NEU 490 Oligodendrocytes

Question 1

What is Myelin(white matter)?
most axons are what? Brain myelin is where? Spinal cord myelin is where?

Myelin is a specialized membrane with what content so why white? surrounds axons to facilitates?

It does so by acting like an what? nodes of Ranvier? what VG concentrated here?

Which cells produce myelin in the nervous system?
Peripheral Nervous System:
Central Nervous System:

Answer 1

most axons are myelin through NS but we also have unmyelinated
Brain myelin is under cortex made up of axons which are primary myelinated
Spinal cord the myelin is more on the outside called tracts or column - dorsal (somatosensory 90% not meylin)/ventral(motor) horn gray matter cell bodies

Myelin is a specialized membrane(high lipid content thats why its white) that surrounds axons, and facilitates RAPID nerve impulse conduction - high lipid content and speeds up conduction velocity of AP

It does so by acting like an insulator along the axon, allowing transmembrane currents at specific locations called the nodes of Ranvier - VG Na concentrated here and appearances of AP skipping along axon

Which cells produce myelin in the nervous system?

Peripheral Nervous System: Schwann Cells

Central Nervous System: Oligodendrocytes

Question 2

Diffusion Tensor Imaging

For what in body?

Anatomical overview of the?

Answer 2

Brain and Spinal Cord

Anatomical overview of the white matter in terms of diffusion anisotropy (directionality of diffusion of H20) Demonstrates fiber orientation

Question 3

interneurons are

Answer 3

mostly inhibitory but can be excit

Question 4

Oligodendrocytes: Myelinating cells of the CNS

Myelinated segments of how many axons?

One cell can myelinate as many how many? In multiple layers while retracting and expelling their what?

Generated from?

Myelin is an extended membrane able to wrap around axon in layers as many as how many layers?

Due to this energy consuming process and associated high metabolic turnover of the cells oligo are vulnerable?

Answer 4

Myelinated segments of MANY axons

One cell can myelinate as many at 50 different axons! In multiple layers while retracting and expelling their cytoplasm in order to generate the mature myelin (insheets axons)

Generated from oligo progenitor cells (OPCs) distributed through CNS and representant pool of migrating and proliferative cells that can different into mature (OLs)

Myelin is an extended membrane able to wrap around axon in layers as many as 100 layers

Due this energy consuming process and associated high metabolic turnover of the cells oligo are vulnerable to cytotoxic and excitotoxic factors

Question 5

Oligodendrocyte dysfunction is associated with a large number of nervous system disorders - MS, schizophrenia, Azlheremines

Loss of an oligodendrocyte would result in?

After injury, the Oligos de- differentiate and proliferate, producing agents that inhibit nerve repair?

What factor is released by oligodendrocytes that can inhibit repair of damaged axons?

Answer 5

Loss of an oligodendrocyte would result in regions of demyelination on many axons.

After injury, the Oligos de- differentiate and proliferate, producing agents that inhibit nerve repair: eg., NOGO-A → protein potent myelin associated inhibitor of exxonal growth, expressed by oligo in NS so OLs can inhibit nerve repairs

NOGO-A

Question 6

Complex cells that can differentiate in culture without neurons have what factors?

Two types of Oligodendrocyte?

When going from OPC to mature you have things that need to occur like?

only meylin when near?

can oligo myelinate each other?

Answer 6

Complex cells that can differentiate in culture without neurons have intrinsic factors that regulate their differentiation rather than requiring extrinsic signal from other cell types

Oligodendrocyte Progenitors AND Mature Oligodendrocyte

When going from OPC to mature you have things that need to occur like morphological differentiation(shape/size change), establishes network of process that are expansive, when neurons nearby see exxonal contact which will lead to ensheathment and generation of compact of myelination - only meylin when near neurons bc neurons release something it is not like oligo can myelinate each other even though they can mature without a neuron

Question 7

Oligodendrocyte development and differentiation

OPCs can be easily isolated from the?

Differentiation in vitro is ?

Stem cell OPC express what two things? - then become mature and can myelinate they have myelin?

Nearby axons release signals via what two things that attract our OPC?

OOC ID by two factors/markers?

Answer 7

OPCs can be easily isolated from the rodent brain

Differentiation in vitro is predictable and controllable

Stem cell OPC express NG2 and PDGFR alpha - then become mature and can myelinate they have myelin basic protein and galactocerebroside but still express the OPC stuff

Nearby axons release signals like via secretion or via direct contact that attract our OPC and can induce differentiation into myelinating oligo

OOC ID by two factors/markers the NG2 and PDGFR alpha then mature OLIG2 and NG2

Question 8

How do oligodendrocytes differentiate and produce myelin? Which help them to mature but they can go without it?

Notch pathway (negative/repulsive signal until after birth): OPC express Notch 1 Receptors and neonatal express the?

Neuregulin(positive signal regulator): axonal signal that promotes?

Answer 8

Can mature without the presence of axons but axons can still play a role in recruiting and helping them to differentiate.
After neonatal optic nerves were transacted there were few olgio that developed and this showed that axons can influence the attraction and survival of oligo nearby. When olgio are growing extended process

Axon signals recruit oligodendrocyte progenitors to differentiate

Notch pathway(negative/repulsive signal until after birth): OPC express Notch 1 Receptors and neonatal express the notch ligand jagged 1 which acts as a down regulator of myelin formation so when jagged is present olgio not as much differentiation from OPC to mature but after birth jagged is down regulated which helps with meyination timing bc don’t want to start myelination axon as soon as born need to have correct timing

Neuregulin(positive signal regulator): axonal signal that promotes schwann cell and oligo development, large family of proteins that are regulated to epidermal growth factors. When see mice that are Neuregulin deficient see reduction in OPC to olgio differentiation and proliferation

Question 9

OLs extend many processes that encounter axons of different sizes - The exact signal(s) that initiate and regulate the process are unknown

of wraps dependent on axon size: increase the amount of myelin for? how myelin thickness can change over time?

Regulate myelination activity also by axon activity: respond to?

G ratio =

Size plus Signals - higher concreation of factors that influence myelin thickness expressed by?
low concentration state of factors with not myline called?

In CNS almost all axons with diameters greater than?

Localization of oligodendrocytes to other cell types
There is interaction of oligodendrocytes with all other cells of the CNS, including?

Answer 9

of wraps dependent on axon size: increase the amount of myelin for larger diameter axons and this is bc we need proper ratio of myelin thickness to axon diameter around neurons so more activated axons end up becoming more thickly myelinated - how myelin thickness can change over time with experience so like playing piano

Regulate myelination activity also by axon activity: respond to extracellular environment

Size plus Signals - higher concreation of factors that influence myelin thickness expressed by larger diameter axons which is like TEN4, intergin, NRG, LN2.
low concentration state of factors with not myline called quiescent state.

In CNS almost all axons with diameters greater than 0.2 μm are myelinated

Localization of oligodendrocytes to other cell types:
There is interaction of oligodendrocytes with all other cells of the CNS, including microglia, astrocytes, and neurons.

Question 10

What is the ideal G-ratio of axons?

Answer 10

0.6

Question 11

Which of the following signals is released by neurons to downregulate myelination of axons during development?

Answer 11

Jagged1

Question 12

True or false: myelin thickness decreases when axon diameter increases.

Answer 12

False

Question 13

Schwann Cells PNS

Myelinating VS Non-myelinating

These cells myelinate axons that are in the peripheral nervous system; i.e., any axon that is not in the?

myelin sheath by wrapping? lamellae?

High lipid content called?

Axons can be what length?

helpful in what three things?

non-Myelinating Schwann Cells called what? – these ensheath small what?

Answer 13

Myelinating (wrapping around axons of motor and sensory)

Non-myelinating (bundle axons into multiple unmyelinated axons called remark fibers)

These cells myelinate axons that are in the peripheral nervous system; i.e., any axon that is not in the brain or spinal cord

myelin sheath by wrapping plasma membrane concentrically around the inner axon - in axon see schwann cell see fixed nucleus but inner turn of glial cell membrane spirals around the axon to add membrane layers also called lamellae to the myelin sheath

High lipid content called cholesterol

-not only for conduction but nerve development and regeneration
-Trophic support - things that help keep neurons alive
-Produced extracellular matrix which helps with synapse formation

Also non-Myelinating Schwann Cells called Remarks – these ensheath small caliber axons

Question 14

One Schwann cell: One axon - only myelinated a what unlike olgio?

Span a considerable length so typically many schwann cells are required to myelinated the length of single axon - diameter of PNS axons range from what microns? unlike CNS go from what microns?

Multiple Schwann cells myelinate the same?

After injury, the Schwann cells dedifferentiate(turn back into OPC) and proliferate, producing agents that?

After injury what degeneration? which occurs what to the injury site?
axon dies and macrophages clear the dead content which promotes? Schwann cells undergo phenotypic changes to upregulation of? create what through basal lamain tube axon? does this also happen in CNS with oligo?

Answer 14

One Schwann cell: One axon - only myelinated a single axon unlike olgio

Span a considerable length so typically many schwann cells are required to myelinated the length of single axon - diameter of PNS axons range from 0.1 microns to 20 microns unlike CNS go from 0.1 to 10 microns

Multiple Schwann cells myelinate the same axon because each Schwann cell is associated with a short segment of the axon

After injury, the Schwann cells dedifferentiate(turn back into OPC) and proliferate, producing agents that Stimulate nerve repair

after injury wallerian degeneration which occurs distal to the injury site so after injury the axon has injury in the middle you will see breakdown of part of the axon which is the degeneration and the axon dies and macrophages clear the dead content which promotes axon degeneration. Schwann cells undergo phenotypic changes to upregulation of cytokines and activate myelin breakdown so recruit macrophages and upregulate neurotrophic factors to stimulate regeneration to increase neuronal and organize a regeneration pathway and create through basal lamain tube axon regrowth and then schwann cells can grown on the regenerated axon so proximal to distal nerve stem- this does not always occur meaning that correct reinueration of target doesn’t always happen but the ability for schwann cells to dice the clean of dead and support neurons this does not happen with oligos. Note this does not happen with oligos in the CNS

Question 15

Neuregulin (NRG type 3) levels regulate thickness of myelination produced by Schwann cells

In transgenic mice engineered to produce various amounts of NRG I type III, the myelin sheath that was produced by Schwann cells was proportional to?

Optimal ratio =

NRGs are predominantly expressed by who? which target them to axons in CNS and PNS so it promotes the what?

Large amount of NRG lead to?

Answer 15

In transgenic mice engineered to produce various amounts of NRG I type III, the myelin sheath that was produced by Schwann cells was proportional to the amount of NRG1 type III they encountered

Optimal ratio = 0.6

NRGs are predominantly expressed by neurons which target them to axons in CNS and PNS so it promotes the survival and proliferation of schwann cells by activating erb2 receptors

Large amount of NRG lead to thick myelin sheath produced by schwann and when had less or litter NRG marks remark bundle the non-myelinated

Question 16

Schwann cells myelinate anything greater than?

Myelinated fibers less than what are rare in the peripheral nervous system?

Non-myelinating Schwann cell bundles the?

Separates axons-does not myelinate them: provide? surrounds? Disruption associated with?

The percentage of axons myelinated increases progressively with increasing?

Answer 16

Schwann cells myelinate anything greater than 1 diameter so anything less than on micron goes to remark bundle which is called radial sorting so bundle small axons close together but not myelinated

Myelinated fibers less than 1 μm in diameter are rare in the peripheral nervous system

Non-myelinating Schwann cell bundles the axons close together by surrounding them

Separates axons-does not myelinate them:
–Provide metabolic support
–Surrounds sensory c-fibers (nociception) - 90% of sensory axons are C-fibers
–Disruption associated with neuropathic pain

The percentage of axons myelinated increases progressively with increasing size of the peripheral target; for the largest targets, 60% of the axons were myelinated - larger muscle group for bigger targets have larger percentage of axons heading to target will be myelinated

Question 17

Myelination thickness is fill in blank (proportional, half of, or exponential) to the presence of fill in blank (Integrin, Neuregulin)

Answer 17

Proportional, Neuregulin

Question 18

Cell Comparison: Oligodendrocytes vs. Schwann Cells

Myelinate how many axons?
Neuronal regeneration after injury?

Both have what?

Answer 18

Oligodendrocytes:
- One myelinate many axons segments, because of the many processes it extends to contact axons - up to 50 different axons
- CNS myelin contains some unique proteins
- Inhibits neuronal regeneration after injury - NoGo-A

Schwann Cells:
- Myelinate 1 axon segment because whole cells is in contact with axon - multiple schwann cells for each axon
- Protein composition of PNS myelin is different
- Can promote neuronal repair after injury bc of encouragement od wallerian degeneration and cleanup of damage and proliferation and mutation of new schwann cells and support for neuronal growth

Both have lamellae for schwann it is their actual plasma membrane and for oligo it is still plasma membrane but on distal processes that releases cytosolic proteins to create layers - but layered approach occurs in both

Question 19

Protein Composition Comparison - myelin made up of?

Myelin in the CNS and the PNS contains a how much proteins?

Oligodendrocytes: which protein - most abundant and %?

Schwann Cells: which protein and % and which family?

Both Oligodendrocytes and Schwann Cells: have which protein - 2nd most abundant? Function?

Answer 19

Protein Composition Comparison - myelin made up of water protein and lipids

Myelin in the CNS and the PNS contains a relatively small quantity of proteins, but they constitute a highly diverse group important for myelination functions

Oligodendrocytes:
Proteolipid protein (PLP): most abundant protein for myelin in CNS so 38% of myelin protein mass, high level required to preserve myelin integrity and helps to form the compact multi layer membrane structure inorder to bring myelin members close together and if you reduce PLP expression leads to alter myelin structure and pathology of the axon so can lead to hypomyelination - little to no in PNS

Schwann Cells:
Protein Zero (P0): 50-60% of myelin sheath proteins and belong to immunoglobulin family which is important for adhesion and for the multiple layers of the myelin sheath and helps to compact the myelin into those tight layers bc of the adhesion

Both Oligodendrocytes and Schwann Cells:
Myelin Basic Protein (MBP): 2nd most abundant protein in the CNS 30% and less abundant in PNS 5-18%

Function and interacts with other proteins participating in cytoskeleton and tight junctions
Called executive bc of its role in compaction of myelin sheath

ALL compact myelin sheath

Question 20

what stains proteins so can use to see myelin?

Myelin is made up of?

Answer 20

immunochemistry stains proteins so can use to see myelin like PLP or MPB

Myelin is made up of? Water, lipids, proteins

Question 21

Myelin Dynamics Throughout the Lifespan

The process of myelination is one of the last events in the?

In humans, it begins in the what?, and continues earnest for the first?

Myelin continues to be laid down until?

Oligodendrocyte precursor cells (OPCs) continuously generate new myelinating oligodendrocytes (Ols) in the? from when to when?

The OL population then declines in?

Lineage tracing of single OPCs show that although?

Most myelin sheaths, once formed, are?

Answer 21

The process of myelination is one of the last events in the formation of the nervous system

In humans, it begins in the third trimester, and continues earnest for the first two years (at least)

Myelin continues to be laid down until ≈ age 25

Oligodendrocyte precursor cells (OPCs) continuously generate new myelinating oligodendrocytes (Ols) in the somatosensory cortex from birth up to middle age

The OL population then declines in old age, accompanied by a reduction in myelin coverage

Lineage tracing of single OPCs show that although pre myelinating Ols are continuously produced in adulthood, only approximately 20% survive to myelinate

Most myelin sheaths, once formed, are stable in length over prolonged period of time, indicating that there is normally very little remodeling of existing myelin

Question 22

Function of Myelin in the Action Potential

Myelin inextricably linked to?

Insulate ?

Accelerate ?

Preserve ?

Maintenance of who?

Conductors: Allow?

Insulators: Slow ?

Answer 22

Myelin inextricably linked to Action Potential Conduction

Insulate Prevent Loss of Charge

Accelerate Action Potential

Preserve Energy

Axonal Maintenance

Conductors: Allow Energy to Pass

Insulators: Slow Energy Transfer

Question 23

Insulator

The axonal membrane has ion channels?
The movement of Na ions ?

In myelinated axons, channels are found only at?

In unmyelinated axons, no further what?

Answer 23

The axonal membrane has ion channels, Na and K ions, along its length
– The movement of Na ions through these channels into the neuron depolarizes the membrane, and generates an action potential
— The action potential depolarizes neighboring membrane by opening more channels

In myelinated axons, channels are found only at the nodes of Ranvier. The signal ‘skips’ down the axons. This is called saltatory or active conduction.

In unmyelinated axons, no further triggering event is necessary. There is a passive depolarization spread called continuous or contiguous conduction.

Question 24

Accelerator?
What happens when you drop a hammer on your toe?

Answer 24

In the case that a rapid response is needed, messages can travel quickly over long distances.

What happens when you drop a hammer on your toe? Without myelin, it might take minutes for the signal to get to the brain. With myelin, it takes milliseconds!

Question 25

Membrane Resistance (R): the degree to which a?
low Rm VS high Rm

Capacitance (C): the ability to?
If Cm is high VS If Cm is low

Capacitance depends on the?

Answer 25

Membrane Resistance (R): the degree to which a membrane prevents facilitates free movement of ions

low Rm allows lots of ion movement out of cell – reduces action potential speed

high Rm reduces ion loss (insulates) -internal current spread is larger, thus increases action potential speed (accelerator)

Capacitance (C): the ability to store charge

If Cm is high - the longer and more charge it takes to charge the capacitor the slower the action potential

If Cm is low - then the capacitor becomes full faster resulting in faster depolarization and faster action potential

Capacitance depends on the size and shape of the capacitor (or in this case the axon!)

Question 26

Myelin Increases Membrane Resistance (NAME?):
What prevents leakage of charge? Encourages diffusion of?

Myelin Reduces Membrane Capacitance (NAME?):
Myelin wraps increase the separation of?
Decreases the amount of?
Smaller change in?

Answer 26

Myelin Increases Membrane Resistance (Insulator):
- Insulated area of the axon prevents leakage of charge
- Encourages diffusion of ions through axoplasm to reach the next node

Myelin Reduces Membrane Capacitance (Accelerator):
- Myelin wraps increase the separation of charge (cations and anions) – as you increase diameter (between the ECF and ICF) you decrease capacitance.
- Decreases the amount of charge stored on both sides of the membrane
- Smaller change in ion concentration is required to initiate an axon potential

Question 27

Factors Affecting Capacitance

The amount of charge that can be stored on the plates of a capacitor is directly?

PLATE AREA:

PLATE SPACING:

Answer 27

The amount of charge that can be stored on the plates of a capacitor is directly proportional to the area of the conducting plates and inversely proportional to the distance between them.

PLATE AREA: All other factors being equal, greater plate area gives greater capacitance; less plate area gives less capacitance

PLATE SPACING: All other factors being equal, further plate spacing gives less capacitance; closer plate spacing gives greater capacitance

Question 28

Predicted versus Actual Efficiency

The g-ratio, equal to the ratio of the?

If volume is a constraint?

Optimal g ratio for neurons:?
g ratio =
d =
D =

Answer 28

The g-ratio, equal to the ratio of the inner-to outer diameter of a myelinated axon, is associated with the speed of conduction

If volume is a constraint (which it is, in a neuron), there is an ideal level of myelination for maximum efficiency

Optimal g ratio for neurons: 0.6
g ratio = d/D
d = diameter of axon
D = diameter of axon + myelin

Question 29

Other Myelin benefits

The presence of myelin reduces energy consumption that is needed to?

It is also important for long term?

Schwann cells secrete molecules that foster?
3 types???

Answer 29

The presence of myelin reduces energy consumption that is needed to restore the proper ionic gradients (i.e., the membrane potential)

It is also important for long term axonal maintenance and stability

Schwann cells secrete molecules that foster axonal health and regeneration after injury
Neurotrophin 3 (NT-3)
Ciliary neurotrophic factor (CNTF)
Nerve Growth Factor (NGF)

Question 30

Recent research has explored whether myelin thickness can change over time based on experience, and emerging evidence indicates this is possible. If an axon for a neuron important for motor learning increases the number of layers of myelin, thus increasing myelin thickness, what will happen to membrane capacitance, internal resistance, and propagation velocity?

a. Increased capacitance; decreased internal resistance; decreased velocity

b. Decreased capacitance; no change in internal resistance; increased velocity

c. Increased capacitance; no change in internal resistance; increased velocity

d. Decreased capacitance; decreased internal resistance; increased velocity

e. Decreased capacitance; increased internal resistance; decreased velocity

Answer 30

Decreased capacitance; no change in internal resistance; increased velocity

Question 31

Effects of Myelin Dysfunction

Importance of myelin proteins

Plp1 mutation - jimpy –severe demyelination mice die?

Plp1 mutation – rumpshaker?

Plp1 null – myelinated but with?

MAG null- ?

MBP – shiverer – severe?

CNP overexpression- ?

Myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes
Ceramide to ?

Answer 31

Plp1 mutation - jimpy –severe demyelination mice die at 4 wks.

Plp1 mutation – rumpshaker – hypomyelination and long-lived - thinner myelin

Plp1 null – myelinated but with severe axon degeneration

MAG null- subtle phenotype axon diameters are smaller

MBP – shiverer – severe dysmyelination leading to death

CNP overexpression- premature and abnormal myelination

Myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes
- Ceramide to CerS2 to Galactocerebroside

Question 32

What Happens to Conduction Velocity If the Length of Myelin Changes?

Answer 32

Increase the # of nodes of Ranvier per length of axon (increase conduction velocity)

Increase the distance between each node (decrease conduction velocity)

Question 33

Disorders of Myelin

Hypomyelination:

Dysmyelination:

Demyelination: Primary VS
Secondary

Answer 33

Hypomyelination: Normal molecular composition, but reduced amount

Dysmyelination: abnormal molecular composition, reduced amount and abnormal morphology

Demyelination:

Primary – direct immune or toxin mediated attack on myelin or oligodendrocytes

Secondary – due to axon loss (Wallerian (PNS) Wallerian-like (CNS) degeneration

Question 34

Multiple Sclerosis

Main subtypes: 2 types?

Disease Pathology: Autoimmune attack of the nervous system
Focal inflammation resulting in? Neurodegeneration?

Etiology/risk factors: 4 things?

Answer 34

Main subtypes:
Relapsing-Remitting
Primary Progressive

Disease Pathology: Autoimmune attack of the nervous system
- Focal inflammation resulting in macroscopic plaques and injury to the blood-brain barrier (BBB)
- Neurodegeneration with microscopic injury involving different components of the CNS including axons, neurons, and synapse

Etiology/risk factors:
Genetic predisposition
Females diagnosed 2:1
Environmental triggers
Viral infection: Epstein-Barr virus