major studies Flashcards

Question

roozendaal (2006)

Answer 1

task 8 - how stress influences memory Interaction between NE and GLUCORTICOIDS – how? They want to know if NA is necessary for the effects of glu on memory Object recognition task – first day gets used to two objects then in second day one is replaced with a new object – if the animal spends more time on new object it means it remembered the old one Two conditions: one with stress and one without. -- to put a rat in a box is already stressful so they habituated them first (top right figure) for one out of two conditions Without habituation (NO STRESS) - Memory is enhanced by glu and it has an interaction with NE as memory is suppressed by propranolol (beta blocker) With habituation (STRESS) - Memory is not enhanced – meaning that glu (stress) enhances memory only in stressful-arousing conditions - if yohimbine (NE stimulant) is given after training then memory is enhanced

Answer 2

task 8 - amygdala and stress Drug RU 29362 (GR agonist) injected in hippocampus after training If NE is blocked in the amygdala then it does not modulate glu in hippocampus If amygdala is not there, you can’t modulate memory – see next slide

Answer 3

task 8 - amygdala and stress Experiment: Condition 1. arousing movie clips Condition 2. static movie clips They look amygdala activity and 3 weeks later they give them a memory test – the higher amygdalar activation was when watching the arousing movie clip the more movie clips they were able to remember :D , for neutral /static material there is NO EFFECT!

Answer 4

task 8 - amygdala and stress When humans are given a beta blocker (beta-adrenergic blocking agents) when watching arousing material there is less activity in the amygdala (figure B) – showing that NE plays a role in activating amygdala

Answer 5

task 5 - sushi belt model - microtubules: Microtubules in a neuron are used to transport substances to different parts of the cell. For example, neurotransmitters are made in the cell body close to the nucleus, but need to travel long distances to the end of axons where they will be used for synaptic transmission. - motor-paint technique developed to see how are the microtubules organized inside the dendrites, they’re interested in that because the microtubules transport the molecules travelling to the synapse . They look specifically at tyrosinated or acetylated microtubules (MT) - microtubules are either end positive or end negative and the motors that travel in these microtubules they are specific for one direction, in dendrides molecules in MT go in both directions - on the left the whiter the more calcium there is - on the right – black ampa receptors, when you have a line that goes from left to right then it is going outward, from top to bottom they are inward (going towards the soma), pause/blue are not moving

Answer 6

task 5 - sushi belt model - things always travel within the dendrite and when the synapse needs something – takes it out of the pool what is available

Answer 7

task 5 - mRNA transmission - where are proteins made in or around the synapse? You can study this by using metabolic labelling, one of the numerous ones is called puromycylation, puromycin is an antibiotic very small molecule. t RNA is the intermediate btw the ribosome and the amino acid which will at the end serve to make a protein. Puromycin is a aminoacyl t RNA analogue so it gets loaded at the place of the amino acid on all the t RNAs – in other words puromycin is transported by t RNA – when all t RNA is loaded with puromycin which is then transported to the ribosome and released to substitute an amino acid – this terminates the translation so you end up having truncated proteins (proteins that are not fully ready) but it carries puromycin that can be detected with an antibody – this way you can see in what location the proteins were being made - figure: neuron expressing GFP in green and v GLUT1 in pink (excitatory terminals) Method used: expansion microscopy , when all the antibodies are ready you put them into a gel that expands when it’s in water so that cell becomes very big and this way we can see synapses very well - red: detecting site of protein synthesis , there is a lot of activity outside the neuron of interest as a lot of cells are on – only a couple of neurons are expressing GFP (what interests us) - red shows that we have a lot of protein synthesis in the dendrite, also inside the spine (in the middle and not in postsynaptic density) and also, unexpectedly, a bit of protein synthesis in the pre synaptic terminal – from these results we can say that protein synthesis is basically happening everywhere  65% in POST SYNAPSE of the spines produce proteins after only 5 minutes, if labelling would have been longer probably the percentage would have been higher, 37% in PRE SYNAPSE of the spines produce proteins - so we induce plasticity on those neurons – protein synthesis – in presynapse, postsynapses and also INHIBITORY presynaptic TERMINALS (not mentioned above) - expain and be able to read the table!

Answer 8

task 5 - surface diffusion - how come the phosphorylation of this really remote RS protein has any impact? To investigate this they use FRET, you have two fluorophores, one that when is directly excited is going to shine some green fluorescence (GFP) – if you have another fluorophore in proximity then it could also excite that and if this happens the green disappears as it will excite another fluorophore that will shine red – there is an overlapping level of energy between the emission and excitation – when an electrode (green) is excited the lifetime of it is going to be reduced a lot as it is going to have multiple ways to escape from that high level of energy as electrodes when they’re in a high state they want to go down so they look at the half-life of green protons – the more green fluorophore interacts with red the more the half-life will go down - in the dendrites it is more green and inside the spine there is red – in the red (spine) there is strong interaction between PDZ-95 and the receptor REVIEW SLIDE MIDDLE AND LOW PART- CAN’T UNDERSTAND FROM LECTURE - why if you modify domain WT (blue circles) then a change in the receptor’s mobility happens?  charge in blue dots is positive , those positive charges bring the domain close to the membrane. If you put a negatively charged amino acid then it will bring it further from the membrane – when charge balance is changed then interaction PSD 95 - if there is a strong interaction between green and red fluorophore then there is WHAT THE FUCK DOES SHE SAY? - in her research she does a mutation that mimics phosphorylation and it results ? CaMKII – phosphorylation mediated by it, it also stops the cargo, it recruits protein and cargos that enable protein synthesis (including the protein synthesis itself), it immobilizes directly the receptors within the transmembrane

Answer 9

task 5 - surface diffusion - AMPAR receptors are made of different proteins, one (RS) that is very important is one that binds to PDZ-95, which is the organizer of the postsynaptic density (reason why postsynaptic density looks so dark when looked in microscopy). RS protein has a domain that can be phosphorylated by CaMKII in 9 different sites - if CaMKII gets activated and if you look at receptors that are diffusing - in normal conditions you have a lot of mobile receptors and little immobile  if CaMKII is always active then receptors do not move anymore and they find a synapse thus caMKII should play a role in recruiting the receptors ... but how does it do that?

Answer 10

task 7 - delay period Correlates: persistent activities during the delay period - In PFC: neurons are cue-selective, some are delay-selective and some are response-selective. ``` Oculomotor delayed response task in macaque monkeys ❖Some neurons in prefrontal cortex were active during the delay ❖These neurons were direction-tuned, i.e. a correlated for spatial ‘working’ memory ❖This example ‘delay neuron’ held on to this piece of information when monkey looked at a blank screen ❖She and colleagues suggested that similarly tuned frontal neurons formed a recurrently connected cluster— similar to how visual cortex works ```

Answer 11

task 7 - delay period Mechanisms: persistent firing: within a neuron or from a network? If persistent activity is within a neuron, photoinhibition should turn it off. If persistent activity is within a neuron, photoinhibition should turn it off. Otherwise: a network mechanism Premotor cortex in mice (activity predictive of correct/incorrect response)

Answer 12

task 7 - persistent stimulus - selective activity Networks? It could be local excitatory networks (excitatory glu neurons giving excitation to each other) or it could be mutual inhibition (excite local network (group 1) but also interneuron which inhibits more surrounding neurons (group 2) which are also inhibiting, so inhibit inhibition leads to excitation which then excite group 1. Plausible to think that neurons are doing long-range synaptic interactions across brain regions - evidence of long-range synaptic interactions: stimulus selective activity during delay period. In vPFC + anterior and ventral Intraparietal sulcus (AIP/VIP) there is a lot of persistent firing in delay period but not in visual cortex

Answer 13

task 7 - attractor dynamic and sensorimotor transformation - recurrent neural network – backward feedback , last layer gives feedback back to the input layer (A-B-A) - in recurrent nn- display increasing persistent activity when the demand of the task increases ``` The alternative: hybrid attractor dynamic and short- term synaptic plasticity model Masse et al 2019 Nat Neuro ❖ The spiking induces temporary (<1 s) changes in synaptic weights, perhaps via calcium dynamics ❖ Such short-term synaptic plasticity (STSP) could keep the information till the next burst of spikes! ❖ Orchestrated by beta and gamma rhythm ```

Answer 14

task 7 - gamma range oscillations task/method: experimental condition: results:

Answer 15

task 3 - replay for memory consolidation ``` task/method: experimental condition: - co-recorded MEC and CA1 grid and place cells to see whehter there was coordinated replay (measured by grid-place cell coherence) between the two brain areas which you would expect if replay is supporting memory consolidation –this was the case but coordination was stronger for forward replay than for reverse (graph gray and yellow) ``` results: hippo replay leads to coordinated grid cell replay in hippo's principal cortical output region - they also found that place cells were initiating the replay and the grid cells were behind 10 ms

Answer 16

task 6 - ``` - hippocampus separates all experiences by time so it can differentiate them - complementary learning system theory  consolidation: hippo is a “fast” learner and high plasticity and cortex is a “slow” learner with low plasticity – this allows extraction of overlapping principles to an abstract system after memory is encoded – this memory will lose details and only remember “gist” like info - advantage of slow learner (pfc) is that contrasting info (e.g penguin after learning wings=flying) is stored without erasing the other info ``` - Schema – great way to test semantic memory – large cortical network that creates long term memory only with one experience and it comes along with rapid systems consolidation (the longer you are in Nijmegen the better schema you’d have) - in rodents there is a task to measure this, rat needs to get the same cue as it ate before (e.g. strawberry flavour)

Answer 17

task 6 - gene expression in the cortex – new pair associate has higher gene expression - if limbic cortex is turned off (ampa receptor inhibitor) during encoding animals do not remember – gene expression in limbic cortex (= rat frontal cortex) is important otherwise they wouldn’t remember – if PFC is not active during updating of schema / semantic memory, then there is no rapid systems consolidation

Answer 18

task 6 - semantic memory in rodents is a under researched field - semantic memory is “facts”. Episodic and semantic memories are both declarative. - there is no rodent test that tests semantic memory  - many contrasting ideas of what the hippo does - Space: path integration and allocentric system (not egocentric) and episodic memory evolves from egocentric to allocentric view of the world (semantic) - Episodic memory: hippo can be responsible for that, hippo is good at bringing everything together (H.M didn’t have episodic memory) - index theory: hippo (the librarian) is a point where all the info are “put” together - circuit researchers: hippo functions only as pattern completion (CA1) and pattern (DG)separation - scene reconstruction: new theory – hippo is not very good for memory bc it has a fast turnover of synapses, instead the hippo does is completing the story that the cortex is telling – need hippo for reconstructing a scene and this would explain false memory formation (the hippo “fills” in missing info which are integrated from other memories)

Answer 19

task 6 - semantic memories could come from episodic memories - semantic memories formation – you have an experience (e.g. sitting in class) and some neurons activate. Recall  all the neurons that were active during memory formation are also active when recalling - some neurons are more important than others (neuronal hubs) as if you inactivate those you lose the whole memory - hippocampal hubs are especially important for episodic memories - frontal cortex (human - pfc, mpfc, rodents - prelimbic and acc) hubs are important for storage - default mode network is the “memory” network as it includes many memory hubs - object space task is developed – based on principle of novelty, explore novel object inserted in space more – they do differently bc they overlap (5 trials spaced with breaks of 45 minutes, they have different objects in each trial but same location – some locations have been presented less and they check whether the animal remembers by seeing if it explores more the item at the least presented location

Answer 20

SCHEMA FIG FROM THIS GUY - lecturer mentions a variety of experiments with him Stress through glocorticoids impair retrival (see next slides) but enhances consolidation Train animal to be in platform, Shortly before recall they stress animal – In control they recall training and stay more in platform, same for 2 minutes after stressor or 4 hours after stressor. Significantly, we see that 30 min after stress they can’t recall where the platform is as well as the other conditions – stress impairs recall after 30 minutes as the cortisol response takes around 20-30 minutes to raise plasma corticosterone levels Glucorticoids impair memory recall!

Answer 21

Task 4 ``` Molecular basis of memory development: NMDARs • GluN1 expression is already high at birth and does not change across development • GluN2A is only expressed post-natally and near-adult levels are reached by ~4weeks of age • GluN2B expression is high at birth and gradually goes down until ~4weeks of age • In the adult, GluN2A is the dominant NMDAR subunit. Monyer et al. (1994) ```

Answer 22

``` Task 4 Molecular basis of memory development: NMDARs • Differences between GluN2A and GluN2B • GluN2Bs have higher affinity for glutamate • GluN2As deactivate more quickly • GluN2B synapses have a lower threshold for LTP! • Over-expression of GluN2B leads to enhanced memory ```

Answer 23

Task 4 Molecular basis of memory development: NMDARs • Training on a contextual fear conditioning task at P17 (infantile amnesia period) accelerated the switch in GluN2A/GluN2B expression • Perhaps this molecular switch represents a critical period for memory development? Travaglia et al. (2016)

Answer 24

Task 4 ``` Molecular basis of memory development: NMDARs • Developmental changes in GluN2A and GluN2B expression levels show that there is a development ‘switch’ in which GluN2 subunit dominates NMDARs • This switch occurs coincidentally with the emergence of episodic memory • What are the differences between GluN2A and GluN2B? ``` ---- Molecular basis of memory development • Synaptic plasticity also involves altering protein interactions in post-synaptic cells via kinases • A key kinase is CaMKII • CaMKII is activated if calcium enters the post-synaptic cell. • Once activated it translocates to the synapse and binds to GluN2Bs, inducing spine growth. • CaMKII-GluN2B interactions are vital for LTP induction and activation of CaMKII is sufficient to potentiate synapses • Interestingly, CaMKII levels reach near- adult levels during 4th post-natal week -The developmental period associated with the emergence of memory is marked by dramatic changes in the molecular composition and processes within excitatory neurons • Based on the developmental timeline of various molecular candidates, memory development may depend on the GluN2A/GluN2B switch and the expression of CaMKII Lohmann & Kessels (2014)