium entry from NMDA receptors when they are active o When there is thus change in voltage, and NMDA receptor will open o When glutamate binds to AMPA and lets in enough sodium, the membrane is able to depolarize to move the magnesium and let in calcium o Coincidence detector  LTP in the hippocampus  NMDA receptors and their calcium is this coincidence detector  A lot of evidence has now linked calcium entry to LTP  If you inhibit NMDA receptors, LTP doesn’t occur What is the rise in calcium doing? o Will active two protein kinases (PKC and CaMKII) o What do kinases do?  They phosphorylate  Attach phosphate groups to something  In this case, they phosphorylate AMPA channels  Leads to an increase in the effectiveness in the postsynaptic AMPA channels through phosphorylation  Allows for more conductance  Insertion of new AMPS channels into the postsynaptic membrane  Works by vesicular organelles that are near the postsynaptic membrane  In response to CaMKII membranes will fuse and the new AMPA receptors are delivered to the synapse  These types of changes are known as synaptic plasticity  The ability of the synapse to be changed or modified

 Also see structural plasticity Structural plasticity  Changes to synaptic structure  At the end of the neuron, there are dendrites/dendritic spines that connect to other neurons  Postsynaptic spines appear to form new synaptic connections  Following LTP, a single axon can make multiple synapses on the same postsynaptic neuron  Does not occur outside of CA1 outside of LTP  More synapses  more surface that is covered (more room for NTs to be released onto receptors)  increases likelihood that NT release will lead to APs of the postsynaptic neuron Weakening synapses  Opposite of LTP  Loss of connections and decrease in synaptic effectiveness  Occurs when they are active at the same time as the postsynaptic cell, but only weakly  When a presynaptic neuron fires with only weak inputs coming from anywhere else, the out of sync will become weakened  “neurons that fire out of sync lose their link”  Same region of CA1 in the hippocampus  Happens with smaller stimuli induced to have a weak response  Called long term depression (LTD)  Two rules that govern how this happens o Synaptic transmission occurring at the same time as strong depolarization of the postsynaptic neuron causes LTP of the active synapses o Synaptic transmission occurring at the same time as weak or modest depolarization of the postsynaptic neuron causes LTD of the active synapses Spike timing dependent plasticity  The properties of LTP and LTD will vary from one synapse type to another  LTP  when the EPSP precedes an action potential in the postsynaptic neuron  LTD  when the EPSP follows an action potential in the postsynaptic neuron  The liming determines LTP vs LTD Mechanisms of LTD in CA1  Shaffer collateral has NMDA receptors that are LTD dependent  A rise in postsynaptic calcium is necessary to trigger LTD  But allowing a large amount of calcium in the cell causes depolarization  So for LTD to occur, only a small amount of calcium can enter  A little bit of calcium indicates that it is not in sync because glutamate is binding but the AMPA channel isn’t activated  These different types of responses to calcium are regulated by protein phosphatases  If LTP is adding phosphate groups, LTD is taking them off  Kinases phosphorylate AMPA channels and result in addition to new ones in the membrane

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AMDA receptors are dephosphorylated, making them less effective and remove them from the membrane o Can lead to internalization of AMPA receptors at the synapse How we know these are related to memory  LTP and LTD can contribute to the formation of declarative memories  NMDA receptor-dependent synaptic plasticity occurs in the hippocampus  Also occurs throughout the neocortex, including area IT o Area IT  Inferotemporal cortex o Place for familiar faces  Plasticity at many synapses in the cerebral cortex may be governed by similar rules and might use similar mechanisms  Important to note that every rule has exceptions o These do not apply to every synapse o This happens often and broadly, but does not always follow this perfectly NMDA receptors and memory  Researchers injected an NMDAR antagonist into the hippocampus of rats undergoing IA training o Prevented formation of a memory of the aversive experience  NMDAR antagonist infused into the hippocampus of rats while they were being trained in a water maze o Failed to learn the task or the location of the platform LTP and memory  Researchers knocked out the gene for one subunit of CaMKII and found deficits in hippocampal LTP and memory  Now, many genes have been manipulated in mice to assessing the role of LTP and LTD mechanisms in learning Limitations to knockouts  Loss of function might be secondary to developmental abnormalities caused by growing up without a particular protein  Researchers sought to restrict their genetic manipulations to specific times and specific locations  Restricted the genetic deletion of NMDA receptors to the CA1 region in mice, starting at about 3 weeks of age o Striking deficit in LTP, LTD, and water maze performance Too much NMDA?  Animals engineered to produce more NMDA receptors show enhanced learning ability  Together, pharmacological and genetic studies show that hippocampal NMDA receptors play a key role in synaptic modification (LTP and LTD) and in learning and memory Synaptic homeostasis  LTP makes the postsynaptic cell more likely to respond, causing further potentiation of coacti...