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Neuroscience Y2S2 > Neurobiology of Disease 9 > Flashcards

Neurobiology of Disease 9 Flashcards

1
Q

Give five general factors which can cause neuroinflammation. (5)

A
  • Ageing
  • Environmental
  • Protein misfolding
  • Vascular factors
  • Small vessel diseases
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2
Q

Give three examples of vascular factors which can contribute to neuroinflammation. (3)

A
  • Stroke
  • Aneurisms
  • Transient ischaemic attack
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3
Q

Give three examples of small vessel diseases which can contribute to neuroinflammation. (3)

A
  • Hypertension
  • Atherosclerosis
  • Diabetes
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4
Q

What is the cause of protein misfolding? (1)

a) genetic mutations

b) environmental factors (sporadic)

A

Both

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5
Q

Give five neurological conditions which feature protein misfolding as part of the neuropathology. (5)

A
  • Alzheimer’s disease
  • Parkinson’s disease
  • Amyotrophic lateral sclerosis
  • Huntington’s disease
  • Prion disease
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6
Q

Is protein misfolding a cause or consequence of neuroinflammation and neurological illness? (1)

A

Can be either

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7
Q

If a disease is caused by protein misfolding, how do we generally try to treat the illness? (2)

A
  • Removal of misfolded protein if possible
  • Modulating neurotransmission (eg. glutamate and ACh)
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8
Q

True or false? Explain your answer if appropriate. (1)

In neurological conditions where proteins misfold and aggregate, there is a common mechanism for misfolding and aggregation.

A

True

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9
Q

Name three proteins which may misfold in amyotrophic lateral sclerosis. (3)

A
  • FUS
  • TDP-43
  • SOD1
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10
Q

Suggest two proteins which may be misfolded in frontotemporal dementia. (2)

A

Tau

FUS (fused in sarcoma)

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11
Q

Complete the sentence relating to neuroinflammation. (

Various neurodegenerative diseases such as ……………………….., …………………….., ………………….. feature neuroinflammation, as either a cause or a consequence.
This neuroinflammation is commonly mediated by …………………………

A

Alzheimer’s disease

Frontotemporal dementia

Parkinson’s disease

protein misfolding

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12
Q

Complete the sentence relating to neuroinflammation. (2)

Neuroinflammation is mediated by ………………………. cells, which are essential for normal neuronal development and function.
However when activated for too long, …………………………….. can happen.

A

microglial

cytotoxicity/they can become cytotoxic

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13
Q

Very briefly describe how protein misfolding leads to neuroinflammation. (1)

A

Misfolded proteins activate microglia - this leads to neuroinflammation

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14
Q

Give two specific mechanisms by which the gut-brain axis can contribute to neuroinflammation. (2)

A
  • Increased BBB permeability
  • Altered cytokines circulating in the blood
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15
Q

At which stage of life do microglia colonise the CNS? (1)

A

During prenatal development

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16
Q

Briefly describe the mechanisms by which the gut microbiome may contribute to neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease. (2)

A
  • Altered microbiome alters circulating cytokines and BBB permeability
  • Which may lead to neuroinflammation and neurodegeneration
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17
Q

True or false? Explain your answer if appropriate. (1)

Microglial cells colonise the CNS during prenatal development, and this microglial population remains consistent throughout life.

A

False - microglial cells self-renew and regenerate

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18
Q

Complete the sentence relating to microglia. (1)

Depending on the anatomical region, microglia account for …………………. of the total cell population in the human brain.

A

10-15%

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19
Q

Give a general factor which significantly shapes the phenotype of the microglia found in the brain. (1)

A

CNS microenvironment

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20
Q

What is the role of the resting/inactivated microglia in the brain? (1)

A

Patrol a set area for damaged cells/debris/aggregates

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21
Q

What is the main role of microglial cells in development? (1)

A

They are key mediators of synaptic pruning

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22
Q

What may be the result of over- or under-pruning of synapses by microglia during development? (3)

A
  • Abnormal neuronal network formation
  • Impaired synaptic development
  • Neurodevelopmental disorders
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23
Q

Microglia set and maintain CNS homeostasis during development.

Give two factors that could disrupt microglial functional and therefore CNS homeostasis during development. (2)

A
  • Inflammation
  • Insult/Injury
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24
Q

As well as microglia, give another type of cell which may help to prune synapses and maintain CNS homeostasis during development. (1)

A

Astrocytes

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25
Q

Describe how, in a pathological situation, stress or insult (such as maternal immune activation) may effect the collaborative actions of microglia and astrocytes working to mediate synaptic pruning and CNS homeostasis. (4)

A

Stress or insult can inhibit microglia

So only astrocytes are now available to prune synapses and maintain CNS homeostasis

Therefore synaptic pruning and homeostasis is altered

Potentially leading to neurodevelopmental disorders

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26
Q

Describe the two phenotypes that microglia can take on when activated in terms of:

a) name

b) role in inflammation

c) effect on cell survival

(6)

A

a) M1 or M2 phenotype

b) M1 = pro-inflammatory; M2 = anti-inflammatory

c) M1 = neurotoxic; M2 = neuroprotective

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27
Q

Describe the phenotype of resting microglia, in terms of the name and the role that it plays in cell survival. (2)

A

M0

Neurotrophic

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28
Q

Name the type of activation which occurs when M0 microglia become M1 microglia. (1)

Give two chemicals/cytokines that can drive this type of activation. (2)

A

Classical activation

IFN-y

LPS (lipopolysaccharides)

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29
Q

Name the type of activation which occurs when M0 microglia become M2 microglia. (1)

Give two chemicals/cytokines that can drive this type of activation. (2)

A

Alternative activation

IL-4

IL-13

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30
Q

Name the three subtypes of the M2 microglial phenotype. (3)

A

M2a

M2b

M2c

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31
Q

What is ‘acquired deactivation’ when referring to microglial phenotypes? (1)

Give three molecules/cytokines which can drive this pathway. (3)

A

Switch from M1 to M2c phenotype

DRIVEN BY:

  • IL-10
  • Glucocorticoids
  • TGF-b
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32
Q

Give nine molecules/cytokines which are produced by/associated with M1 activated microglia. (9)

A
  • NOS2 or iNOS
  • ROS
  • TNF-a
  • IL-1b
  • IL6
  • IL12
  • IL23
  • STAT3
  • NFkB1/2
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33
Q

NFkB1/2 are proteins produced by M1 microglia.

What are these proteins? (1)

A

Nuclear factor of kappa light polypeptide gene enhancer in B cells 1/2

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34
Q

M1 microglia can produce TNF-a.

What is the role of TNF-a in cells? (1)

A

Necrosis or apoptosis

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35
Q

M1 microglia can produce IL-1beta.

What is the role of IL-1beta? (1)

A

It is a key mediator of the inflammatory response

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36
Q

M1 microglia can produce STAT3 protein.

What is the role of STAT3 in cells? (1)

A

Involved in maturation of immune cells

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37
Q

Give an advantage and a disadvantage of M1 microglia producing inflammatory cytokines such as TNFa and IL-1b. (2)

A

ADVANTAGE:

  • Provides defence against pathogens and tumour cells

DISADVANTAGE:

  • Cytotoxicity to neurones (so some neurones are lost)
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38
Q

Give five molecules/cytokines which are produced by/associated with M2 activated microglia. (5)

A
  • IL-10
  • IL-4
  • IL-13
  • TGF-b
  • IGF-1 (insulin like growth factor 1)
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39
Q

Give 2 general effects on neurones and brain tissue of the anti-inflammatory cytokines such as IL10 and TGFb produced by M2 microglia. (2)

A
  • Promotes tissue remodelling/repair
  • Angiogenesis
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40
Q

Microglia can be activated in various pathways to form both pro-inflammatory and anti-inflammatory cells and molecules.

What factor determines the level of neuroinflammation experienced when M0 microglia are activated? (1)

A

The balance between M1/M2 microglia, and inflammatory and anti-inflammatory cytokines.

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41
Q

Give four pro-inflammatory cytokines which have been associated with the pathogenesis of Alzheimer’s disease. (4)

A
  • TNF-a
  • IL-1b
  • IL-6
  • IL-18
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42
Q

There are four pro-inflammatory cytokines which have been associated with the pathophysiology of Alzheimer’s disease.

Give two possible cells which are responsible for producing these cytokines. (2)

A
  • Activated microglia
  • Astrocytes
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43
Q

IL-6 has been suggested as having a role in the pathophysiology of Alzheimer’s disease.

It is able to rescue neurones, prevent synaptic loss, and reduce Amyloid beta deposition.

How then, can it contribute to AD? (1)

A

Increases phosphorylation of tau

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44
Q

There are four pro-inflammatory cytokines which have been associated with the pathophysiology of Alzheimer’s disease.

Give two physiological processes, and two proteins that are effected by these cytokines. (4)

A
  • LTP
  • Synaptic plasticity
  • Amyloid-beta
  • Tau
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45
Q

Describe a piece of immunohistochemical evidence that supports the role of microglia in Alzheimer’s disease. (1)

What is the proposed role of microglia in Alzheimer’s disease? (1)

A

Co-localisation can be demonstrated between beta-amyloid plaques and microglia.

Microglia would normally clear plaques and remain intact, but this may not happen in AD.

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46
Q

It has been suggested that dysfunction of microglia removing beta-amyloid plaques may contribute to Alzheimer’s disease.

Describe what would usually happen when microglia encounter beta amyloid plaques in healthy brain tissue. (3)

A
  • Microglia encounter beta amyloid plaques and become activated
  • Microglia take up beta amyloid and clear it from brain tissue (eg. via phagocytosis)
  • Microglia then remain intact
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47
Q

Apart from increasing cholinergic neurotransmission, explain why muscarinic agonists (specifically M1) may be useful to treat Alzheimer’s disease. (3)

A
  • Activates PKC

2 EFFECTS OF PKC:

  • stimulate a-secretase
  • inhibit glycogen synthase kinase 3, which would usually phosphorylate tau
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48
Q

Give two reasons why metal ion chelators may be useful in treating Alzheimer’s disease. (2)

A
  • Metal ions may contribute to neurodegeneration
  • Metal ions may play a role in the aggregation of beta-amyloid
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49
Q

Give three cytokines and one microglial surface marker which show increased expression in cerebral ischaemia-reperfusion. (4)

A
  • IL-1b
  • IL-6
  • TNFa

Microglial M1 surface marker CD16/32

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50
Q

How might phytochemicals act to reduce the amount of brain damage after cerebral ischaemia-reperfusion? (3)

A
  • Phytochemicals inhibit M1 microglial phenotype
  • and enhance M2 microglial phenotype
  • So microglia take on anti-inflammatory, neuroprotective roles
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51
Q

Give four effects of M2 microglia on brain tissue after cerebral ischaemia-reperfusion. (4)

A
  • Anti-inflammatory response
  • Neurogenesis
  • Angiogenesis
  • Trophic factors
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52
Q

How might extracellular zinc be involved in the brain’s response to ischaemia? (2)

A
  • Released from hippocampal neurones in response to brain ischaemia
  • Triggers morphological changes in microglia
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53
Q

Give a potential neuroprotective treatment for stroke which involves extracellular trace elements. (1)

How is this thought to be neuroprotective? (2)

A

CaEDTA

CaEDTA is a chelating agent for zinc, so decreases zinc levels

to reduce activation of M1 microglia following stroke.

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54
Q

Give three components of the neural circuitary of mood. (3)

A
  • Prefrontal cortex
  • Amygdala
  • Dopaminergic projections from VTA to Nucleus accumbens
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55
Q

Describe how neural circuitry controlling mood, and neuroinflammation may interact in major depressive disorder. (4)

A
  • Altered neural circuitry controlling mood induces M1 polarisation of microglia
  • Resulting in neuronal dysfunction
  • And further hypoactivation of 5HT neurones projecting from raphe neurones to prefrontal cortex
  • Affecting prefrontal cortex, which controls neural circuitry of mood
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56
Q

Describe how microglia may be able to induce a remission period in MDD. (2)

A

M2 microglia promote dampening of inflammation

also promote recovery of 5HT neural pathways between raphe neurones and frontal cortex

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57
Q

Complete the sentence regarding neuroinflammation and psychiatric illness. (1)

Periods of relapse and remission in illnesses such as depression and schizophrenia may be related to………………………………

A

balance between M1 microglial activation (relapse) and M2 microglial activation (remission)

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58
Q

A key pathological mechanism causing schizophrenia is a cortical excitation-inhibition balance.

Suggest how microglia may be able to cause this imbalance. (2)

A

Altered synaptic pruning

and indirect neurotransmitter dysfunction

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59
Q

Give a piece of evidence which supports the hypothesis that altered synaptic pruning by microglia may lead to cortical excitation-inhibition imbalance, which can cause schizophrenia. (1)

A

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination.

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60
Q

Experiments can be carried out assessing synaptic pruning by stem cells derived from schizophrenic patients (patient-derived induced microglia-like cells; iMG).

Describe what you would expect to see in a culture of neurones without iMG, compared to a culture of neurones with iMG. (1)

A

Neurones with iMG show decreased spine density compared to neurones without iMG.

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61
Q

Experiments can be carried out assessing synaptic pruning by stem cells derived from schizophrenic patients (patient-derived induced microglia-like cells; iMG).

Describe what you would expect to see in a culture of iPSC neurones from healthy controls vs a culture of iPSC neurones from schizophrenia patients (both cultures contain no microglia). (1)

What does this suggest about altered synaptic pruning in schizophrenia? (1)

A

No differences in synaptic spine density

This suggests that microglia are responsible for the altered synaptic pruning

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62
Q

Experiments can be carried out assessing synaptic pruning by stem cells derived from schizophrenic patients (patient-derived induced microglia-like cells; iMG).

Describe what you would expect to see in a culture of healthy control iPSC neurones and healthy control iMG, compared to schizophrenia iPSC neurones and schizophrenia iMG. (1)

What does this suggest about synaptic pruning in schizophrenia? (1)

A

Decrease in spine/synaptic density in schizophrenia neurones cultured with schizophrenic iMG.

Suggests that microglia over-prune synapses in schizophrenia.

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63
Q

Hint: This question relates to neuroinflammation.

What is the normal function of fractalkine/CX3CL1 ligand/receptor interaction? (4)

**Fractalkine/CX3CL1 is ligand and receptor is called CX3CR1

A
  • Fractalkine is a chemokine produced by neurones
  • Receptor (CX3CR1) only expressed by microglia
  • Ligand instructs microglia on neuronal and synaptic maturation
  • And receptor is able to control microglial migration and functions
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64
Q

Why is the CX3CR1 receptor on microglia so essential for microglial function and neuroinflammation? (1)

A

It is the only microglial receptor which receives a signal from neurones.

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65
Q

The Fractalkine/CX3CL1 ligand and CX3CR1 receptor interaction is important in microglial function.

Give two neurological conditions which a person may be at risk for in they have genetic variants for the CX3CR1 receptor. (2)

A
  • Schizophrenia
  • Autism spectrum disorders
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66
Q

The Fractalkine/CX3CL1 ligand and CX3CR1 receptor interaction is important in microglial function.
Genetic variants of the CX3CR1 receptor may increase risk of schizophrenia and ASD.

Describe the mechanism of how this might happen. (3)

A
  • Disrupted communication between neurones and microglia
  • Results in altered pro-/anti-inflammatory cytokine release
  • Which alters synaptic pruning activity
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67
Q

The Fractalkine/CX3CL1 ligand and CX3CR1 receptor interaction is important in microglial function.

Genetic variants of the CX3CR1 gene may particularly impair functional development of synapses in what brain regions? (2)

A

Thalamocortical regions

68
Q

The Fractalkine/CX3CL1 ligand and CX3CR1 receptor interaction is important in microglial function.

Electrophysiological studies show that knockout of CX3CR1 receptor on microglia changes properties of neuronal and neuronal circuits.

Give two examples of changes that may be seen in neurones/neuronal circuits. (2)

A
  • Altered AMPA/NMDA ratio (altered synaptic strength)
  • Altered postsynaptic responses
69
Q

The Fractalkine/CX3CL1 ligand and CX3CR1 receptor interaction is important in microglial function.

Describe how knockout of the CX3CR1 receptor on microglia changes microglial invasion of the barrel cortex in rodents. (1)

What will the longer term effects of this change be? (1)

A

Receptor knockout results in reduced microglial invasion.

Altered neuronal development and function.

70
Q

Prolonged, or chronic inflammation, is more associated with which microglial phenotype? (1)

A

M1

71
Q

Describe the cycle of inflammation inducing M1 microglia. (3)

A

Inflammation and inflammatory cytokines activate M1 microglia

which then release more inflammatory cytokines and further induce inflammation

which maintains and enhances the M1 phenotype

72
Q

Which microglial phenotype is most likely to show impaired phagocytosis? (1)

A

M1

73
Q

Therapeutic agents such as glatiramer acetate, bexarotene, and PPARy agonists have been used to treat neuroinflammatory diseases.

How might these work to treat neuroinflammatory diseases? (2)

A
  • Inhibit inflammation
  • Induce M2 microglial activation
74
Q

Which microglial phenotype shows enhanced phagocytosis? (1)

A

M2

75
Q

Which microglial phenotype expresses nitric oxide synthase? (1)

Which isoform of NOS is expressed in these microglia? (1)

A

M1 microglia express iNOS (inducible)

76
Q

Give two general effects of M1 microglia expressing iNOS and producing NO. (2)

A
  • Nitro-oxidative stress
  • Cytotoxicity
77
Q

M1 microglia produce NO in high concentrations via iNOS in response to inflammation.

This level of NO is cytotoxic, potentially working by posttranslational modification of proteins.

Give two examples of protein modification by NO. (2)

A

S-nitrosylation

Protein tyrosine nitration (also called nitrotyrosination)

78
Q

M1 microglia produce NO in high concentrations via iNOS in response to inflammation.

These high levels of NO cause posttranslational modification of proteins.

What is the effect of this? (1)

Give a piece of evidence supporting this conclusion. (1)

A

Modifications alter function of proteins and may cause protein misfolding.

EVIDENCE:

  • Increased numbers of modified proteins are seen in protein misfolding neurodegenerative diseases
79
Q

Give the exact nitric oxide molecular species causing the following protein modifications. (2)

Also state whether the modifications are reversible or irreversible. (2)

a) S-nitrosylation

b) nitrotyrosination

A

a) NO, reversible

b) ONOO-, irreversible

80
Q

Describe the molecular chemistry behind s-nitrosylation of proteins by nitric oxide. (3)

A

NO group

binds to sulphur atom

on a cysteine reside of a protein

81
Q

Describe how NO can be both neuroprotective and neurotoxic. (2)

A

Neuroprotective at low concentrations

but once it reaches a concentration threshold (at high concentrations) becomes neurotoxic

82
Q

Give a piece of evidence supporting the hypothesis that NO may be involved in beta amyloid plaque formation. (1)

A

The core of a beta amyloid plaque is highly positive for nitrotyrosine, so the proteins which form the plaques may be nitrotyrosinated.

83
Q

What is the significance of the core of the beta-amyloid plaque testing highly positive for nitrotyrosine in AD? (3)

A

Core thought to be the origin of plaque formation

so nitrotyrosination may initiate plaque formation

and nitrotyrosination results from inflammation and NO signalling

84
Q

Describe the intensity of GFAP staining you would expect to see in mice with prion disease. (1)

What conclusions can we draw from this? (2)

Make another suggestion regarding NO in Prion disease. (1)

A

GFAP expression enhanced

  • Mice with prion disease have increased numbers of activated microglia (and maybe astrocytes)
  • So they show a strong inflammatory response

NO may be increased due to inflammation, which may increase levels of protein modification

85
Q

In a mouse model of prion disease, describe what you would expect to see when inflammatory markers such as nitric oxide stress and oxidative stress are assessed. (2)

A

Increased NO and oxidative stress

86
Q

A mouse model of prion disease was created, which was then given a daily NOS inhibitor from 6 weeks after induction of disease.

Give the effects of excitatory neurotransmission and evoked release of NT in hippocampus in the mouse model with and without NOS inhibitor. (4)

Give a one sentence conclusion. (1)

A

EXCITATORY NEUROTRANSMISSION:

  • No NOS inhibitor = reduced excitatory neurotransmission
  • NOS inhibitor = excitatory neurotransmission maintained

EVOKED RELEASE:

  • No NOS inhibitor = reduced
  • NOS inhibitor = no deficit

CONCLUSION:

NOS inhibition prevents decline in neurotransmission in prion disease

87
Q

Complete the sentence regarding somatic sensory nerves. (3)

Somatic sensory nerves transmit information via the ………………………., and connect with motor neurones in the ………………… They are also able to project to ……………………

A

dorsal root ganglion

spinal cord

the brain

88
Q

Complete the sentence regarding autonomic nerves. (2)

Autonomic nerves leave the spinal cord, synapse in ………………., and innervate ………………..

A

ganglia

effector organs

89
Q

Which sensory nerve fibres (Aa, Ab, Ad, C) have dual afferent and efferent roles?

Give another name for these nerve fibres.

A

Ad and C fibres

Another name is sensory-motor nerves.

90
Q

Give two afferent functions of sensory-motor nerves. (2)

A

Sensation/pain

Reflex homeostasis

91
Q

Give two general ways in which activation of a sensory-motor nerve fibre is able to initiate efferent functions of that neurone. (2)

A
  • Initiated by DRG/spinal cord
  • Activation can travel between collateral branches of the same axon (stimulus in one terminal branch spreads to an adjacent terminal branch)
92
Q

Give the meanings of afferent and efferent, as used when describing the dual roles of sensory-motor nerves. (2)

A

afferent - going towards the spinal cord

efferent - travelling away from the spinal cord

93
Q

Give two general types of stimulus that can activate sensory-motor nerves. (2)

A
  • A self-detected stimulus (eg. pain or pressure)
  • Inflammatory mediators or signals from other neurones
94
Q

Briefly describe how sensory-motor nerves are able to have efferent effects on a tissue. (1)

A

Release of neuropeptides by terminal (peripheral) branches

95
Q

What is the proper scientific name for when a sensory-motor nerve causes widening of blood vessels in the periphery? (1)

A

Antidromic vasodilation

96
Q

Stricker (1876) found that if the trunk of a sensory-motor nerve is cut, ………………………. (1)

What does this suggest about the efferent function of sensory nerves? (1)

A

a response is still seen in the periphery

It can happen even if the DRG is not present (perhaps by collateral branches)

97
Q

Bayliss (1901) found that removing the DRG sensory neurone resulted in …………………… (enhanced/abolished) peripheral vasodilation. (1)

They also found what effect of removing the sympathetic ganglion but keeping sensory-motor nerves intact? (1)

What does this suggest about the efferent function of sensory nerves? (1)

A

abolished

Vasodilation response still occurred (SNS would result in vasoconstriction)

Sensory nerves are responsible for vasodilation, while SNS is responsible for vasoconstriction.

98
Q

Lewis (1927) found that denervating the skin (so removing sensory-motor nerves) has what effect on the axon reflex mechanism and neurogenic inflammation? (2)

What does this suggest about the efferent function of sensory nerves? (1)

A

Axon reflex mechanism and neurogenic inflammation was no longer seen in response to injury

Suggests that the efferent function may be dependent on afferent function being intact

99
Q

Give four examples of diseases/conditions linked to sensory nerves and their efferent functions. (4)

A

Asthma

Eczema

Psoriasis

Migraine

100
Q

Give a molecule/chemical which is used to characterise sensory-motor nerves. (1)

How does this molecule help to characterise these nerves? (1)

A

Capsaicin

Afferent neurones which also have efferent functions are sensitive to capsaicin

101
Q

Name the class of molecule to which capsaicin belongs. (1)

A

Vanilloids

102
Q

Afferent sensory neurones involved in blood flow regulation (so have efferent functions) are sensitive to capsaicin.

Describe the effects of low doses (ug/Kg) for short periods of time, and high doses (mg/Kg) for extended periods of time of capsaicin on the electrophysiological function of sensory-motor neurones. (2)

A

LOW DOSE:

  • transient excitation

HIGH DOSE:

  • desensitisation and long lasting damage
103
Q

Which types of sensory nerve fibres (Aa, Ab, Ad, C) are sensitive to capsaicin?

A

Ad and C fibres

104
Q

Which receptor does capsaicin act on in the membrane of sensory-motor nerves? (1)

A

TRPV1

105
Q

Capsaicin acts on sensory-motor nerves by activating the TRPV1 receptor.

Describe the TRPV1 receptor. (2)

A

Ion channel

which is non-selectively permeable to cations

106
Q

Describe how capsaicin acting at TRPV1 for extended periods on sensory-motor nerves leads to these nerves becoming desensitised. (3)

A

Activation of TRPV1 leads to depolarisation (because TRPV1 is a non-selective cation channel)

This leads to neurotransmitter release

And if this is happening for an extended period of time, supply of neurotransmitter is depleted and the neurones become desensitised.

107
Q

Capsaicin acts on sensory-motor nerves by activating TRPV1.

Give two endogenous/’natural’ TRPV1 ligands. (2)

A
  • Endocannabinoids
  • H+ ions
108
Q

Give a particular bodily system (other than the nervous system) which contains high numbers of sensory-motor nerves. (1)

Give two components of this system which have a wide distribution of these nerves. (2)

A

Cardiovascular system

  • Heart
  • Blood vessels
109
Q

Name two neuropeptides which are used as transmitters by sensory-motor nerves in the cardiovascular system. (2)

Which is used more? (1)

A

Substance P

Calcitonin gene-related peptide (used more)

110
Q

Give a particular location of the cardiovascular system which contains high densities of sensory-motor nerves. (1)

A

Adventitia of arteries

111
Q

Briefly describe a method that could be used to identify sensory-motor nerves in the cardiovascular system. (2)

A

Immunostaining

for substance P and CGRP

112
Q

Sensory-motor nerves in the cardiovascular system could usually be identified by immunostaining for substance P and CGRP.

Give a reason/condition in which this would not work. (1)

Explain your answer. (1)

A

Would not work after capsaicin treatment

because capsaicin depletes the nerves of substance P and CGRP

113
Q

Apart from substance P and CGRP, give another neuropeptide which can function as a cotransmitter in sensory-motor nerves of the cardiovascular system. (1)

A

Neurokinin A

114
Q

Describe the relative half lives of substance P and CGRP when acting as transmitters in sensory-motor nerves of the cardiovascular system. (1)

How are the actions of these transmitters terminated? (1)

A

Short

Removed by proteases

115
Q

True or false? Explain your answer if appropriate. (1)

In sensory-motor nerves of the cardiovascular system, CGRP and substance P are synthesised in the cell body, stored in separate vesicles, and then transported to the peripheral endings of nerves.

A

False - they are co-stored in the same vesicles

Everything else is true

116
Q

Substance P, CGRP, and neurokinin A are the three main neuropeptides used by sensory-motor nerves in the cardiovascular system.

Give eight other potential cotransmitters that may be used by these nerves. (8)

A
  • ATP
  • Bombesin/gastrin releasing peptide
  • Cholecystokinin
  • Dynorphin
  • Galanin
  • Leucine enkephalin
  • Nitric oxide
  • VIP
117
Q

Give four inflammatory mediators which may play a large role in stimulating sensory-motor nerves of the cardiovascular system. (4)

A
  • ATP
  • Histamine
  • Bradykinin
  • Prostaglandins
118
Q

CGRP, Substance P, and neurokinin A are used by sensory-motor nerves in the cardiovascular system.

Name the receptors which these neuropeptides bind to on the vascular smooth muscle. (3)

Are these receptors inotropic or GPCRs? (3)

A

Substance P - NK1/2/3 receptor

NKA - NK1/2/3 receptor

CGRP - CGRP receptor

All receptors are GPCRs

119
Q

CGRP, Substance P, and neurokinin A are used by sensory-motor nerves in the cardiovascular system.

CGRP acts on CGRP receptors, and SP and NKA act on NK1/2/3 receptors.

Which G proteins are CGRP receptors and NK1/2/3 receptors coupled to? (2)

A

CGRP receptors coupled to Gs or Gq

NK1/2/3 coupled to Gq

120
Q

What effect do the neuropeptides CGRP, substance P, and NKA have on smooth muscle of the blood vessels? (1)

A

Vasorelaxation

121
Q

How can inflammatory mediators cause sensory-motor nerves to release neuropeptides such as CGRP, substance P, and NKA? (2)

A

Inflammatory mediators bind to receptors and depolarise neurones

Action potential results in release of neuropeptides from nerves

122
Q

Give eight roles of sensory-motor nerves in the cardiovascular system. (8)

A
  • Neurogenic inflammation (defence against challenges to homeostasis)
  • Vasodilation and regulation of blood flow
  • Regulation of cardiac function
  • Trophic effects
  • Ageing
  • Hypertension
  • Diabetes
  • Migraine
123
Q

Sensory-motor nerves are involved in neurogenic inflammation and defence against injury and challenges to homeostasis.

Give two afferent roles of sensory-motor nerves which are involved in this function. (2)

A
  • Pain sensation
  • Nocifensive reflexes (eg. hand withdrawal from heat)
124
Q

Sensory-motor nerves are involved in neurogenic inflammation and defence against injury and challenges to homeostasis.

Give two efferent roles of sensory-motor nerves which are involved in this function. (2)

A
  • Vasodilatation
  • Plasma extravasation
125
Q

Give two components/processes involved in neurogenic inflammation. (2)

A

Vasodilation

Plasma extravasation

126
Q

Describe how neurogenic inflammation is able to provide resistance against further damage and aid repair of an injury. (3)

A

Neurogenic inflammation = vasodilation and plasma extravasation

Hyperaemia and increased vascular permeability facilitate delivery of leukocytes to tissue

And leukocytes can help repair damage

127
Q

How does neurogenic inflammation cause redness and swelling after an injury? (2)

A

Vasodilation and hyperaemia (increased blood flow) cause redness

Increased vascular permeability and extravasation cause swelling

128
Q

Sensory-motor nerves are involved in neurogenic inflammation.

Give two neuropeptides released from sensory-motor nerves, along with another mediator released from a different cell type, which causes arteriolar vasodilation in neurogenic inflammation. (3)

A

CGRP

substance P

histamine from mast cells

129
Q

Sensory-motor nerves are involved in neurogenic inflammation.

Give two neuropeptides released by sensory-motor nerves which are involved in the increased vascular permeability component of neurogenic inflammation. (2)

A

Substance P

Other tachykinins such as NKA

***CGRP does not cause increase in vascular permeability

130
Q

Sensory-motor nerves are involved in neurogenic inflammation.

One component of neurogenic inflammation is an increase in vascular permeability, which results in plasma protein extravasation.

What is meant by ‘plasma protein extravasation’? (1)

A

Protein leakage from plasma (which is contained in blood vessels) into the interstitial space.

131
Q

CGRP does not directly cause an increase in vascular permeability during neurogenic inflammation, however is involved in a different way.

How is CGRP involved in increasing vascular permeability? (1)

A

CGRP is co-released with substance P and facilitates substance P induced increase in permeability

132
Q

Sensory-motor nerves are involved in neurogenic inflammation.

Release of substance P and CGRP by sensory-motor nerves has what effect on monocytes/macrophages? (4)

A

RELEASE OF:

  • cytokines
  • prostaglandins
  • leukotrienes
  • thromboxanes
133
Q

Sensory-motor nerves are involved in neurogenic inflammation.

How might neuropeptides released from sensory-motor nerves increase the excitability of afferent neurones during inflammation? (3)

What is this process called? (1)

A

Neuropeptides act on monocytes/macrophages

which then release cytokines and other inflammatory mediators

which could increase excitability of afferent neurones.

This is called sensitisation.

134
Q

How might sensory-motor nerves change due to/contribute to chronic inflammation? (3)

A

Nerves become hyperactive,

contribute to hyperalgesia,

and perpetuate the inflammatory response.

135
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in moment-to-moment control of blood vessel diameter.

What effect does CGRP have on blood vessels? (1)

A

Potent prolonged vasodilation

136
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in moment-to-moment control of blood vessel diameter.

CGRP causes a potent, prolonged, vasodilation.

Describe the receptors involved in this in terms of the following. (3)

a) which receptors are they?

b) where are they located in the blood vessels?

c) what are the downstream effects of activating this receptor?

A

a) CGRP receptors

b) located in the smooth muscle of blood vessels

c) increased cAMP, which acts on KATP channels

137
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in moment-to-moment control of blood vessel diameter.

What effect does substance P have on blood vessels? (1)

A

Vasodilation

138
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in moment-to-moment control of blood vessel diameter.

Substance P is thought to be involved in vasodilation.

Describe this effect, in terms of the receptors involved, and where these are located in the blood vessel. (2)

A

NK1 receptors

in endothelium

139
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in moment-to-moment control of blood vessel diameter.

What effect is neurokinin A thought to have on blood vessels? (1)

A

Contraction

140
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in moment-to-moment control of blood vessel diameter.

Neurokinin A is thought to contract blood vessels.

Describe how this effect is achieved, in terms of the receptors and their locations in blood vessels that are involved. (2)

A

NK2 receptors

in the smooth muscle of blood vessels

141
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

An upwards deflection indicates vasoconstriction, and a downwards deflection indicates vasodilation.

What direction would you expect the deflections to be when sensory-motor nerves were stimulated? (1)

A

Downwards

142
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

An upwards deflection indicates vasoconstriction, and a downwards deflection indicates vasodilation.

What direction would you expect the deflections to be when sympathetic nerves were stimulated? (1)

A

Upwards

143
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

In the experiment, sensory-motor nerves were stimulated in the presence of methoxamine, which is a a1 agonist.

Why was the a1 agonist present? (1)

A

To contract the blood vessels, so that the vasorelaxation response would be optimised

144
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

In the experiment, sensory-motor nerves were stimulated in the presence of guanethidine, which blocks sympathetic neurotransmission.

Why was the sympathetic blocker present? (1)

A

So that only the vasodilatory effects of the sensory-motor nerves were seen

145
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

What would you expect to see when the sensory-motor nerves were stimulated in the presence of TTX? (1)

What does this show about blood vessel regulation? (1)

A

Blood vessels neither contract or relax

Shows that blood vessel regulation is dependent on neuronal activity

146
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

What would you expect to see when the sensory-motor nerves were stimulated in the presence of capsaicin? (1)

What does this show about blood vessel regulation? (1)

A

The blood vessels would not dilate

Vasodilation is due to capsaicin-sensitive nerves

147
Q

An experiment was done which investigated the effect of sensory-motor nerves in blood vessel regulation.

What would you expect to see when the sympathetic nerves were stimulated in the presence of capsaicin? (1)

Why does this happen?

A

Larger contraction responses

which happen because the sensory-motor neurogenic dilation response has been abolished by capsaicin

148
Q

Briefly describe five pieces of evidence supporting a prominent role of CGRP in sensory-motor vasodilation. (5)

A
  • Neurogenic relaxation is abolished by capsaicin (which desensitises CGRP-containing nerves)
  • Neurogenic relaxation is blocked by CGRP antagonists such as CGRP8-37
  • Neurogenic relaxation is mimicked by exogenous CGRP (but not substance P or VIP)
  • Higher levels of CGRP in tissue fluid after vasodilation response was seen
  • Immunohistochemical localisation of CGRP within nerves of blood vessels, but sparse SP and VIP innervation
149
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in the regulation of cardiac function.

Describe the effects of short-term administration of capsaicin on cardiac function. (3)

A
  • Potent cardiostimulant
  • Positive inotropic effects
  • Positive chronotropic effects
150
Q

Describe the mechanism by which capsaicin is able to stimulate cardiac function. (2)

A

Capsaicin activates sensory-motor nerves

which release neuropeptides which act on the heart.

151
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in the regulation of cardiac function.

Name the three neuropeptides which are co-released from cardiac sensory-motor nerves. (3)

A
  • CGRP
  • Substance P
  • Neurokinin A
152
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in the regulation of cardiac function.

Describe the effects of CGRP on cardiac function. (3)

A

Potent cardiostimulant

Positive inotropic effects

Positive chronotropic effects

153
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in the regulation of cardiac function.

Compare the effects of CGRP and capsaicin on cardiac function. (1)

What does this suggest about the neuropeptides acting on the heart? (1)

A

CGRP mimics actions of acute capsaicin administration

Does this mean that CGRP is the predominant neuropeptide acting on the heart?

154
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in the regulation of cardiac function.

What is the effect of substance P on cardiac function? (1)

A

It is inactive - no effect

155
Q

Sensory-motor nerves and the neuropeptides that they release are thought to be involved in the regulation of cardiac function.

Describe the effects of neurokinin A on cardiac function. (2)

A

Negative inotropic effects

Negative chronotropic effects

156
Q

What is the main stimulus causing activation of cardiac sensory-motor nerves? (1)

A

Mediators of inflammation and ischaemia

157
Q

Fill the gaps relating to the trophic effects of sensory-motor nerves. (2)

Sensory-motor nerves promote maintenance of tissue ……………………. and ability of tissue to ……………….. in response to injury.

A

integrity

repair

158
Q

Fill the gaps relating to the trophic effects of sensory-motor nerves. (2)

When sensory-motor innervation is removed, there is ……………………. survival of skin flaps, and increased appearance of ……………………….

A

reduced

skin wounds

159
Q

Sensory-motor nerves are thought to have trophic effects, which are able to play a large role in wound healing and maintenance of tissue integrity.

Substance P, neurokinin A, and CGRP are thought to stimulate the proliferation of which three cell types following injury? (3)

A
  • Endothelial cells
  • Smooth muscle cells
  • Skin fibroblasts
160
Q

Sensory-motor nerves are thought to have trophic effects acting on sympathetic nerves.

Describe the general relationship between the number of sensory-motor nerves and sympathetic nerves. (1)

A

Less sensory-motor nerves = more sympathetic nerves

161
Q

Sensory-motor nerves are thought to have trophic effects acting on sympathetic nerves.

Describe and explain the effects of removing sensory-motor nerve innervation from the cardiovascular system. (2)

A

Increased sympathetic innervation

potentially due to competition for nerve growth factor.

162
Q

Experiments looking at the roles of sensory-motor nerves on ageing are often done on rat mesenteric arteries.

Describe two changes that are seen in sensory-motor nerves of the rat mesenteric arteries in ageing. (2)

A
  • Decreased CGRP content
  • Decreased vasorelaxation
163
Q

Experiments looking at the roles of sensory-motor nerves on hypertension are often done on rat mesenteric arteries.

Describe a change seen in sensory-motor nerve function observed in mesenteric arteries of hypertensive rats. (1)

A

Decreased sensory-motor neurogenic vasorelaxation

164
Q

Describe three changes in sensory-motor nerve function that are seen in diabetes. (3)

A
  • Decreased sensory-motor nerve conduction velocity
  • Decreased neuropeptide content
  • Decreased neurogenic vasorelaxation
165
Q

How might sensory-motor nerves be involved in the pathophysiology of migraine? (1)

How do current migraine treatments support this theory? (1)

A

Migraine may be caused by CGRP-mediated vasodilation

Triptans used for treatment lead to cerebral blood vessel constriction (via 5HT receptors)

Neuroscience Y2S2 (15 decks)

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