Memory Flashcards
Learning
Process of acquiring new understanding, knowledge, behaviours, skills, values, attitudes and preferences
Memory
Faculty of the mind by which data or information is encoded stored and retrieved when needed. It is the retention of info over time for the purpose of influencing future action
Reasons to research memory
Neurodegen diseases - dementia
Improve human memory
Get rid of unwanted memories (PTSD)
Basic mechanisms
Technology to improve memory
Ageing and enhancing lifespan of memory
What systems can be used to study memory
Humans - brain imagining (london taxi drivers), average memory span
Mice - behaviour, invasive brain studies
Invertebrates - aplecia (snail), sensitisation, gene expession, calcium signalling
Computer simulations
Distinctions of memory types
Memory vs habit
Explicit vs implicit
Knowing that vs knowing how
Memory without record vs memory with record
Declarative vs procedural
Biological info
Structure to function
Explicit - hippocampal
Implicit - striatum
Neocortex
Context and perceptual learning
Amygdala
Emotional responses (PTSD)
Medial temporal lobe
Declarative memory
Patient HM - medial temporal lobe removed to cure epilepsy, could not form new memories
Frontal lobe also needed for acquisition and refinement of new memories
Task: predict weather based on 14 card combos
Cards and whether guess
AD - damage in hippocampus so cannot make associative memories
Parkinson’s - damage in striatum cannot make procedural memories
Control - gets better
AD - got better at it
Parkinson’s - didn’t not get better
Training episode eg room, person etc
AD very low memory
Parkinson’s good
Virtual reality study with flag collection
Strategies
spatial and landmarks so hippocampal activation
Non soatial eg habit like the striatal activation, caudate nucleus
So different types of memory
What strategy is VPM Essen using to memorise pi digits
Declarative - visual, cake at entrance of his house
So probably Hippocampal
Ethical considerations in memory research
Emotional memories - psychological harm
Animal experiments - regulations
Invasiveness - so imagining studies
Informed Consent , right to withdraw (Helsinki convention)
Clinical trials - no unwanted effects
Up to individual not higher authorities (eg memory deletion)
Anterograde
No new memories
Retrograde
Lose old memories
Engram cells
Memory trace
The neuronal substrate responsible for storing and recalling memories, not yet a memory but provides physical conditions for memory to emerge
Memory emerges when appropriate retrieval cues reactive engram
Activated by learning experience
Physically or chemically changed by learning experience
Deactivated by subsequent presentation of the stimuli present at the learning experience
Multiple levels of analysis to understand memory storage
Network of brain regions
Population of nucleus
Cells (spines needed)
Synapse (NTs)
Nucleus (gene expression and histones)
Morris water maze
Test learning and memory in rodents
Finds platform and learns where it is and go straight there each time after learning
Prost training prove test
Control stay in the region of platform after removal
Hippocampus lesion, doesn’t remember so spend same amount of time in each quadrant
Same with subuculum lesion and when both lesions
NMDA receptor blockade
Blocks memory (so need NMDA for memory)
Molecular mechanisms of memory
Neuronal plasticity
Long term potentiation of synaptic response
Change of synaptic connections
Post synaptic response
Change in post synaptic spine number
Studies in invertebrate systems
Aplysia
Sensitises to poke (learns to ignore)
AP decreases
No longer reacts
Synaptic plasticity: neural circuits can change following stimulation
Synapses in the hippocampus whose efficient is influenced by activity which may have occurred several hours previously
In rabbit in denate area
These procedures are invasive
Long term potentiation: a cellular and molecular model of learning and memory
In mouse (invasive)
Extract mouse brain and extract hippocampus, Cut transverse hippocampus slices and place into recording chamber and place electrodes to record post synaptic activity
Response mediated by glutamate
How does synaptic plasticity occur
AMPA and NMDA receptors
Low Neurotransmitter release only AMPA receptors open as NMDA usually blocked by magnesium ions
Increased glu AMPA and NMDA open due to AP and so magnesium moves
NMDA also permeable to calcium so intracellular calcium requirement
Hebbian plasticity
Cells fired together are wired together
need for associative firing for plasticity
Hebbian learning: Presynaptic activity is well timed with postsynaptic depol leading to postsynaptif ca2+ increase (importance of NMDA receptors)
High frequency stimulation = LTP so increase synaptic function
Low frequency firing = LTD so decrease synaptic function
Postsynaptic cell - LTP causing high calcium influx so more AMPA receptors in post synaptic membrane
LTD weak calcium increase and can only activate some phosphotases which change phosphorylation of post synaptic receptors sometimes leading to internalisation
Low frequency LTP 1 every 10 seconds to make it spike and achieve LTP with greater postsynaptic activity
Vs same condition but lower post synaptic activity causing LTD
Intrinsic properties of neurons and their make up of voltage dependent channels influence their integration of signals and plasticity
Adult neurones vs newly generated neurones
Dentate gyrus (makes new neurons here)
Demonstrated immature neurones are relatively weak TBS were able to undergo plasticity more than mature neurones
Needed for new learning and memory
Spike timed dependent plasticity
Low frequency stimulation constantly
If firing doesn’t correlated with time of post synaptic response then doesn’t cause AP so depression
Demonstrates in cortical neurones of rats (EPS constant response but EPS and APs result in increased response)
TIMING MATTERS
AP before EPSP = LTD
Critical window for induction of synaptic potentiation and depression
LTP - EPSP followed by spike of AP
LTD - EPSP after spike of AP
Theta burst stimulation
Rapid burst of 4/5 spikes that are separated by 10 ms
Activity of hippocampal neurones in vivo when animal exploring a new environment
Cause LTP
Postsynaptic sppines importance in memory
Memory storage
May be locus storage of the brain (theory)
Hebbian idea of plasticity
Axon A near enough to excite cell B of repeatedly/ consistently takes part in firing it, some growth or metabolic change takes place in one or both cells such that As efficiency as one the cells firing B is increased
Glutamate signalling in synapse
Recording of hippocampal slice
Stable baseline induce LTP and LTD
Basal conditions, glu bind to AMPAR AND NMDAR but NMDAR blocked due to low stimulation
Strong, glu bind AMPAR and NMDAR mg leaves and so ca2+ and na+ enters cell
How to measure plasticity
Extracellular stimulation and recording for post synaptic response
Extracellular stimulation and patchbclamp recording
Dual path clamp/ paired recordings
Voltage and current
Induction protocols that induce plasticity
High/low frequency
Low frequency stim couple with weak/string postsynaptic depol
Spike timing dependent plasticity
Theta burst stimulation (100 Hz with 5Hz frequency)
0.1 Hz once every 10 seconds
1Hz once per second
100Hz 100 times per second
What is happening in postsynaptic spines during plasticity?
Glutamate and depol
Block NMDAR no LTP
So ca2+ and NMDAR needed for plasticity
What is downstream of ca2+ signalling
CAMKII activation - molecular switch for memory
In hippocampus- 1-2% of total protein by mass, ~10% of protein in post synaptic density (PSD), acutely activated by auto phosphorylation
CAMKII
Association and regulatory domains
Regulatory domain binds CaM, separation of domains and so exposure and activation of threonine (T286)
CAMKII becomes independent and keep self phosphorylated
Molecular switch for memory
Changes in post synaptic AMPA receptor number and conductance are associated with LTP/LTD
CAMKII leads to insertion of new AMPAR in the membrane through trafficking mechanisms
Rab11a protein important for trafficking of receptors to membrane due to LTP
LTD - lower inpulses we have through synapses still require calcium, activates calcineurin and PP1 (phosphotase) which removes AMPAR from membrane (internalisation)
Structure of AMPRA and NMDA receptors
Detrimers (4 subunits)
N terminal domain is outside cell
C terminal inside cell (post transcriptional modifications)
AMPAR - post translation modification important to determine synaptic inclusion (eg phosphorylation of serine 831 seen after LTP and interacts with trafficking mechanism)
Hypothetical timescale of CaMKII signalling in dendritic spines
Ca2+ in via NMDAR
CA2+ CaM binding
T286 phosphorylation
CaMKII activity (CaNKII and NMDA containing subunits gluN2B- maybe more plastic)
Actin polymerisation And AMPAR insertion
CaMKII: central molecular organiser of synaptic plasticity, learning and memory
Inactive spine to begin with sewn through blue flouresence
End - spine frown and active
CaMKII activity (keeps growing due to auto phosphorylation) and CaMKII-CaM (stays same ish) association separated relatively quickly
Immature spine
Plastic
Lots of glua2b in receptors
Some synapses start with only NMDA receptors (strong input causes insertion of AMPAR)
Mature spine
Store own history in its proteomic composition and it’s shape
Does associative plasticity actually occurs in vivo after learning? Does it mediate learning?
Electrophysiological observation of LTP in vivo
Inhibitory avoidance - dark side has footshock, stays in light despite wanting dark so learnt something
CA1 electrodes - trained has increased post synaptic function in the ca1 neurones
LTP increase isn’t that high and varies on intensity and electrodes
Serine 831 is phosphorylated after LTP in trained mice
It shows associative plasticity
Shows correlation so doesn’t really showing it mediates learning - manipulations are quite global so unknown if it’s really due to the LTP and AMPAR
Ways to delete an engram
Non targeted ablation
Targeted ablation
Neuron specific ablation
Engram neurone specific ablation
Deleting engram experiment
Contextual fear learning
Activation of neurones in dentate gyrus, cortex and lateral amygdala
Tag neurons
CREB viral vector to make neurones more likely to be part of engram. Same vector allowed toxin mediated destruction
Mice with ablated neurones could still acquire fear learning but worse memory
Ablating similar number of random neurones did not disrupt memory
Capturing then reactivating an engram
Cfos expressed when learning
Causes expression of tTA which activates TRE (promoter)
Channel redopsin 2 will be expressed too
So can label neuron that has undergone learning make it fire by activating with light
On DOX - sequesters tTA so do not express channel redopsin
Off DOX - channel redopsin expressed
Baseline, context a (gear learning), context b (light and freezing despite not having fear learning in that context)
Optogenetic stimulation of circuits
Express exogenous a protein in the brain
Ion channels incorporated
Shine laser results in activation (channel redopsin is sensitive to blue)
Modulation of plasticity in L and M
Behavioural states influence memory formation (brain states)
Neuromodulators (ACh), monoamine and catecholamines
Excitatory/Inhibitory balance
Synapse
Glial (tropic, release of neuro modulators)
Field activity
Regular steel electrode
Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation of at the goal location
Spike amplitude clustering
Separate activity of individual neurones
Sleeping animal - can reply the route it took backwards
Two stage model of memory formation
ACH for exploration and initial encoding of memory trace brain state 500ms
DA for reward and novelty enhance SWRs during immobility and for reactivation of memories. Brain state 50ms
Volume transmission
Main producer of ACh in the brain
Medial septum (MS)
Main producer of dopamine in the brain
Ventral tegmental area (VTA) and Loccus coeruleus (LA)
Areas activated by vagus nerve
Rat in novel cage evokes DA release in accumbens
Increase DA levels
Hippocampal VTA loop - controls the entry of info into long term memory
2 input experiment
Baseline and activated neurones
Block of dopamine receptors blocks late phase LTP
Memory - inhibitor, rats explore more because couldn’t make the memory as well
Cholinergic activation
Promotes theta/gamma oscillation
Suppresses ripple oscillation
Regulation of cholinergic tone allows switching between attentive and offline memory
Disrupted cholinergic activity impairs memory
Eg AD loss of ACh signalling
Impaired spatial learning and suppression of sharp wave ripples by cholinergic activation at the goal location
Impairs DA part of two stage learning
Fewer sharp wave ripples
Synaptic tagging and protein synthesis dependent plasticity
Code place when something important happens
A lot of protein synthesis happens at spine
Strong stimulus before weak can make weak strong
2 input study
Weak stimulus at stimulus 2 - LTP iffy
Strong stimulation to s1 and then weak to s2 gives good LTP
Cell active, increased CREB levels and excitability, input if recently fired synapse becomes stronger of new stimulus
Synaptic tagging
Presynaptic AP
Synaptic tag and E-LTP
Increased CREB levels
Synapse specific potentiation and LLTP
Increased CREB levels
Memory a and b positive neurone
Systems consolidation of memory
Interinal cortex maps position in general space without landmarks
Hippocampus is putting landmarks on
Other cortical areas also include info eg prefrontal cortex (have I been here before?)
Context learning
Hippocampus - electrodes
Dendogram - how correlated is the firing of a particular neurone depending on what the animal has to do
Object, valence, position, context encoded in that order
Prefrontal cortex
Helps hippocampus have control of what it retrieves and what it doesn’t
Hippocampus maps
Prefrontal cortex guides what info gets retrieved by interacting with dorsal hippocampus
Oscillation in the brain
Context exploration - hippocampus leads
Object sampling - PFC leads, hippocampus follows
Anatomical mapping
Brain Waves - theta waves (field), spikes (individual cells)
Spike before theta oscillation like animal is anticipating (ACh)
Organisation and control
Prefrontal cortex supports cognitive control of memory by developing representations that employ current contextual cues to select context appropriate memory representations and suppressing context inappropriate memories
Eg PTSD
Conclusions on memory
Distinct types of memory eg hippocampus and associative memory
Associative plasticity requires NMDA receptor signalling, ca2+ increase and CAMKII
