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YEAR 2 - The Nervous System > 18.1. CNS Morphology (CNS Compartments) > Flashcards

18.1. CNS Morphology (CNS Compartments) Flashcards

1
Q

Why is there a need to separate different liquid compartments from each other?

A

Allow different compartments to have different liquid compositions and hence to specialise.

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2
Q

What are the different fluid compartments in the brain?

A
  • Intracellular fluid
  • Interstitial fluid
  • CSF
  • Blood
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3
Q

What are the different barriers between compartments in the brain?

A
  • Cell membrane (intracellular - interstitial fluid)
  • Blood brain barrier (interstitial fluid - blood) -> Not in all parts of the brain
  • Blood CSF barrier
  • CSF interstitial barrier -> Specialised parts of the brain only
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4
Q

What compartments is the blood brain barrier between?

A

Interstitial fluid and blood

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5
Q

What is the function of the blood brain barrier?

A

It is involved in homeostasis of the internal environment of the brain:

  • Produces interstitial fluid
  • Allows selective transport of substance between blood and brain parenchyma
  • Astrocytes maintain stable ionic composition and clearance of neurotransmitters and other molecules/metabolites
  • Neurovascular coupling allows control of blood flow in response to neuronal demand
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6
Q

Describe the structure of the blood brain barrier.

A
  • Endothelial cells form the inner barrier
  • Pericytes cover these
  • Astrocytes extend feet onto the blood vessel (communicating with the endothelial cells and pericytes)
  • Endothelial cells and pericytes are embedded in the basal membrane
  • Microglia are also frequently considered to be involved
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7
Q

How do neurons relate to the blood brain barrier?

A

Neurons are connected to the blood brain barrier directly and also via astrocytes.

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8
Q

Explain the concept of a neurovascular unit.

A

It is a structure composed of part of the blood brain barrier and the associated astrocytes and neurons involved in its control.

[CHECK THIS]

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9
Q

How is brain and blood vessel development related?

A
  • The two systems use many of the same signalling factors in their development, meaning that their development is linked.
  • Some examples include VEGF and other angioneurins, such as BDNF and neurotrophins
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10
Q

What is the role of endothelial cells in the blood-brain barrier and how does their structure reflect this?

A
  • Form the main barrier, enabling selective transport across it
  • The adaptations:
    • Are connected by tight junctions
    • High number of mitochondria, indicating high metabolic activity
    • Very few intracellular transport vesicles
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11
Q

What is the role of pericytes in the blood brain barrier?

A
  • They surround the endothelial layer and contract to control blood flow
  • Phagocytose debris
  • Control permeability of endothelial cells
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12
Q

What is the ratio of endothelial cells to pericytes in the blood brain barrier?

A

3:1

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13
Q

Give some experimental evidence for the function of pericytes in the blood brain barrier.

[EXTRA]

A

Stimulation of pericytes causes their diameter to decrease and for the blood flow in the adjacent blood vessels to decrease.

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14
Q

Summarise the position and structure of astrocytes in the blood brain barrier.

A
  • Send “end feet” processes onto endothelial cells
  • Ensheathe the entire outer side of blood vessel
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15
Q

What is the function of astrocytes in the blood brain barrier?

A
  • Clear interstitial fluid solutes (via aquaporin 4 and Kir4.1 channels in the end feet)
  • Induce the properties of the BBB
  • Connect endothelia to neurons
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16
Q

Explain the concept of astrocyte induction.

[IMPORTANT]

A
  • Astrocytes contribute to induction and maintenance of the blood–brain barrier
  • This is done by paracrine interactions with the pericytes and endothelial cells.
  • The astrocytes secrete factors with either barrier-promoting or barrier-disrupting effects depending on signals received from neurons and/or endothelial cells.
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17
Q

What are microglia?

A

Resident macrophages in the CNS.

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18
Q

What is the function of microglia in the blood brain barrier?

A
  • Control in inflammation, destroy pathogens and clean up debris from dead or damaged cells
  • Repair breaches in the BBB very quickly
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19
Q

How do the endothelial cells of the blood brain barrier enable selective permeability?

A
  • They have tight junctions between cells.
  • Permeability is achieved in these ways:
    • Modulating tight junctions
    • Diffusion across cells
    • Aquaporins allow water movement
    • Transcytosis (movement across the cell in vesicles) -> Either receptor-mediated or non-selective
    • Diapedesis (transcellular/paracellular movement of mononuclear cells across the epithelial layer)
    • Transporters
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20
Q

How does lipophilicity of molecules determine how quickly they diffuse across the blood brain barrier?

A

More lipophilic molecules tend to diffuse more rapidly, but there are some exceptions to this.

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21
Q

What explains the increased permeability of these molecules across the blood brain barrier?

A

The presence of transporters that assist with their diffusion.

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22
Q

How do mononuclear cells get across the blood brain barrier?

A
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23
Q

What are the different types of transporter found in the blood brain barrier?

A

Two main types:

  • Solute transporters (SLCs)
  • ATP binding cassettes (APCs)

These include several different types:

  • Various glucose transporters (GLUT1)
  • Various AA transporters
  • Nucleotides/-sides/-bases
  • Monocarboxylic acids (ketones, lactate)
  • Thyroid hormone (T3)
  • Organic an/cation transporter
  • Amine
  • Choline
24
Q

What are some explanations for the impermeability of the blood brain barrier to certain molecules?

A
  • Transporters, especially ABCs, pumping substances out
  • Endocytosis followed by degradation of the molecule intracellularly
  • Enzymatic conversion of the molecule (either following endocytosis or extracellularly)
  • Tight junctions between endothelial cells, and the presence of two membranes (apical and luminal)
25
Q

What are ABCs and what is their function?

A
  • ATP-binding cassette transporters
  • They are found on the luminal membrane of epithelial cells in the blood brain barrier
  • They function to pump out exogenous substances that enter the epithelial cells, thus protecting the brain from exogenous substances
  • Form dimers with 2 ATP binding/hydrolysis domains and 2-3 transmembrane ligand binding and transport domains
26
Q

Give some clinical importance of ABCs.

[EXTRA]

A
  • ATP binding cassettes make use of drugs in the brain difficult, because many of them will be extruded by the ABCs
  • P-glycoprotein (Pgp) = Multi Drug Resistance 1 (MDR1) = ABCB1 extrudes 50% of commonly used drugs
27
Q

What explains the decreased permeability of these molecules across the blood brain barrier?

A

They are largely extruded by ATP binding cassettes.

28
Q

Compare and explain the uptake of L-DOPA and dopamine across the blood brain barrier. How is this clinically important?

A
  • Both are taken up by the same transporter, so you would expect there to be a similar rate of uptake
  • However, there are intracellular enzymes in the epithelial cells that convert dopamine more than L-DOPA, so the rate of uptake is slower for dopamine
  • L-DOPA is a better treatment for Parkinson’s than dopamine, for this reason
29
Q

What are some causes of blood brain barrier dysfunction?

A
  • Developmental causes:
    • Angiogenesis
    • Differentiation
    • Maturation
  • Disease causes
30
Q

How does the blood brain barrier mature?

A
  • Maturation and maintenance of the BBB is achieved by the persistence of tight junction proteins expression and their redistribution throughout the whole BBB structure
  • Alterations in barrier development and in TJ expression may lead to increased predisposition to develop metabolic diseases
  • For example, maternal obesity can increase BBB permeability in offspring
31
Q

What are some diseases that my lead to blood brain barrier dysfunction?

[EXTRA?]

A
32
Q

What is medulloblastoma and how does it relate to the blood brain barrier?

[EXTRA]

A
  • A medulloblastoma is a common pediatric tumour of the cerebellum
  • There are 4 types, but WNT-MB is the most easily treated
  • (Phoenix, 2016) found that this is because WNT-MB secretes an inhibitor of endothelial WNT signalling, such that the blood brain barrier becomes more permeable
  • This means that the tumour is treated more easily using drugs
33
Q

Where is CSF found?

A
  • In ventricles of the brain
  • In a layer around the outside of brain and spinal cord in subarachnoid space
34
Q

In which space around the spinal cord is the CSF?

A

In the subarachnoid space.

35
Q

What are some functions of the CSF?

A
  • Reduces weight of brain (from 1400g to less than 50g)
  • Shock absorber
  • Control of cerebral blood flow
  • Immunological protection of brain
  • Homeostasis of interstitial fluid
  • Limits the consequences of raised intracranial pressure
36
Q

What is the total volume of CSF and how much is it renewed each day?

A

140ml, renewed 3-4 times a day

37
Q

The composition of the CSF is very tightly regulated. What are some differences between it and the blood?

[IMPORTANT]

A
  • K+ concentration is lower than in blood
  • pH is lower than in blood
  • Amino acids are lower than in blood (since many of them act as neurotransmitters)
  • Proteins are lower than in blood
38
Q

Draw a graph to show how potassium in the CSF varies with plasma potassium.

A

This shows how the CSF potassium is almot independent from plasma concentration, meaning that the barrier between them must be good at excluding potassium.

39
Q

How is CSF produced?

A

It is produced from plasma in the choroid plexus, which is a highly vascularised epithelial structure, into the ventricles

40
Q

Draw the structure of the blood-CSF barrier (at the choroid plexus) and describe how CSF is secreted.

A
41
Q

Compare the permeability of the blood-CSF barrier and the blood-brain barrier.

A

The blood-CSF barrier is much more permeable.

42
Q

Compare where the CSF and intersitial fluid are produced. How are the two related?

A
  • CSF is produced by the choroid plexus, while interstitial fluid is produced by cells of the BBB
  • They are not the same, althought they are in diffusion equilibirum and we do not know how interstitial fluid differs from CSF since it is hard to study
43
Q

Where is the choroid plexus?

A

It is in all of the ventricles of the brain.

44
Q

How does the CSF exit the ventricle system?

A

Through the Foramen of Magendie and Foramen of Luschka (from the fourth ventricle) into the subarachnoid space (around both the brain and the spinal cord).

45
Q

What are the two exit routes for drainage of CSF?

A
  1. Return to blood via arachnoid villi (both intracranially and at spinal nerve roots)
  2. Drainage into the nasal lymphatic system via the cribiform plate and nasal mucosa

(The diagram shows the location and structure of both of these)

46
Q

What are arachnoid granulations and what is their function?

[IMPORTANT]

A

They are projections of the arachnoid mater into the dural venous sinuses (in the subdural space), which allow for the CSF to drain into the venous blood.

47
Q

Summarise the flow of CSF.

A
48
Q

Summarise the two types of blood-CSF barrier.

A
  • Ventricular blood - CSF barrier
    • It is at the choroid plexus
    • This is what we think of when we talk about the blood-CSF barrier
    • It is where most of the CSF production happens
  • Subdural blood - CSF barrier
    • Not much exchange happens here
    • The CSF (in the subarachnoid space) is separated from blood vessels in the subarachnoid space due to the tight junctions in these capillaries and it is also separated from blood vessels in more superficial layers (e.g. the dura) by the arachnoid membrane
49
Q

Describe the CSF - interstitial fluid barrier and where it is found.

A
  • In general, the CSF and interstitial fluid are free to mix due to a lack of a selective barrier between CSF and interstitial fluid
  • The exception to this is the CSF-interstitial fluid barrier in the circumventricular organs
50
Q

What are circumventricular organs and what makes them distinct?

A
  • They are structures in the brain near the ventricle system
  • They act as sensory and secretory organs involved in homeostasis and body water balance
  • They are unusual because they do not have a blood-brain barrier, but they are the only parts of the brain that have a true CSF-interstitial fluid barrier
  • This allows them to sample the blood passin into the brain
51
Q

What forms the CSF-interstitial fluid barrier at the circumventricular organs?

A

Specialised neuroepithelial cells called tanycytes, which possess tight junctions at their apical side that prevent mixing of brain interstitial fluid with CSF.

52
Q

Summarise the flow between various compartments in the brain.

A
53
Q

What are CSF cisterns (a.k.a. subarachnoid cisterns)?

[IMPORTANT]

A

They are large spaces in the brain (not the ventricles though!) that contain CSF. You do not need to know named ones, but be aware that CSF flows there after exiting the ventricle system of the brain.

54
Q

Describe the ventricle system of the brain.

A
  • There are two lateral ventricles, where most CSF is produced
  • These are connected to a third ventricle
  • The third ventricle is connected to the fourth ventricle via a cerebral aqueduct
55
Q

What is hydrocephalus?

[IMPORTANT]

A
56
Q

What cells line the ventricles in the brain and what is their function?

[IMPORTANT]

A
  • Ependymal cells (a type of glial cells, although they are not always considered so)
  • They are involved in the production and regulation of CSF
57
Q

How does the blood brain barrier differ in the embryo/foetus?

A

It is more permeable in the embryo/foetus. However, this has been debated with some people calling it an urban myth.

YEAR 2 - The Nervous System (18 decks)

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