Neurobiology of Learning and Memory PDF

8/26/24 Ne u rob iology of Le a rn in g a n d Me m ory PSYU2236 / PSYX2236 Biop s ychology & Le a rning Le c t ure r: Dr Chris t ina Pe rry 1 2 1 ...

8/26/24 Ne u rob iology of Le a rn in g a n d Me m ory PSYU2236 / PSYX2236 Biop s ychology & Le a rning Le c t ure r: Dr Chris t ina Pe rry 1 2 1  8/26/24 Ou t lin e How do w e define learning and memory? How our neuronal circuits can change How do they change w i t h experience Specifics o f neuronal connections Synaptic Change – Long Term Potentiation & Long Term Depression Memory, hippocam pus and Memory Deficits (A lzheim er’s Disease) 3 De fin it ion s 4 2  8/26/24 Le a rning t o Rem em b er DEFINING LEARNING AND MEMORY Learning is a change in behaviour as a result of experience Learning: Acquisition o f new knowledge or information Memory: Retention o f learned information 5 5 Me m ory DEFINING LEARNING AND MEMORY How do we fo rm memories? Declarative E.g. what you did this week Generic (reference library: facts, words) or had for breakfast. Explicit (memory w i th awareness; w hat you wore yesterday - requires conscious effort) Nondeclarative Implicit (memory w ith o u t awareness: past experience influences current task - procedural memory) 6 6 3  8/26/24 Me m ory DEFINING LEARNING AND MEMORY Declarative Medial temporal lobe (hippocampus) Nondeclarative Procedural: cerebellum (muscular response), striatum (habits, skills) & amygdala (emotional response) Ø Procedural (learning a m o to r procedure in response t o sensory input) Non-associative learning: change in behavioural response to a repeated stimulus (e.g. Habituation & Sensitisation) Associative learning: forming associations between events (e.g. classical conditioning & instrumental conditioning) E.g. learning your way to the lecture theatre 7 7 Me m ory DEFINING LEARNING AND MEMORY Short-term (working) memory May last seconds or hours Easily disrupted (distraction, head traum a) Apparent holding capacity is approx. 7 w o rd s * Long-term memory E vents/facts held fo r days, m o n th s or years a fte r storage N ot easily disrupted How do w e learn to associate one thing w ith another? The sm e ll o f a rose w i t h its flow er? Need t o engage w i t h th e target, n o t ju st be exposed t o it 8 8 Because when we smell vanilla the context (having vanilla in sweet contexts) we interpret vanilla as a sweet smell. 4  8/26/24 You can disrupt memories by disrupting this consolidation period. This is what happens when you're drunk and black out. Le a rning t o Rem em b er DEFINING LEARNING AND MEMORY In fo rm a tio n in sh o rt t e r m m em ory is lo s t if n o t consolidated Sensory S h o r t - t e r m m em ory Long-t e r m m em ory Inform ation For a m em ory t o be stored lo n g -te rm , i t does n o t necessarily have t o be a s h o r t - t e r m m em ory first: It may be stored due t o an em otional response, conscious e ffo r t Spaced-practice (repeating over tim e) is b e tte r th a n massed practice (i.e., cramming) The reason for that is because it gives you a chance to consolidate your memories over time. 9 9 St ru c t u ra l Ch a n ge a n d Re orga n is a t ion 10 5  8/26/24 Cha nge s in Bra in Funct ion: Ne urop la s t ic it y STRUCTURAL CHANGE AND REORGANISATION Neurogenesis New neurons f r o m precursor cells Neurodegeneration is more like a pruning Neurodegeneration process (more like re ning your circuits) Death o f neurons and rearrangem ent o f synapses Changes in Dendritic Branching Increases in dendritic branches Pruning o f dendritic branches Long Term Adaptations to Synapses Long Term Potentiation = enhancem ent o f synapse strength Long Term Depression = weakening th e strength o f a synapse Strength = ability t o produce EPSP t o p ro m o te action potentials 11 11 Neurogenesis is a slightly contentious area, they used to think you were born with the brain you had and that was it. How important neurogenesis is for learning and memory is still being researched. Ne uroge ne s is STRUCTURAL CHANGE AND REORGANISATION New neurons grow in th e brain f r o m s te m cells Embryonic (pluripotential s te m cells) - taken f r o m fertilised eggs (blastocyst) or Tissue specific Neural s te m cells (ie s te m cells w h ich w ill becom e neurons) Developm ent o f m a tu re cell depends on exposure t o g ro w th factors All neurons have the same DNA but which genes are expressed is dependant on other chemicals in the environment (these chemicals are called growth factors) 12 12 6  8/26/24 It' called stem cell therapy concerning whether you can implant them into the brains of Parkinson's disease patients (since they're de cient in dopamine in the striatum). Grow t h a nd Diffe re nt ia t ion STRUCTURAL CHANGE AND REORGANISATION J. William Langston (JCI, 115:23-25), Parkinson’s Institute CA 13 13 Ne ura l St e m Ce lls STRUCTURAL CHANGE AND REORGANISATION Ependyma cells line th e ventricles Neural s te m cells lie beneath th is layer Neural stem cells are in the subependyma of the ventricular system 14 14 7  8/26/24 Ne ura l St e m Ce lls STRUCTURAL CHANGE AND REORGANISATION Neural stem cells manufacture constitutively proliferating (CP) progenitor cells CP cells migrate out of subependyma and form new neural cells when exposed to certain conditions (e.g., growth factors such as BDNF = brain derived neurotrophic factor) So far, evidence has shown migration of these cells to Cortex Striatum Olfactory Tubercles of forebrain Migration of these new neurons are helped by the ependymal cells. The development of new neurons is called Neurogenesis A lot of neurogenesis also occurs in the dentate gyrus of the hippocampus 15 15 Ne uroge nes is and Ps ychia t r ic Dis ord e rs STRUCTURAL CHANGE AND REORGANISATION Depression associated with decreased neurogenesis in hippocampus (dentate gyrus) Use of antidepressants enhance neurogenesis in dentate gyrus granular layer cells in the dentate gyrus (clustered pyramidal cells) David et al. (2009) Neuron DOI: 10.1016/j.neuron.2009.04.017 16 16 They repeatedly gave rats a corticosteroid which simulates stress in the brain. They consistently stressed out the rats and found out that the rats were getting depressed. They found DCX which is a chemical present in new neurons. The dark matter was decreased (neurogenesis) but they also gave them prozac which increased the neurogenesis. 8  8/26/24 Cardio exercise will increase neurogenesis, the rats that are allowed to run showed a rather large increase in DCX. Which is why exercise is often recommended to help with depression and to prevent cognitive decline. Ne uroge nes is and Exe rc is e STRUCTURAL CHANGE AND REORGANISATION Neurons change in response t o our experiences Exercise enhances learning through neurogenesis in hippocam pus (van Praag e t al., Journal o f Neuroscience 25(38):8680-8685, 2005) Regular physical exercise may p r o te c t against cognitive decline and dem entia as w e age (for review see Paillard, T., 2015 Sports Med Open 1:4 (PMID: 26284161) Environm ental e n rich m e n t also shows b e n e fit fo r learning and m em ory (Garthe A, e t al 2015, Hippocam pus PMID:26311488) Lugert et al. (2017) Scientific Reports DOI: 10.1038/srep46543 17 17 Enrichment i.e. keeping yourself interested and in some ways it's more important than exercise because it increases neurogenesis. Neuroplasticity means that the brain can change. Ne urons ca n Cha nge (Ne urop la s t ic it y) STRUCTURAL CHANGE AND REORGANISATION Neuron death and rearrangement of synapses N orm al neurodevelopm ent depends on th e death o f som e neurons Neurons grow t o m e e t ‘target’neurons If a growing neuron does n o t get th e g ro w th fa cto rs (and guidance) i t needs f r o m target cells they die o ff Neuron death helps t o focus th e o u t p u t o f remaining neurons - sm aller n u m b e r o f postsynaptic cells = selectivity o f neurotransm ission There's a lot of contention about how much neurogenesis is happening in the adult brain. Also neurogenesis will depend on the death of certain neurons. 18 18 9  8/26/24 Ne uron Dea t h STRUCTURAL CHANGE AND REORGANISATION In p u t neurons Target neurons Competition for growth factors Only the successful survive! This helps t o focus the connections “pruning a rose garden” 19 19 Syna p s e Elim ina t ion STRUCTURAL CHANGE AND REORGANISATION Synapses can also be ‘pruned’ to focus contact between cells 20 20 10  8/26/24 Exp e r ie nce a nd De nd r it ic Bra nching STRUCTURAL CHANGE AND REORGANISATION Neurons change in response to our experiences – they physically grow more dendrites! These are social animals they need to be raised in social environments. Notice how the neuron raised in social environments is larger and more well organised. Animals in enriched environments have greater dendritic branching. They also have improved learning skills Kalat, Figure 4.18 Raised in Raised with isolation others 21 21 De nd r it ic Pruning STRUCTURAL CHANGE AND REORGANISATION Similar t o synaptic elim ination – dendrites can be pruned back if n o t used regularly à Use i t or lose it B B C A C A axon axon If A does not receive input, the A dendrite will recede 22 22 11  8/26/24 Exp e r ie nce a nd Cort ica l Re orga nis a t ion STRUCTURAL CHANGE AND REORGANISATION Our cortex changes in order to accommodate the motor activity that we need / use Somatotopic reorganisation of the cortex 1. Normal representation of the fingers in the cortex: 2. With extensive music practice, expanding representations of the fingers might look like this: From Kalat module 4.2 (p129 in 12th Ed.) 23 23 The brain will devote more surface area to an area of your body that you use more of the time (e.g. piano playing) Cognit ive Be ha vioura l The ra p y STRUCTURAL CHANGE AND REORGANISATION Cognitive Behavioural Therapy can also produce reorganisation of our “neural circuits” Paquette et al., (2003) Neuroimage 18:401-9 doi 10.1016/S1053- 8119(02)00030-7 Dorsolateral Prefrontal Cortex 24 24 12  8/26/24 Ch a n ge s a t t h e Syn a p s e 25 Cha nge s t o our s yna p s e s CHANGES AT THE SYNAPSE Our synapses change in response to our experiences Synaptic Plasticity = long term changes in how our synapses work Long Term Potentiation à pervasive increase in excitability of a neuron Long Term Depression à pervasive decrease in excitability of a neuron With repeated activation it will change the way the downstream neuron responds to the stimulus from the presynaptic neuron. 26 26 13  8/26/24 Le a rning from Ap lys ia CHANGES AT THE SYNAPSE Much of what we have learned about changes in neurons (neuroplasticity) comes from the sea slug Aplysia (Eric Kandel) Aplysia have been used extensively to study the neuroplasticity associated with sensitisation and habituation by investigating their gill withdrawal reflex Simple invertebrates Few and large neurons - easy to study Their neurons are very similar from one aplysia to the next 27 27 Eric Ka nd el a nd Ap lys ia CHANGES AT THE SYNAPSE Nobel Prize 2000 (Medicine) (with Arvid Carlsson & Paul Greengard) 28 28 Kandel discovered that long term potentiation and long term depression occurs that neurons or circuits are not xed int he way that they respond to incoming stimuli. 14  8/26/24 The process of synaptic plasticity has three characteristics and the rst characteristic is speci city, the second is co-operativity and the third is associativity Sp e c ific it y of Syna p t ic Conne ct ions CHANGES AT THE SYNAPSE The m ore it ’s us e d , t he s t ronge r it ge t s Dendrites See Rose Presynaptic 🌹 Axon hillock Terminals ++ + ⚡⚡ ⚡⚡ ⚡⚡ Axon The sight of the rose causes an EPSP. With repeated exposure to seeing the rose the EPSP will become large enough to produce an action potential: the synapse is strengthened 29 29 So the next time you see a rose and the more frequently you see a rose that will strengthen the snapse. Does that mean that you'll be more likely to experience an EPSP, which in turn strengthens the synapse? Yes, according to synaptic connectivity (neurons that re together wire together) so next time when you see a rose it will produce an even bigger EPSP. Syna p t ic Co- op e ra t ivit y CHANGES AT THE SYNAPSE How do we learn to associate one thing with another? Ne urons t ha t fire The smell of a rose with its flower? t oge t he r w ire See Rose Presynaptic t oge t he r (He bb ia n Smell 🌹 Axon hillock Terminals Princip le ) Rose + ++ +++ ⚡⚡⚡⚡⚡⚡⚡⚡ Dendrites Axon If tw o sensory signals are repeatedly received within 50 ms of an action potential they become linked and strengthened. This means that one 30 signal can have the same effect as two 30 E.g. the combination of vanilla and sweetness. Or how next time just the sight of the rose reminds you of the smell. I personally- don't nd roses to be that fragrant so I would think of a Lily ower instead. 15  8/26/24 E.g. Classical Conditioning Bell (week signal) Food (strong signal) Which means the bell will cause the whole neuron to re even if initially it had a week EPSP Syna p t ic As s ocia t ivit y CHANGES AT THE SYNAPSE Weak inputs paired Dendrites See Rose Presynaptic with a strong EPSP Axon hillock Terminals and action potential will become stronger ++ with more pairings + Touch + Axon Rose Weak If two sensory signals are repeatedly received input within 50 ms of an action potential they become linked and strengthened. This means that a weak signal can end up being a lot stronger. 31 31 Dona ld He bb CHANGES AT THE SYNAPSE The neural representation of objects is the pattern of all cortical cells activated by the external stimulus (rose) Some cortical cells are simultaneously active in response to this object If the simultaneous activity of these cells occurs for long enough (or repeatedly), there w ill be a change (growth) in the neurons to consolidate this “neurons that fire together, wire together” This means th a t only a certain number of cells in this assembly would need to be activated in order to represent a rose (e.g.): different combinations instead of needing many different neurons Successful pairing only occurs if both signals occur w ithin 50 ms of an action potential - requires huge depolarisations 32 32 16  8/26/24 Ne uron Firing CHANGES AT THE SYNAPSE Neurons fire at different frequencies (Hz) When neurons fire they release neurotransmitter into the synapse Frequency means the number of synaptic excitations per second Low frequency = 1-5 Hz High frequency = 50-100 Hz Differences in firing frequencies can greatly alter communication between synapses Which can either cause weakening or strengthening to occur in LTP or LTD 33 33 Firing Fre q ue ncy a nd Ne urop la s t ic it y CHANGES AT THE SYNAPSE Long Term Potentiation (LTP) Brief high frequency electrical stimulation of an excitatory pathway leads to a long-lasting enhancement in the strength of the stimulated synapses Long Term Depression (LTD) Brief low frequency electrical stimulation of an excitatory pathway leads to a long-lasting weakening of the strength of the stimulated synapses LTP and LTD rely on the function of Glutamate receptors 34 34 17  8/26/24 Break Bre a k Tim e 35 The ionotropic receptors are ion channels and for Glutamate they let in Ca++ or Na+ Glut a m a t e Rece p t ors CHANGES AT THE SYNAPSE Glutamate Ionotropic & metabotropic receptors NMDA R Mg++ Ionotropics let in calcium (Ca++) or sodium (Na+) Ionotropic: NMDA (N-methyl-D-aspartate) Ionotropic: AMPA (α-amino-3-hydroxy-5-methyl-4 - isoxazoleproprionic acid) Ionotropic: Kainate receptors Metabotropic (mGluR1 - mGluR7) - linked to second messenger systems NMDA receptors are unique - usually “plugged” with Magnesium (Mg++) Only when the dendrite becomes depolarised does the Magnesium leave the NMDA receptor (if glutamate is bound) so that positive ions can come into the cell 36 18  8/26/24 Norm al Glut am at e Tra ns m is s ion ⚡⚡⚡ Presynaptic Terminal glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 37 The action potential is received at the terminal of the glutamatergic neuron which causes glutamate to be released into the synaptic cleft, which then binds to NMDA receptors which won't open because they're still plugged. But they will open the AMPA receptors. Ac t ion Pot e n t ia l is Re ce ive d Presynaptic Terminal ⚡⚡⚡⚡⚡⚡ ⚡⚡⚡⚡⚡⚡ ⚡⚡ glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 38 On this slide above you can see that the NMDA receptors won't open because they are still plugged. 19  8/26/24 Glut a m a t e is Re le as e d : Ac t iva t e s AMP A R CHANGES AT THE SYNAPSE Presynaptic Terminal Na glutamate Postsynaptic NMDA R Dendrite Na Na Na AMPA R Mg++ 39 Afterwards, the AMPA receptors will open and they will let Na+ (sodium) in which is positively charged- it will ow into the cell. This means that when the Glutamate is released it's going to ow into the AMPA receptor. (That's what this process refers to). This increase in Na+ (sodium_ will cause a small EPSP. AMP A R Ac t iva t ion: Sm a ll EPSP CHANGES AT THE SYNAPSE Presynaptic Terminal Na glutamate Postsynaptic NMDA R Dendrite Na AMPA R Na Na Mg++ 40 20  8/26/24 More AMP A R Ac t iva t ion: Me d ium EPSP CHANGES AT THE SYNAPSE Presynaptic Terminal Na Na glutamate Postsynaptic NMDA R Na Na Dendrite Na Na Na AMPA R Na Na Mg++ 41 With enough Na+ (sodium) at the Postsynaptic terminal to classify it as a Medium EPSP- then Mg++ (magnesium) can start leaving the NMDA receptors. Then the channel becomes unblocked and can ow into the cell. Now we get a large change in the neuron since more positive ions ow in as Mg leaves and it means the neuron will be more likely to re. Me d ium EPSP: Ac t iva t e s NMDA R CHANGES AT THE SYNAPSE Presynaptic Terminal Mg is displaced by depolarisation (EPSP) Na Ca Na glutamate Postsynaptic Ca NMDA R Ca Dendrite Ca CaNa Na Na Ca Na AMPA R Na Na Na Mg++ 42 21  8/26/24 Excit a t ory Pos t Syna p t ic Pot e n t ia l CHANGES AT THE SYNAPSE Presynaptic Terminal Ca Na Na glutamate Postsynaptic Ca NMDA R Ca Dendrite CaNa Na Ca Na Ca Na Na AMPA R Na Na Mg++ 43 Sys t e m Re t urns t o Norm a l *neurons have different Presynaptic firing patterns or Terminal frequencies* glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 44 22  8/26/24 Long Te rm Pot e nt ia t ion (St re ngt he ning) CHANGES AT THE SYNAPSE Presynaptic Terminal glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 45 Long Te rm Pot e nt ia t ion (St re ngt he ning) CHANGES AT THE SYNAPSE Presynaptic Terminal High frequency Stimulation (50-100 Hz) glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 46 23  8/26/24 Long Te rm Pot e nt ia t ion (St re ngt he ning) CHANGES AT THE SYNAPSE Presynaptic Terminal High frequency Stimulation (50-100 Hz) glutamate Postsynaptic NMDA R Dendrite Na Na Na Na Na AMPA R Na Mg++ 47 Long Te rm Pot e nt ia t ion (St re ngt he ning) CHANGES AT THE SYNAPSE Presynaptic Terminal High frequency Stimulation (50-100 Hz) glutamate Postsynaptic NMDA R Dendrite Na Ca Ca Ca Na Na Ca Ca Na AMPA R Na Mg++ Huge EPSP! 48 Another process occurs in addition to this EPSP ring is the strengthening because there's a high level of Ca (calcium) that enters into the cell, you get an up-regulation of CaMKII and Protein Kinese C (PKC). 24  8/26/24 Long Te rm Pot e nt ia t ion (St re ngt he ning) CHANGES AT THE SYNAPSE Postsynaptic Dendrite Ca Ca Ca Na Na Na Ca Na glutamate Na Ca CaMKII NMDA R Protein Kinase C AMPA R High level o f Ca entry into cell upregulates Mg++ Calcium-calmodulin-dependent protein kinase II and Protein Kinase C 49 Ca MKII/ P KC - Enha nce s AMP A R Signa l CHANGES AT THE SYNAPSE Postsynaptic Dendrite Ca Ca Ca Na Na glutamate Ca Ca Na CaMKII NMDA R PKC AMPA R Mg++ High level of Ca entry into cell upregulates CaMKII and PKC - these enhance AMPA R 50 Because of that you get an enhancement of AMPA receptors which are inside the neuron and they get inserted into the membrane so now you have more AMPA receptors on the dendrite which means there's more potential for Glutamate signals to be received. 25  8/26/24 Ca MKII/ P KC - Enha nce s AMP A R Signa l CHANGES AT THE SYNAPSE Postsynaptic Dendrite Ca Ca Ca Na Na Ca glutamate Na Ca CaMKII NMDA R PKC AMPA R Mg++ CaMKII/PKC makes more AMPA R available and makes existing AMPA R more sensitive 51 Long Te rm Pot e nt ia t ion (St re ngt he ne d ) CHANGES AT THE SYNAPSE Postsynaptic Dendrite glutamate CaMKII NMDA R AMPA R The cell is strengthened It will depolarise a lot faster& stronger with next glutamate signal That's what long-term potentiation is. 52 26  8/26/24 Hebb Theory You might have multiple dendrites and a signal coming in on one dendrite which produces and EPSP but it's not strong enough to re the neuron. At the same time you get a stimulus coming in from another dendrite that is strong enough to cause a larger depolarisation that is strong enough to re and that in addition to it ring the depolarisation propagates to the other dendrite which will cause the NMDA receptors to open and an increase in that potential which could cause a depolarisation there- making it strong enough to re the initial dendrite with the weaker EPSP. Syna p t ic Co- Op e ra t ivit y CHANGES AT THE SYNAPSE Cells that fire together wire together High frequency stimulation is not enough to cause LTP EPSP in one part of the neuron requires an action potential to occur at the same time in order to produce HUGE depolarisations This results in back propagation (i.e., more positive to the dendrites from the axon hillock of the firing neuron) Synapses that co-operate to produce this action potential are wired together and can induce firing later on - independently! Hebb Theory (Donald Hebb 1940s) 53 BCM The ory CHANGES AT THE SYNAPSE Bidirectional regulation of synaptic strength (up or down) Long Term Potentiation Long Term Depression Named after Elie Bienestock, Leon Cooper & Paul Munro (Brown Uni) Synapses that are active when the cell is only weakly depolarised (i.e., only small EPSP, not action potential) will become weaker. Long Term Depression 54 27  8/26/24 Long Te rm Dep re s s ion (w e a ke ning) CHANGES AT THE SYNAPSE Presynaptic Terminal glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 55 In the weakening of LTD (weakening) the Glutamate is sitting in the vesicles upstream and it's released onto both the NMDA receptors and the AMPA receptors. Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Presynaptic Terminal Low frequency Stimulation (1-5 Hz) glutamate Postsynaptic NMDA R Dendrite AMPA R Mg++ 56 28  8/26/24 Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Presynaptic Terminal Low frequency Stimulation glutamate Postsynaptic NMDA R Dendrite Na Na AMPA R Mg++ 57 Opening of the AMPA receptors provides a weak EPSP (1-5) Hz and then a small amount of Ca (calcium) enters the cell but the depolarisation is not as large. Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Presynaptic Terminal Low frequency Stimulation glutamate Postsynaptic NMDA R Ca Dendrite Na Na AMPA R Mg++ Small amount of Calcium enters cell 58 29  8/26/24 Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Presynaptic Terminal Low frequency Stimulation glutamate Postsynaptic NMDA R Ca Dendrite Na Na AMPA R Mg++ Leads to overall small EPSP 59 Because there's a small EPSP there's not as much Ca (calcium) in the postsynaptic dendrite. So instead of getting CaMKII in the postsynaptic dendrite you're getting Phosphatase instead. Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Presynaptic Terminal Low frequency Stimulation Postsynaptic glutamate Dendrite Ca Na NMDA R Na Phosphatase AMPA R Small levels of calcium activate phosphatases 60 30  8/26/24 Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Postsynaptic Dendrite Phosphatase glutamate Phosphatases deactivate AMPA R NMDA R AMPA R 61 They can even cause it to become endocytosed (to leave the membrane and come into the cell body) Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Postsynaptic Dendrite Phosphatase glutamate Phosphatases deactivate AMPA R and NMDA R internalise them Glutamate cannot open AMPA R AMPA R so NMDA R cannot work either 62 31  8/26/24 Long Te rm Dep re s s ion (We a ke n ing) CHANGES AT THE SYNAPSE Postsynaptic Dendrite Phosphatase glutamate The neuron will be less affected NMDA R by glutamate AMPA R 63 After LTP; you're going to get a lower ratio of NMDA compared to AMPA in the membrane. LTD; you're going to get a higher ratio of NMDA compared to AMPA in the membrane. These terminals grow (they're called mushroom spines) the terminals increase or decrease in size depending on whether they experience more LTP or LTD. Ne ura l Pla s t ic it y (Neurop la s t ic it y) CHANGES AT THE SYNAPSE Bidirectional regulation o f th e AMPA Receptor a ffe c ts h o w strongly or weakly in p u ts are received a ffe c ts fu tu r e signalling/firing o f th e neuron in question How does th is relate t o memory? Anim al m odels (Morris w a te r maze) have show n t h a t NMDA receptor antagonists cause animals t o ‘fail t o remember’. Antagonists directed a t Calcium entry t o cell or t h a t block PKC/CaMKII have sim ilar e ffe cts because they're going to stop that up-regulation of AMPA receptors so they're going to stop that learning and memory from occurring. NMDA receptors are needed for the acquisition or consolidation of memories 64 32  8/26/24 The intracellular messengers involve metabotropic receptors which lead to a physical change in the neuron. In addition to the previous slides, you're going to need genes to be switched on to produce output receptor proteins and to increase dendritic branching. All of this involves protein synthesis which is dependant on these intracellular messengers which are activated by the metabotropic receptors. So they're all linked together but they ultimately result in this increase or decrease in the synapses (Ch. 12 of Kalat). Ne ura l Pla s t ic it y a nd Me m ory CHANGES AT THE SYNAPSE What about ‘maintenance’ of memories? These occur by changes in the intracellular messengers (upregulation) which then lead to physical change in the neuron Synthesis of new proteins and neuronal circuits (dendritic branching) (Chapter 12 in 13th Ed Kalat) Disassembly of existing circuits (dendritic pruning) 65 Ne ura l Pla s t ic it y a nd Me m ory CHANGES AT THE SYNAPSE LTP - strengthens the connections that our brains require to remember Extinction is not unlearning LTD - prunes unwanted connections to correct incorrectly learnt pathways or to ‘unlearn’ a behaviour (extinction). The increase in phosphatases also helps us to forget ‘unimportant’ information - you don’t need to remember everything! Memories begin as electrical signals temporarily remain by changes in second messenger systems become long-term when synaptic proteins/structures are modified CamKII and PKC 66 33  8/26/24 Sum m a ry I CHANGES AT THE SYNAPSE Aplysia are used fo r studying neuroplasticity o f habituation and sensitisation as they have sim ple nervous system s w h ich rem ain sim ilar betw een individual slugs LTP has three properties: - Specificity (active synapses becom e stronger), - Co-operativity (synapses t h a t are active together, w ire together) - Associativity (weak in p u ts paired w i t h strong in p u ts becom e strengthened). Hebb’s theory is t h a t only synapses t h a t are active w ith in 50 m s o f an action p o te n tia l w ill produce LTP. 67 67 Sum m a ry II CHANGES AT THE SYNAPSE LTP is produced by upregulation o f CaMKinase II & Protein Kinase C in th e dendrite - these upregulate AMPA glutam ate receptors LTD is produced by th e activation o f phosphatases, w h ich deactivate AMPA glutam ate receptors Activation o f AMPA receptors is im p o r ta n t fo r opening NMDA glutam ate receptors T reatm ent w i t h NMDA receptor antagonists reduce ro d e n t m em ory Memories begin as electrical signals, are tem porarily stored by changes in second messenger system s and are stored long t e r m by physical changes in th e neurons. 68 68 34  8/26/24 Wh e re is m e m ory s t ore d ? 69 Working Me m ory WHERE IS MEMORY STORED W hat is working memory? Temporary storage o f in fo rm a tio n so t h a t our actions are ongoing In addition t o sh o rt t e r m re te n tio n i t also means t h a t you can use th is t o ‘m anipulate’ in fo rm a tio n – (e.g., do a sim ple m a th s equation ‘in your head’) Working m em ory involves th e p re fro n ta l cortex o f th e fro n ta l lobe Working memory is best tested using a delayed response task Subject receives a s tim u lu s (light over one lever (o u t o f 10)) Light goes o ff, delay period (longer th e delay, b e tte r th e working m em ory) Subject asked t o press lever t h a t light was over O ther te s ts - Card came: m em ory or in anim al m odels: T - maze 70 70 35  8/26/24 Hippoca m pus a nd Me m ory WHERE IS MEMORY STORED Patient H.M. (1953) à Loss of the Medial Temporal Lobe Impaired Functions - Amnesia (loss of memory) - Anterograde amnesia (cannot form new memories) - Retrograde amnesia (cannot remember recent memories before surgery) - Cannot learn new facts (declarative) - bad at explicit memory (aware) where you can explain what you're remembering Preserved Function - Intellect and language - Can learn new motor skills (procedural) - Ok with implicit memory (unaware) H.M.’s condition suggested t h a t th e hippocam pus was m ore im p o r ta n t fo r som e m em ories th a n others. 71 71 Delayed nonmatching to sample task Hippoca m pus a nd Me m ory WHERE IS MEMORY STORED The hippocampus is involved in several types of memory. Two of the main memory types are: Declarative (explicit) memory - many of ours are episodic (single events) - “object recognition” tests - require animals to show which object is familiar and which is novel (rodents) - “Delayed matching-t o - sample task” which is familiar (primates) - “Delayed nonmatching-t o - sample task” which is new (primates) Spatial memory - memories of things in space - “radial arm maze” - rodents (rats learn to enter each arm once for food reward) - “Morris water maze” - finding the platform submersed in milky solution they should learn where to swim to so they can rest Animals with hippocampal damage have trouble with all of these tasks Kalat Figs 12.7 & 12.8 72 72 36  8/26/24 Me m ory Loss in Alzh e im e r ’s Dise a se WHERE IS MEMORY STORED Selective death o f Acetylcholine cells (ACH) ☠☠☠ Slowly progressing dem entia Memory loss Change in personality Apraxia - loss o f ability t o c o - ordinate m ovem ents Aphasia - loss o f ability t o articulate ideas and com prehend w ritte n /s p o k e n w ord Agnosia - cannot in te rp re t sensory stim u li 73 73 Alzh e im e r ’s Dis e a s e : Ac e t ylcholine WHERE IS MEMORY STORED Patients w ith Alzheimer’s Disease have reduced Acetylcholine (ACh) Acetylcholine is prevalent in brain regions involved in memory - Hippocampus, cortex And movement - Striatum Acetylcholine binds to t w o (cholinergic) receptor subtypes - Nicotinic - Muscarinic The muscarinic antagonist atropine can disrupt memory processing. Atropine has also been shown to inhibit the process of neurogenesis Acetylcholine is involved in proliferation and differentiation of neural stem cells! (Zhou et al., 2004, Cell Biology International 28:63-67) 74 74 37  8/26/24 What is the radial arm maze? Sum m a ry III WHERE IS MEMORY STORED Working (tem porary) m em ory involves th e p re fro n ta l cortex and is te s te d using a delayed response task Amnesia is th e loss o f m em ory - anterograde amnesia is th e loss o f new m em ories (or inability t o f o r m new m em ories) a fte r brain damage, retrograde amnesia is th e loss o f m em ories t h a t have fo rm e d recently before brain damage The hippocam pus is m o s t im p o r ta n t fo r declarative and spatial m em ory Declarative m em ory can be te s te d by object recognition and spatial m em ory can be te s te d in radial a rm maze or Morris w a te r maze Alzheimer’s Disease is slow degeneration o f neurons, w i t h dem entia and m em ory loss Patients w i t h Alzheimer’s Disease have reduced Acetylcholine (ACh) Acetylcholine binds t o m uscarinic and nicotinic receptors Atropine is a m uscarinic receptor antagonist t h a t can d isru p t m em ory processing and neurogenesis 75 75 Ne xt Tim e The le ctu re to p ic next week is “A ddiction” Reading: Kalat Chapter 14 Remember t o p o s t questions in team s if you d o n ’t understand anything! Ha ve a good d a y! 76 38