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
Fill the gaps relating to LTP. (4)
LTP can be thought of as a change in the probability that ……………………. will occur.
LTP = an increase in the probability of a certain ………………………. causing a ………………………
LTP causes a shift in the …………………………….. distribution.
a synaptic event
glutamate concentration
synaptic event
cumulative probability
There is a large overlap between chronic pain and depression.
Which brain area in particular is involved? (1)
Name four specific changes in this brain area that is thought to be common to both chronic pain and depression. (4)
Hippocampus
- Decreased volume
- Increased inflammatory mediators (TNFa and IL1b)
- Decreased BDNF (and maybe other neurotrophic factors)
- Decreased neural plasticity and neurogenesis
Describe 6 general structural and functional changes in the brains of chronic pain sufferers. (6)
- Expansion and shifts of cortical representations
- Alterations in grey matter volume
- Altered resting-state and pain-evoked functional connectivity
- Altered glial activity
- Impaired descending inhibitory control
- Altered structural integrity and connectivity of white matter
Fill the gaps relating to brain networks and chronic pain. (8)
The ………………… receives stress signals from the ………………… and ……………….. (potentially relating to pain), and activates the ……………… axis.
However there are some intermediate structures which are involved, such as the ………………………, …………………………, …………………………., and …………………………..
amygdala
thalamus
cortex
HPA
nucleus tractus solitarius
dorsomedial hypothalamic nucleus
medial preoptic area
bed nucleus of the stria terminalis
Match the following brain areas, which may be involved with chronic pain and stress/anxiety/depression, with their functions. (3)
a) nucleus tractus solitarius
b) dorsomedial hypothalamic nucleus
c) bed nucleus of the stria terminalis
1) controls autonomic, neuroendocrine and behavioural responses
2) involved in autonomic stress responses
3) the principal visceral sensory nucleus in the brain
a) and 3)
b) and 2)
c) and 1)
Fill the gaps relating to a study investigating maladaptive plasticity and chronic pain. (4)
There is a contribution of ………………… receptor-mediated LTD in the ………………. to …………………. pathway to comorbid aversive depressive symptoms in neuropathic pain.
These cellular and network changes are known as ……………………….
AMPA
lateral amygdala / basolateral amygdala
central amygdala
maladaptive plasticity
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced symptoms in rodents by performing spinal nerve ligation.
What general effects did SNL have on rodents? (3)
Pain (reduced paw withdrawal threshold)
Anhedonia (reduced sucrose preference)
Depression (increased immobility time)
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
Describe the time course of when these symptoms developed after SNL. (2)
Pain developed almost immediately
Anhedonia and depression developed after about 4-5 weeks
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
Describe how lesioning the LA/BLA affected paw withdrawal threshold after SNL. (1)
Draw a conclusion. (1)
LA/BLA lesion after SNL doesn’t alter PWT (pain).
Therefore, the LA/BLA may not contribute to neuropathic pain.
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
Describe how lesioning the CeA affected paw withdrawal threshold after SNL. (1)
Draw a conclusion. (1)
CeA lesion after SNL increases PWT (decreased pain)
Therefore, the CeA may contribute to neuropathic pain.
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
How did they look at the morphology and complexity of neurones in the LA/BLA and CeA? (1)
Use Golgi-cox staining
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They used Golgi-cox staining to look at the morphology and complexity of neurones in the LA/BLA and CeA. They performed a Sholl analysis.
What is a Sholl analysis? (3)
Draw concentric circles around the neurones with the cell body in the middle
Count the number of crossings of the neurones with the circles
Can analyse whether complexity changes with distal and proximal neurites (i.e. how does complexity change moving away from the soma?)
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They used Golgi-cox staining to look at the morphology and complexity of neurones in the LA/BLA and CeA. They performed a Sholl analysis.
What results did they find regarding neuronal morphology and complexity in the LA/BLA after SNL? (3)
Complexity increased near to soma with SNL
Complexity not altered further from soma
Increased spine density with SNL
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They used Golgi-cox staining to look at the morphology and complexity of neurones in the LA/BLA and CeA. They performed a Sholl analysis.
What results did they find regarding neuronal morphology and complexity in the CeA after SNL? (2)
No change in the complexity of neurones with SNL
Reduced spine density with SNL
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They used Golgi-cox staining to look at the morphology and complexity of neurones in the LA/BLA and CeA. They performed a Sholl analysis.
True or false? Explain your answer if necessary. (1)
The different parts of the amygdala show similar neuroplastic changes in response to chronic pain (SNL).
False - different parts of the amygdala change in different ways in response to chronic pain
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
How did they look at functional changes in neurotransmission in synapses from the LA/BLA to CeA? (1)
Electrophysiological field EPSP recordings
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
What were the findings regarding LTD at synapses from LA/BLA to CeA after SNL? (1)
How did they induce LTD? (1)
Long-lasting, enhanced LTD after SNL
Induced by a low frequency stimulus for about 8 minutes
What type of stimulus is used to induce LTP? (1)
High frequency
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They induced LTP in control and SNL neurones with 2 separate high frequency stimuli.
What were the results regarding LTP in SNL rats? (1)
Reduced LTP (for both high frequency stimuli)
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
How did the amplitude of EPSCs change in SNL rats? (1)
Reduction in the amplitude of EPSCs in SNL rats.
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They looked at functional changes in neurotransmission in synapses from the LA/BLA to CeA.
Describe the overall results regarding functional changes, including the time scale of when changes were seen. (3)
Enhanced LTD
and reduced LTP in CeA synapses of SNL (chronic pain) rats
4-5 weeks after chronic pain was induced.
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
Describe the specific changes in phosphorylation of 2 specific glutamate receptor subunits after SNL in the CeA. (2)
Reduction of phosphorylated GluA1-Ser845
Elevation of phosphorylated GluA2-Ser880
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They found elevated phosphorylated GluA2-Ser880 after SNL.
What is GluA2? (1)
What is the effect of phosphorylating GluA2-Ser880? (2)
AMPA subunit
Phosphorylation of GluA2-Ser880 is critical for promoting GluA2-containing Ca2+ impermeable-AMPAR endocytosis
and leads to LTD
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They found elevated phosphorylated GluA2-Ser880 after SNL, and measured field EPSPs to determine AMPA currents.
Describe how we can determine specific AMPA currents by measuring field EPSPs. (2)
Field EPSPs are usually made up of both AMPA and NMDA currents.
To measure AMPA current only, add NMDA blocker before measuring EPSPs.
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They found elevated phosphorylated GluA2-Ser880 after SNL, and measured field EPSPs to determine AMPA currents.
How would you expect AMPA currents to be different following SNL? (1)
Smaller AMPA current
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They found elevated phosphorylated GluA2-Ser880 after SNL, and reduction of phosphorylated GluA1-Ser845.
They measured these with Western blots.
What was used as a control protein in these experiments? (1)
GAPDH
Which AMPA subunit is thought to determine calcium permeability? (1)
GluA2
Describe how the GluA2 subunit determines whether an AMPA receptor is permeable to calcium. (2)
GluA2-containing receptors are impermeable to calcium.
GluA2-lacking receptors are more calcium permeable.
Describe how phosphorylation of the GluA2 subunit occurs, and the results of this. (5)
Phosphorylated at Ser-880
by PKC
which is activated by low frequency stimulation
and the AMPA receptors are then internalised
which results in a reduction of neurotransmission (LTD).
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They found elevated phosphorylated GluA2-Ser880 after SNL, and determined that this would lead to AMPA endocytosis and LTD.
Describe how they could block this process in SNL rats. (3)
What control would be used? (1)
Use Pep2-EVKI
which is a peptide that was developed to bind to an internal site of the AMPA receptor
and this will prevent endocytosis.
The control peptide was Pep2-SVKE which will not prevent endocytosis of AMPA receptors.
A study looked at the contribution of AMPA receptor-mediated LTD in LA/BLA-CeA pathway to comorbid aversive and depressive symptoms in neuropathic pain.
They induced pain, anhedonia, and depressive symptoms in rodents by performing spinal nerve ligation.
They found elevated phosphorylated GluA2-Ser880 after SNL, and determined that this would lead to AMPA endocytosis and LTD.
Therefore, they blocked AMPA endocytosis using Pep2-EVKI.
Describe the effects of Pep2-EVKI on LTD (and describe how this was shown) after SNI. (2)
Also describe the effects on PWT, immobility time, and sucrose preference. (3)
Draw a conclusion. (2)
Prevents enhanced LTD
which is shown by an increase in ESPC amplitude.
- Increases PWT
- Increases sucrose preference
- Decreases immobility time
This shows that the endocytosis of AMPA receptors plays a role in chronic pain and comorbid depressive symptoms in rats.
And it also shows that chronic pain is not just sensory, but also emotional, because manipulating amygdala function is able to reduce chronic pain.
Fill the gaps relating to the research paper on LTD in the LA/BLA and CeA in chronic pain. (4)
Chronic pain induces ……………………… in the …………………………. of the amygdala, and this contributes to anxiety and depression-like symptoms.
Reversing this helps to treat both ………………….. and ………………………….. after spinal nerve ligation.
maladaptive plasticity
central nucleus
chronic pain
anxiety/depressive symptoms
Fill the gaps relating to the BNST. (6)
The bed nucleus of the stria terminalis (BNST) is a …………………. structure and is thought to play a central and critical role in:
- the integration of information on …………………… (the degree to which something is pleasurable),
- …………. and ………………… states,
- the processing of ……………….. information,
- stress, ……………. and fear-related behaviours.
forebrain
hedonic-valence
mood
arousal
emotional
anxiety
The BNST integrates information on which four brain processes/types of information? (4)
Hedonic-valence (the degree to which something is pleasurable)
Mood and arousal states
Processing of emotional information
Stress, anxiety, and fear-related behaviours
Fill the gaps relating to the BNST. (2)
The BNST receives direct and indirect nociceptive information from the …………………….. and plays a critical role in determining the ………………………….. of acute noxious stimuli.
spinal dorsal horn
affective consequences
Fill the gaps relating to the BNST. (5)
Most BNST neurons are …………………….ergic and there are sub-populations of BNST neurons that synapse on ……………………………………. neurons.
Selective activation of the anterodorsal BNST output neurons projecting to the lateral hypothalamus has been reported to produce an …………………. effect.
Chronic pain elevates the excitability of ……………………….. that synapse on LH-projecting adBNST neurons causing their sustained suppression which ………………….. anxiety-like behaviour.
GABA
lateral hypothalamus-projecting anterodorsal BNST neurones (adBNST)
anxiolytic
GABAergic inhibitory interneurones
enhances
True or false? Explain your answer if necessary. (1)
The BNST is very connected, with both afferent and efferent projections from/to the amygdala, hypothalamus, and other forebrain and brainstem regions. It plays an important role in regulating stress and anxiety alongside the amygdala.
True
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain.
Describe the effects on mechanical threshold over 4 weeks post-injury. (1)
Reduced mechanical threshold for the whole 4 weeks
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and measured behaviour after about 4 weeks.
Give three anxiety tests that could be used. (3)
Elevated plus maze
Light/dark box
Open field test
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and measured behaviour after about 4 weeks.
Describe the results seen in the elevated plus maze, light/dark box, and open field tests. (6)
*2 results for each test
What do these results indicate? (1)
EPM:
- decreased distance in open arms
- decreased time spent in open arms
LDB:
- decreased time spent in light side
- no difference in latency to light
OFT:
- no difference in time spent in centre
- reduced centre entries
SNI induces anxiety-like symptoms after about 4 weeks.
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
Describe how they identified these neurones. (4)
Retrobeads injected into hypothalamus, and travel backwards to BNST.
So when you look at BNST you can see neurones which project to the hypothalamus.
Biocytin injected into BNST and travels towards lateral hypothalamus,
to confirm connections between BNST and hypothalamic neurones.
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They measured the Ih currents in the adBNST cells before testing them.
What is the Ih current? (4)
Why was it measured? (1)
Activated when the cell is hyperpolarised
e.g. in the hyperpolarisation after an action potential
and mediated by opening of the HCN channels
and the current aims to bring membrane potential back to resting
- Potentially measured so that they only measured activity of Ih-negative cells so the Ih current didn’t interfere with measurements
True or false? Explain your answer if necessary. (1)
Not all neurones have HCN channels present - about 75% are Ih positive.
False - only about 25% are Ih positive
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They measured the Ih currents in the adBNST cells before testing them.
Describe how nerve injury changes the number of neurones in the adBNST which are Ih positive (show Ih currents). (1)
It doesn’t change it
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They measured the Ih currents in the adBNST cells before testing them and only carried out experiments on Ih-negative neurones.
How does nerve injury affect the frequency and amplitude of spontaneous ISPSs in LH-projecting adBNST neurones? (2)
- Increased frequency
- Increased amplitude
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They measured the Ih currents in the adBNST cells before testing them and only carried out experiments on Ih-negative neurones.
How does nerve injury affect the frequency and amplitude of spontaneous ESPSs in LH-projecting adBNST neurones? (2)
No change to frequency
No change to amplitude
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They were able to use chemogenetics to manipulate the activity of these neurones.
What is chemogenetics? (2)
What is the advantage of chemogenetics? (1)
Channels expressed in cells that are activated by exogenous ligands
and are sometimes called DREADDs (designer receptors activated by designer drugs).
Advantage - can activate/inhibit cells for much longer than optogenetics
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They were able to use chemogenetics to inhibit the activity of these neurones.
What receptor/channel did they use? Describe it and its actions. (4)
What is the drug that was injected which can activate these channels? (1)
hM4Di
which is a GPCR based on the mAChR
and is coupled to Gi
so activation of the receptors will inhibit cells.
Drug = CNO (clozapine-N-oxide)
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They were able to use chemogenetics to inhibit the activity of these neurones, then about 5 weeks later carried out behavioural testing.
What were the results regarding:
a) open field test
b) elevated plus maze
c) light-dark box test
d) emotionality Z score
e) von frey mechanical thresholds
(5)
What is the overall conclusion from these tests? (1)
a) reduced time spent in centre, reduced centre entries when neurones were inhibited
b) reduced time spent in open arms, reduced distance in open arms when neurones were inhibited (no difference in number of open arm entries)
c) reduced time spent in light side, increased latency to light, reduced transitions when neurones were inhibited
d) reduced emotionality z score when neurones were inhibited
e) no difference in von frey mechanical thresholds when neurones were inhibited
OVERALL CONCLUSION:
Inhibiting LH-projecting adBNST neurones induced anxiety-like behaviour in rats, but there was no change in pain thresholds.
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They were able to use chemogenetics to activate these neurones.
What receptor/channel did they use? Describe it and its actions. (3)
hM3Dq
which is a stimulatory receptor
coupled to Gq protein
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and wanted to test function of lateral hypothalamus-projecting anterodorsal BNST neurones.
They were able to use chemogenetics to activate these neurones, then carried out behavioural testing.
What were the results for the following tests? (4)
a) elevated plus maze
b) light/dark box
c) open field test
d) von frey mechanical thresholds
What is the overall conclusion? (1)
a) ameliorated the reduced time spent in open arms seen with nerve injury
b) ameliorated the reduced time spent in light side seen with nerve injury
c) no change when nerve injury was induced or when neurones were activated
d) no significant difference
OVERALL CONCLUSION:
- Activation of BNST neurones following nerve injury is able to reduce anxiety (but not pain)
Describe the complete neural circuit from the BNST to the hypothalamus that is thought to be involved in chronic pain-induced maladaptive anxiety (under normal conditions). (4)
CART GABAergic neurones in the ovBNST
project to LH-projecting adBNST neurones (and inhibit them)
adBNST neurones release GABA onto lateral hypothalamus neurones (to inhibit them)
so inhibition of the inhibitory neurones activates LH neurones and causes anxiety
How are CART neurones in the ovBNST affected in chronic pain? (1)
Describe the consequences of this. (3)
- Increased excitability
This causes sustained suppression of LH-projecting adBNST neurons,
thereby enhancing activity of LH neurones,
and anxiety-like behaviour.
Describe the overall change in lateral hypothalamus activity during chronic pain-induced anxiety. (1)
Increase
A study investigated chronic pain-induced neuronal plasticity in the bed nucleus of the stria terminalis and maladaptive anxiety.
They used a rodent spared nerve injury (SNI) model of neuropathic pain, and tested the function of ovBNST CART neurones.
Describe the results for the following tests on ovBNST CART neurones after SNI. (4)
a) resting membrane potential
b) rheobase
c) action potential amplitude
d) action potential threshold
What is the overall conclusion? (1)
a) no significant difference
b) reduced
c) increased
d) reduced
OVERALL CONCLUSION:
- SNI increases excitability of ovBNST CART neurones
True or false? Explain your answer if necessary. (1)
As well as chronic pain-induced anxiety, the BNST is also thought to be involved in pain-induced aversive motivation.
True
Describe the complete neural circuit from the BNST to the VTA that is thought to be involved in pain-induced aversive motivation (under normal conditions). (5)
GABAergic type II neurone in the BNST
projects to GABAergic type III neurone in the BNST (and inhibits it)
GABAergic type III neurone projects to GABAergic VTA neurone
which normally projects to DAergic VTA neurone
so under normal conditions, activation of the type II BNST neurone results in reduced VTA DA release
Fill the gaps relating to a potential mechanism underlying pain-induced aversive motivation. (12)
Noxious stimuli increase …………………. and ………………………. release in the BNST. ………………………. transmission is also enhanced which may increase nNOS-derived ………….. production. CRF depolarizes ………………… neurons, whereas …………………….. and ………………. activate Ih-positive (likely type II) BNST neurons.
Activated type II BNST neurons suppress …………………………….
The suppression of these neurons activates ………………………….. via a disinhibition mechanism.
Activation of these neurons results in the suppression of …………………………, thereby inducing aversive motivation that promotes both avoidance behaviours to escape from noxious stimuli and aversive learning to avoid the cue (conditioned stimulus) associated with noxious stimulation.
…………………. and ………………….. hyperpolarize type II BNST neurons, thereby suppressing induction of aversive motivation.
CRF
noradrenaline
glutamatergic
NO
type II BNST
noradrenaline
NO
VTA-projecting BNST neurones
VTA GABAergic neurones
VTA DAergic neurones
NPY
enkephalin
BNST projections to which brain area are thought to mediate pain-induced aversive motivation? (1)
VTA
True or false? Explain your answer if necessary. (1)
Brain connectivity is very complex, and maladaptive plasticity in various brain regions ultimately results in stress and anxiety-like behaviours.
True
Describe the role of the hippocampus in chronic pain. (1)
Fear conditioning
Describe the role of the striatum in chronic pain. (1)
Motivational processing
Describe the role of the PFC in chronic pain. (1)
cognitive control
Describe the role of the ACC in chronic pain. (1)
attention
Describe the role of the BNST in chronic pain. (1)
Uncertainty and anticipation
Describe the role of the hypothalamus in chronic pain. (1)
Stress regulation
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
What is TIAM1 and what is its role? (3)
T cell lymphoma invasion and metastasis 1
Rac1 guanine nucleotide exchange factor
Promotes dendrite, spine, and synapse development during brain development
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
TIAM1 is highly associated with the function of which receptor? (1)
NMDA
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
Fill the gaps relating to TIAM1. (8)
Once activated by the ……………….. receptor, Tiam1 exerts its effect on ……………….. and ……………………. development at least in part by stimulating the activity of its downstream target, ………………
This downstream target is known to play a central role in the regulation of …………………………………
By activating its downstream target in response to receptor stimulation, Tiam1 contributes to the …………………… that is required for dendritic arbour growth and spine and synapse development.
In addition, these actions may play a role in ……………………., since blocking these actions with pharmacological inhibitors impairs …………………..
NMDA
dendritic spine
branch
Rac1
dendritic branch and spine morphology
actin cytoskeletal remodelling
synaptic plasticity
hippocampal LTP
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
Activating Tiam1, and its downstream target, Rac1, results in which 3 cellular processes which contribute to development of dendrites, spines, and synapses? (3)
Actin remodelling
Protein trafficking
Protein synthesis
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
In which specific brain area is Tiam1 activated in mouse models of chronic pain? (1)
ACC
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out behavioural tests several weeks later.
What were the results for the following tests? (5)
a) Von Frey mechanical threshold
b) forced swim test
c) tail-suspension test
d) elevated plus maze
e) open field activity
What is the overall conclusion? (1)
a) reduced mechanical threshold with SNI
b) increased immobility time with SNI
c) increased immobility time with SNI
d) decreased time spent in open arms with SNI
e) decreased time in centre with SNI
OVERALL CONCLUSION:
- SNI induced chronic pain, and anxiety/depression symptoms
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
How did SNI affect the levels of active Tiam1 in the ACC? (1)
Increased
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out behavioural tests several weeks later.
They developed mice with conditional deletion of Tiam1 from postnatal forebrain excitatory neurones.
Describe the effects of this on:
a) von frey mechanical thresholds
b) acetone evaporation test
c) mechanical conflict-avoidance test
(3)
What is the overall conclusion? (1)
No effect of Tiam1 cKO on any test.
Conclusion:
cKO does not affect mechanical threshold or affective pain (shown with acetone and mechanical conflict-avoidance).
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out behavioural tests several weeks later.
They developed mice with conditional deletion of Tiam1 from postnatal forebrain excitatory neurones.
Describe the effects of this on the following tests. (5)
a) forced swim test
b) tail suspension test
c) sucrose preference test
d) elevated plus maze
e) open field activity
What is the overall conclusion? (1)
a) Prevents the increased immobility time seen with SNI
b) Prevents the increased immobility time seen with SNI
c) Prevents the decreased sucrose preference seen with SNI
d) prevents the decreased time in open arms seen with SNI
e) prevents decreased time in centre seen with SNI
OVERALL CONCLUSION:
Conditional knockout of Tiam1 does prevent depression and anxiety-like symptoms in rodents who have undergone SNI.
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
Describe how SNI alters expression of the following glutamatergic subunits in the ACC. (5)
a) GluN1
b) GluN2A
c) GluN2B
d) GluA1
e) GluA2
How is this different after SNI in Tiam1 knockout mice? (1)
What is the overall conclusion? (1)
a) increased
b) increased
c) increased
d) not altered
e) not altered
In Tiam1 KO mice, these expression differences are not seen.
CONCLUSION:
- Tiam1 may contribute to increased expression of some NMDA subunits after SNI
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
They also developed mice with conditional deletion of Tiam1 from postnatal forebrain excitatory neurones.
Describe how NMDA current is usually affected by SNI, and Tiam1 KO alters this. (2)
NMDA current is usually increased in SNI
however Tiam1 KO prevents this increase in NMDA current
True or false? Explain your answer if necessary. (1)
Tiam1 is thought to mediate functional synaptic plasticity of PFC neurones in a mouse model of chronic pain.
False - it is thought to mediate functional synaptic plasticity of ACC neurones
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
After induction of LTP, how did NMDA EPSC amplitudes change with and without SNI? (1)
WITHOUT SNI:
- increase in NMDA EPSC amplitude
WITH SNI:
- larger increase in NMDA EPSC amplitude
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
They also developed mice with conditional deletion of Tiam1 from postnatal forebrain excitatory neurones.
After induction of LTP, how did SNI normally change NMDA EPSC amplitude, and how was this different in Tiam1 KO mice? (2)
What is the overall conclusion? (1)
NORMAL:
- Larger increase in NMDA EPSC amplitude (enhanced LTP)
Tiam1 KO:
- LTP did not produce a larger increase in EPSC amplitude in SNI mice compared to sham mice
CONCLUSION:
Tiam1 may contribute to enhanced LTP in the ACC in chronic pain
How does adding a GluN3A/B subunit to NMDA receptors affect calcium influx and Mg block? (2)
- Lower calcium influx
- Lower affinity Mg block
Describe how LTP in the ACC is thought to be altered in chronic pain. (1)
Thought to be enhanced
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
In one series of tests, they tested the effects of inhibiting the NDMA receptors in the ACC.
How did they do this? (1)
Ketamine
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
In one series of tests, they tested the effects of inhibiting the NDMA receptors in the ACC.
What effects were seen regarding biochemistry and morphology of ACC neurones after ketamine was added following SNI? (4)
Prevented the increased expression of NMDAR subunits usually seen following SNI
Prevented the increase in NMDA current usually seen after SNI
Prevented the increase in active Tiam1 usually seen following SNI
Prevented the increased spine density usually seen following SNI
A study investigated TIAM1-mediated synaptic plasticity and comorbid depression-like symptoms in chronic pain.
They induced spared nerve injury (SNI) and then carried out tests several weeks later.
In one series of tests, they tested the effects of inhibiting the NDMA receptors in the ACC.
What effects were seen regarding behaviour, including pain, after ketamine was added following SNI? (2)
What behavioural tests were carried out? (4)
Reduced pain 1h after ketamine administration, however pain returned after 1 day
Reduction in depression and anxiety-like behaviours following SNI
- forced swim
- elevated plus maze
- open field activity
- tail suspension test
Fill the gaps relating to ACC function and chronic pain. (8)
In chronic pain, you get ACC ……………….., potentially mediated through ……………… and its actions on the …………………. receptor.
The ACC is important for ……………………….. and activating the ……………………..
The changes to ACC function may be reduced with …………………….
This mechanism is proposed to contribute to ……………… and ……………….. symptoms in chronic pain.
hyperactivity
Tiam1
NMDA
bringing attention to pain
PFC
ketamine
depression
anxiety
Describe how halorhodopsin-mediated manipulation of ACC excitatory neurones affects pain behaviour. (1)
Decreases pain behaviour
Describe how channel rhodopsin-mediated manipulation of ACC inhibitory neurones affects thalamic activity and pain behaviour. (2)
Suppresses thalamic activity
Suppresses pain behaviour
Describe chronic pain from a predictive coding perspective. (4)
Hyperexcitable ACC brings attention to pain
and this results in a heightened prior expectation of pain
therefore more pain is felt due to bigger anticipation
and posterior shifts towards prior expectation.
