Pain, Synaptic Plasticity, and Memory Encoding Flashcards
Name the three components of the multidimensional pain experience. (3)
Sensory-discriminative
Affective-motivational
Cognitive-evaluative
Describe the sensory-discriminative aspect of pain. (1)
The somatosensory perception of the noxious stimulus (ie. location, temperature, pressure)
Describe the affective-motivational aspect of pain. (1)
Encoding of negative affect within emotional and motivational circuits, and the drive to halt the unpleasant percept.
Describe the cognitive-evaluative aspect of pain. (1)
Evaluation and modulation of pain experience by cognitive circuits
Only when which brain region is activated do descending pathways become active? (1)
PFC
Why are all three components of pain necessary? (1)
The ‘components’ are:
- sensory-discriminative
- affective-motivational
- cognitive-evaluative
To optimally select actions that limit exposure to noxious stimuli and pain experience.
What specific role might the motor cortex and supplementary motor area have in pain? (2)
Escape planning and motivation
Integration of motor and sensory aspects of pain
What roles might the somatosensory cortex, insula, and thalamus have in pain? (2)
Encode intensity of pain
Receive nociceptive input from spinal cord
What roles might the temporoparietal junction have in pain? (2)
Multisensory integration
Chronic pain: altered higher-level pain processes
Fill the gaps relating to affective aspects of chronic pain. (6)
Fear of ……………………, or “kinesiophobia”, as well as the associated fear of …………………., are important factors in the development, maintenance, and ……………………… of pain.
Chronic pain patients learn to …………………….. impending pain and increasingly avoid activities, resulting in the development of ………………… and ………………..
movement
pain
chronification
pay attention to
anxiety
depression
Describe the sustained behavioural cycle produced when someone associates neutral stimuli with pain experiences. (5)
pain -> tension -> fear -> stress -> chronic pain
True or false? Explain your answer if necessary. (1)
Associating neutral stimuli with pain experiences can enhance moderate pain.
True
Describe how pain-associated memories are produced - the neuronal circuits from stimulus to memory trace. (10)
- Pain stimulus is present
- Primary afferent fibres activated
- Dorsal horn and ascending tracts activated
- Pain signals sent to thalamus and somatosensory cortex
- Information distributed throughout rest of cortex (especially entorhinal)
- Entorhinal cortex to dentate gyrus granule cells via perforant pathway
- Dentate granule cells to CA3 pyramidal neurones via mossy fibres
- CA3 to CA1 via Schaffer collaterals
- From CA1, through the subiculum and back to entorhinal cortex
- Information then sent out to other cortical areas to be stored as a memory trace
True or false? Explain your answer if necessary. (1)
Pain inhibits memory formation.
False - pain is a strong trigger of memory formation
Describe and explain a passive avoidance memory task. (6)
Rodent in cage
light side with no foot shock; dark side with mild foot shock stimulus
put rodent into light side of box
rodents do not like light side at first because it is brighter and more exposed, so they run to the dark side
they get a foot shock on dark side of the box so learn to avoid this side and the associated pain stimulus
test rodent’s pain memory by putting them back into light side of box 24 hrs later - if they don’t go to the dark side it suggests that they have remembered the painful stimulus
Name the brain area which is vital for the development of contextual memories. (1)
Hippocampus
Fill the gaps relating to passive avoidance. (2)
A key concept of the passive avoidance task, is that the pain stimulus is ……………………., and animals learn to ………………….. the stimulus.
escapable
avoid
Describe the concept of contextual fear conditioning. (4)
- External stimuli detected by sensory systems (visual, odours, sounds, touch)
- contribute to the formation of feature-rich spatial-contextual memories
- so put a rodent in a box with a foot shock and specific external stimuli
- and they will show fear response if put in that environment again, even without foot shock
Fill the gaps relating to contextual fear conditioning in rodents. (8)
An ………………………….. foot shock is paired with ……………………………..
You let the rodents get acquainted with the environment and form a ……………………. of the context.
Then give a foot shock, which will produce …………………………
Then measure …………………………. to test fear responses when put into similar contexts.
A different context should produce ……………………. because external cues are ……………….., and the new context is ……………………….. with fear and pain.
unavoidable/inescapable
external environmental cues
memory
a pain/fear memory
freezing/immobility time
no fear response
different
not associated
Describe why pre-exposure habituation is important in contextual fear conditioning in rodents. (4)
- Giving an immediate shock does not exert a fear response in the same context 24 hours later
- So a certain amount of time is required for the animal to process and form a memory of the novel context
- Performing pre-exposure habituation to the context in the absence of the unconditioned stimulus 24 hours before shock exposure enhances the association between the context and the shock
- Longer durations spent in a context result in stronger unified representations of the context
Briefly describe how we can investigate how memories are encoded in the brain. (2)
Put mice in a novel context and measure cellular responses in the brain.
Attach mice to stereotactic frame and run on a ball, either in their home cage or a novel virtual reality environment.
When investigating how memories are encoded in mice while they’re running in a novel virtual reality setting, how can we ensure that mice will participate in the experiment? (2)
Water-deprive them
and give water as a reward for running.
What is a memory engram? (3)
A long-lasting biochemical or physical/structural alteration to the homeostatic functioning of a neural network,
caused by changes in activity in a subset of neurons due to episodic stimuli (sensory input),
and can be reactivated following the re-experience of all, or part, of the original stimuli, leading to memory recall.
Describe and explain how you could visualise which neurones in the brain are activated when a rodent is exposed to a certain stimulus. (3)
Use FosGFP
which is a fusion between C-Fos (immediate early gene) and GFP gene
meaning that GFP is produced when C-Fos is produced, so when a neurone has been activated.
Describe the activation that we see in the brain when rodents are put in a novel virtual reality context. (3)
What does this indicate? (1)
Increased activation of dentate gyrus
especially the outer, upper blade
with fewer active neurones in the inner, lower blade.
- This indicates lots of new memory formation
Describe where in the dentate gyrus neural stem cells and newly born neurones are located. (1)
Are these types of cells activated more or less than mature neurones when creating a memory engram? (1)
Inner layer
less (mature neurones activated more when creating a memory engram)
What happens to memories (memory engrams) during sleep? (3)
Memories are reactivated
which helps to strengthen synaptic connections in the memory engram
via Hebbian plasticity (LTP).
True or false? Explain your answer if necessary. (1)
Sleep helps to strengthen memories and the memory engram.
True
True or false? Explain your answer if necessary. (1)
A partial stimulus, which only directly activates part of the memory engram, will lead to recall of the whole memory.
True
Describe how a partial stimulus, which only directly activates part of the memory engram, will lead to recall of the whole memory. (2)
The connections between all the neurones in the memory engram is strengthened
so the partial activation will lead to the other neurones in the memory engram becoming activated.
Describe how memory engrams relating to fear can be studied using optogenetics. (3)
Label cells which were recently activated following fear stimulus with ChR2
Shine blue light to activate these neurones
This will produce fear response in different context due to activation of the memory engram
Fill the gaps relating to pain-associated memory encoding and recall. (2)
Memory encoding is carried out by the ……………………, but long-term storage of memories is largely carried out by the ………………………..
hippocampus
prefrontal cortex
Fill the gaps relating to memory encoding and storage. (6)
Kitamura et al. (2017) found that engrams are formed simultaneously in the early stages of context memory acquisition (Day-1) in both the ……………………. and the ……………………….. where long-term memory is eventually stored.
The …………………… engram cells which were generated in the early stages are not reactivated during recent memory recall (Day-2). Instead, they exist as “silent engrams” that …………………………..
The ………………………….. engrams also mature and strengthen over time, whereas ………………………… engram cells gradually become silent.
hippocampus
medial prefrontal cortex (mPFC)
mPFC
strengthen over time
basolateral amygdala (BLA)
hippocampal
When recent memories are recalled, activating the hippocampal memory engram, via which cortical area do the neurones communicate the memory? (1)
Medial entorhinal cortex
All fear/context-related memory engrams, whether involved in recent or remote memory recall, project via which brain area? (1)
Amygdala
True or false? Explain your answer if necessary. (1)
Despite the observed shift in the active cell population (engram) from the hippocampus to mPFC over time, the long-term storage of the contextual memory remains stable.
True
Which brain region is central to cued fear conditioning? (1)
(Basolateral) amygdala
Describe cued fear conditioning. (3)
When a footshock is delivered with a signal (eg. a bell or alarm)
the animal will show fear
and will subsequently show fear in a completely different context on exposure to the bell/alarm, even if footshock is not present.
Fill the gaps relating to cued fear conditioning. (7)
The ……………………… receives foot-shock (unconditioned stimulus) information via the ascending pain pathways including the ……………………………. and the …………………………. It also receives auditory (conditioned stimulus) information via the …………………… It projects not only back to the ……………………., but to the ……………….
This shows that cues can strongly activate memories related to fear/pain, and this is mediated by the …………………..
basolateral amygdala
periaqueductal grey (PAG)
parabrachial nucleus (PBN)
thalamus
hippocampus
prefrontal cortex
amygdala
Fill the gaps relating to memory formation and recall. (2)
The ……………………. plays an important role in forming memories of similar contexts, but not getting them mixed up. This is called ………………………
dentate gyrus
pattern separation
True or false? Explain your answer if necessary. (1)
Some memory engrams feature overlapping neurones, especially if the contexts are similar.
True
How is the hippocampus (dentate gyrus) able to differentiate between different memory traces when only partial reactivation occurs? (1)
Due to Hebbian plasticity strengthening connections between certain neuronal circuits.
Describe how we might get partial reactivation of a memory engram. (1)
If some of the stimulus matches but other parts don’t (eg. if auditory stimulus matches but visual doesn’t)
Why might adult neurogenesis affect pattern separation and memory encoding? (1)
The dentate gyrus (where pattern separation takes place) is a region of adult neurogenesis.
Fill the gaps relating to the role of neurogenesis in pattern separation. (9)
If levels of neurogenesis are high (e.g. in young people), some neurones in the memory engram are ………………., and some are ………………
These cells mature and …………………, forming a memory engram if they have been activated during a ………………………….
The new neurones are sent to the ………………. layer of the DG, and are …………………. (readily/not) available to be used for subsequent memory engrams.
If levels of neurogenesis are low (e.g. Alzheimer’s), there are less ……………………….. available to be activated during memory formation.
Therefore there is more ………………… between memory engrams, and a novel context may produce a ………………… engram to an already-established memory.
mature
stem cells
migrate
contextual memory
outer
not
neural stem cells
overlap
similar
Describe how adult neurogenesis contributes to pattern separation in the dentate gyrus. (4)
Stem cells can be activated during memory encoding
they mature and migrate to the outer layer of the dentate gyrus and become part of the memory engram
however they are not available to be activated for subsequent memories
but if neurogenesis levels are low, there are less neural stem cells and more overlap between mature neurones activated in memory engrams.
Name the process by which connections between neurones making up memory engrams are strengthened. (1)
LTP (Hebbian plasticity)
Briefly describe the process and receptors contributing to LTP. (7)
- AMPA receptors activated by glutamate
- Membrane depolarisation
- NMDA receptors activated by glutamate (Mg block removed)
- Calcium influx into postsynaptic neurone
- Ca-Calmodulin activates adenylate cyclase and CaMKII
- Leads to altered gene expression
- And phosphorylation of AMPA receptors and new AMPA receptors inserted into membrane
Describe the structural and cytoskeletal changes that occur when LTP is induced in a postsynaptic cell. (4)
- Integrin signalling
- ECM reassembly
- Cytoskeletal expansion
- Synapse stabilisation
Fill the gaps relating to LTP and memory formation. (11)
LTP is due to a number of putative cascades triggered by the input signal. First, the activation of …………………. receptors, activated by the neurotransmitter …………………………, initiates several calcium-dependent signaling cascades important for regulation of ……………………… activity and nuclear ………………….. Second, the interaction of presynaptic ………………….. and postsynaptic …………………. cell adhesion molecules stabilizes transient synaptic contacts for synapse specification. Third, ………………. receptors detect extracellular matrix (ECM) signals and promote the disassembly of ………………………… One downstream integrin mechanism is the activation of cofilin or other actin-related proteins (ARPs), which leads to the depolymerization and reorganization of …………………….. Fourth, ………………….. receptors, which are activated by …………………, are trafficked to the postsynaptic density (PSD). Together, these mechanisms rebuild the dendritic spine head, increase the concentration of glutamatergic receptors, and stabilize synaptic connections.
NMDA
glutamate
synaptic protein
transcription
neurexin
neuroligin
integrin
cytoskeleton proteins
actin filaments
AMPA
glutamate
What is metaplasticity? (2)
The concept that new information coming into the hippocampus can change synaptic strength
and the subsequent ability of synapses to change their strength.
What is ‘depotentiation’? (1)
Give two ways that depotentiation can occur. (2)
Reversing LTP
- Removing extra AMPA receptors which were put into the membrane
- Dephosphorylating AMPA receptors
What happens to the number of AMPA receptors in the postsynaptic membrane during LTD? (1)
Decrease
Complete the sentence. (1)
LTP and LTD are both dependent on the size of the ……………………………..
*Hint: it is a phrase
calcium influx in the postsynaptic neurone.
Does LTP or LTD tend to occur when a new context is experienced? (1)
LTP
Describe the specific intracellular mechanism of LTP. (8)
High levels of glutamate released at the synapse,
resulting in a very large calcium influx.
Calcium binds to CaM (calmodulin),
which can activate calcium-dependent kinases such as CaMKII via phosphorylation.
Phosphorylated CaMKII can then phosphorylate AMPA receptors, making them more likely to open in response to glutamate.
Additionally, CaM activates adenylyl cyclase and upregulates cAMP, leading to PKA activation.
PKA phosphorylates an inhibitor of PP1 (protein phosphatase 1),
so PP1 is inhibited and cannot dephosphorylate CaMKII.
Describe the type of stimulus that typically causes LTD. (1)
Low frequency
Describe the exact cellular mechanism which causes LTD. (7)
Low frequency results in only moderate glutamate release
and a smaller calcium influx.
Calcium still binds to calmodulin,
however CaM now preferentially activates calcineurin (a calcium-dependent phosphatase).
This dephosphorylates the inhibitor of PP1
so PP1 is able to dephosphorylate CaMKII
and AMPA receptors cannot be phosphorylated.
Describe how increasing calcium concentration in the postsynaptic cell changes the synapse strength, from very low calcium influxes to very high calcium influxes. (4)
Very low - no change
Fairly low/moderate - LTD
High - LTP
Very high - excitotoxicity
