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Neuroscience > Injury/regeneration and brain cell death > Flashcards

Injury/regeneration and brain cell death Flashcards

1
Q

2 types of injury to nerve cells

A
  1. Axon damage
  2. Neuron loss
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2
Q

when axotomy occurs where is function lost?

A

distal to the cut => toward the axon terminal

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3
Q

what happens with Schwann cells when axonomy occurs?

A

the cells will start to chew up the myelin they made and incorporate macrophages

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4
Q

what happens with oligodendrocytes when axotomy occurs?

A

they will more slowly break up and astrocytes will help w/ this ⇒ end seals

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5
Q

what happens with ions when axotomy occurs?

A

K+ leaks out of cell and Na+/Ca++ leaks into cell within seconds

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6
Q

how long does it take for proximal and distal axon segments to reseal away from cut ends?

A

2 hours

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7
Q

spinal cord injury (SCI)

A

loss of sensation + muscle paralysis below the level of injury
- Can be partial or complete
- Probably wont die

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8
Q

Peripheral nerve injury (PNI)

A

loss of sensation and paralysis in region served by injured nerve
- Nerve may die

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9
Q

what is another name for anterograde effects?

A

wallerian degeneration

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10
Q

what end is anterograde?

A

axon terminal end

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11
Q

what are anterograde effects? (5)

A
  • Axon swells ⇒ w/in 2 hours
  • Axonal membrane fragments ⇒ w/in 3 days
  • Myelin fragments over the dead axon ⇒ w/in 1 week
  • Astrocytes (CNS) or schwann cells (PNS) proliferate ⇒ 1-4 weeks
  • Glia and microglia phagocytose debris ⇒ 1 month PNS and 3 months CNS
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12
Q

transneural effects

A

without innervation downstream neurons die
- the effect is reduced by presence of other connections and increased age
- Muscle atrophy if their innervation is lost

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13
Q

as motor axons degenerate what happens spontaneously?

A

spontaneous action potentials lead to muscle contractions for the following 1-2 hours
- denervation atrophy of muscle

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14
Q

what is muscle denervation?

A

loss of LMNs and their axons which leads to muscle atrophy

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15
Q

how fast doest LMN denervation occur?

A

very rapidly and severely

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16
Q

how fast does UMN loss occur?

A

slow and mild atrophy

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17
Q

disuse atrophy

A

stopping exercising

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18
Q

how fast does disuse atrophy occur?

A

Slowest and least severe atrophy

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19
Q

what are some retrograde effects of axotomy? (3)

A
  • neurotrophic supply from the target cell is lost (such as brain derived neurotrophic factor)
  • changes in the soma (2-3 days)
  • distance between injury and soma is important alongside age
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20
Q

do younger or older animals have more severe responses to axotomy?

A

younger animals and the longer the distance between target the more effects there are

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21
Q

chromatolysis; how does it try to solve the problem?

A

dissolving of color and is a loss of RER, soma swells, nucleus moves off center
- Occurs within 3 days ⇒ the metabolism of the cell is profoundly changed
- It tries to recreate the axon and grow back to its target
- the cell down regulates expression of molecules required for neuronal communication (neurotransmitters) and up regulates synthesis of molecules needed for axon growth so the axon will regrow in 1-2 weeks

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22
Q

how fast do axons travel

A

2-4 mm/day (1.5 mm/day used)

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23
Q

how do axons follow their old path?

A
  • Axons growth within the connective tissue sheath along channels formed by Schwann cells
  • Optimal regeneration requires the nerve sheath to be intact
    Note: ends of a cut nerve can be connected surgically with sutures in the connective tissue sheath
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24
Q

neuroma

A

axons that grow outside of the sheat are very painful

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25
Q

where do regenerating axons form synapses?

A

at or close to their original synaptic sites

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26
Q

Sensory axons

A

will reinnervate their original territory and may displace axons that have invaded their territory
- Synapses ⇒ neurotrophins (TF) ⇒ gene expression switches to that for neurochemical communication instead of growing still
- The myelin sheath is eventually re-established by Schwann cells

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27
Q

why is regeneration not perfect? (4)

A
  • Less strength and dexterity
  • Less sensory discrimination
  • Motor units are larger
  • Conduction velocity is down 20%
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28
Q

how long does it take for CNS axon growth to fail?

A

axons may sprout after axonal damage
- Axon growth fails after 1 month
- Spinal cord injury and other CNS injuries due to axotomy don’t resolve

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29
Q

what are injury hypotheses? (3)

A
  1. Glial scars
  2. myelin inhibitory molecules
  3. Intrinsic inability of mature CNS neurons to grow axons
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30
Q

glial scars

A

increased density and alignment of glial processes leads to thick, parallel astrocytic processes (proliferation) ⇒ interferes with axon regrowth

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31
Q

Myelin inhibitory molecules

A
  • NOGO
  • MAG
    Note: MAG and NOGO both interfere with axon extension
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32
Q

how do PNS and CNS axons regenerate?

A

through a peripheral nerve if they are given a path
- This does not occur through the optic nerve so adult CNS myelin appears to include molecules that inhibit axon growth

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33
Q

what are the myelin cells for the CNS and PNS?

A
  • CNS is oligodendrocytes
  • PNS is Schwann cells
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34
Q

what happens when you cut the optic nerve and either graft a peripheral nerve or not?

A
  • cut optic nerve and do nothing further result in no sign of regeneration of axons
  • Cut optic nerve and transplant peripheral nerve to bridge between optic nerve head and superior colliculus and find regeneration and function
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35
Q

what is NOGO? What does blocking do?

A

neurite out-growth inhibitor
- Blocking nogo promotes CNS regeneration by allowing corticospinal axons to regenerate 9 mm beyond injury sites
- Unfortunately there are few axons and they don’t go very far

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36
Q

what is MAG

A

Myelin associated glycoprotein
- does the same thing as NOGO

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37
Q

what do mature CNS cells express as far as intrinsic inability to grow axons?

A

KLF4 protein

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38
Q

KLF4; knocked out?

A

a transcription factor that blocks the ability of the cell to express molecules needed for axon growth ⇒ if KLF4 gene is knocked out, adult retinal ganglion cells are able to regenerate in the optic nerve
- This limits their ability to regenerate axons

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39
Q

axotomy near the soma is likely to result in what?

A

cell death
- Young neurons are more likely to undergo cell death in response to axotomy regardless of the position of the axotomy
- In adult neurons, they may die but are more likely to atrophy if regeneration fails

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40
Q

why do neurons die? (5)

A
  • normal development
  • disease => neurodegenerative, metabolic, infectious
  • toxins
  • trauma
  • hypoxia => heart attack, stroke, drowning, carbon monoxide
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41
Q

functional plasticity

A

the nervous system learns to perform missing functions with remaining neurons
- Generation of new neurons by CNS is minimal

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42
Q

clinical approaches to replacing neurons? (3)

A
  • Transplantation of embryonic neurons
  • Transplantation of stem cell derived neurons
  • Reprogramming glia to become neurons
43
Q

what disease is helped with transplanting neurons from human embryos?

A

Parkinsons disease
- ignoring ethical issues it is impractical because it requires large amounts tissue and excessive embryo amounts

44
Q

stem cells

A

capable of self renewal indefinitely and generating multiply types of differentiated cells

45
Q

types of stem cells (5)

A
  • Embryonic stem cells (ESC)
  • Umbilical cord stem cells
  • Induced pluripotent stem cells (iPSC)
  • Neuronal stem cells (NSC)
  • Other stem cells from adult tissues
46
Q

Embryonic stem cells (ESC)

A

embryo produced in vitro fertilization and ESC are generated from inner cell mass of blastula
- Can be used as a source of neural tissue
- When this is done the resulting tissue is heterogenous and may form teratomas in vivo ⇒ multiple tissue types

47
Q

Induced pluripotent stem cells (iPSC)

A

can be generated from many different types of differentiated cells ⇒ usually made from skin cells
- Can be generated from the person requiring treatment which has a reduced risk of rejection

48
Q

Neuronal stem cells (NSC)

A

divide in culture and lead to neurospheres
- neurospheres
- have been isolated from many parts of the adult nervous system

49
Q

neurospheres (do 3 things)

A

give rise to neurons, astrocytes, and oligodendrocytes

50
Q

where can neuronal stem cells be found in the brain? (6)

A
  • Subventricular zone ⇒ base of lateral ventricles
  • Subgranular zone (hippocampus)
  • Cerebellum
  • Midbrain
  • Retina
  • Spinal cord
51
Q

what is glial cell reprogramming

A

glia becomes reactive following injury and are susceptible to reprogramming
- Treat with proneural transcription factors
- Glial cells develop into neurons
- Develop appropriate morphology
- Make and receive functional synapses

52
Q

what does successful therapeutic neuron replacement require? (7)

A
  • Appropriate donor cell type
  • Purified donor cell populations at proper stage of development
  • Delivery of new cells to proper location
  • Survival of afferent and target cell populations
  • Growth of axons from new cells to appropriate targets
  • Connection of original afferent to new cells
  • Myelination of new axons
53
Q

what kills neurons? (4)

A
  1. Normal development => more neurons are born than needed
  2. Trauma
  3. Toxins
  4. Disease
54
Q

apoptosis

A

programmed cell death due to events within the cell ⇒ tightly regulated in mature neurons since they are built to last a lifetime
- Various cell signals can initiate it

55
Q

results of apoptosis? (4)

A
  1. Mitochondrial malfunction
  2. Cell shrinkage and or blebbing
  3. Breakup of nucleus
  4. Cutting off DNA into characteristic 185 bp pieces
56
Q

Traumatic brain injury (TBI)

A

a brain insult causing temporary or permanent impairment (physical, cognitive, or psychosocial) and resulting from an external force

57
Q

closed vs open trauma

A
  1. Closed trauma: Skull is not penetrated
    - Includes wartime blast trauma, which can be severe
  2. Open trauma: Something penetrated the skull and stayed there ⇒ bullet/skull fragment
    - Perforating injury
58
Q

sources of TBI (4)

A
  • sports injuries
  • Car accidents
  • Gunshots
  • Explosions, etc.
59
Q

results of TBI (3)

A
  1. Necrotic cell death
  2. Less severe TBI may result in apoptosis
  3. Specific neuronal populations may be more susceptible
    - GABA neurons in hippocampal dentate gyrus
60
Q

edema

A

swelling from a collection of fluid

61
Q

why does necrotic cell death occur?

A
  • Loss of blood supply due to laceration of vessels
  • Contusion (bruising) ⇒ edema ⇒ compression of vessels and loss of blood supply
62
Q

what areas of neurons in the dentate gyrus are highly affected after injury?

A

Hilus
- dentate makes C shape at bottom interlocking with the hippocampus ⇒ where they interlock the damage tends to be worse

63
Q

hypoxia

A

the body is receiving less oxygen than needed
- The normal oxygenation is hemoglobin > 90% saturated with oxygen
- Often measured with a pulse oximeter
- Low oxygen can lead to cyanosis

64
Q

cyanosis

A

skin turns blue

65
Q

pathological consequences of hypoxic cell death? (7)

A

(blocked aerobic metabolism in the brain)
1. Decreased ATP
2. Failure of Na+/K+ ATPase
3. Depolarization ⇒ excitotoxicity
4. Loss of Mg++ block of NMDA receptors ⇒ excitotoxicity
5. Opening of NMDA receptors ⇒ excitotoxicity
6. Ca++ inflow ⇒ excitotoxicity
7. Mitochondrial damage, release of toxins, apoptosis or necrosis ⇒ excitotoxicit

66
Q

excitotoxicity

A

the depolarization of nerve cells including loss of magnesium and calcium inflow (excess calcium)
- NMDA receptors open and mitochondrial damage

67
Q

causes of hypoxia (2 areas)

A
  • Local
  • Global
68
Q

Local hypoxia

A

comes from ischemic stroke

69
Q

Global hypoxia (6)

A
  • Cardio respiratory dysfunction ⇒ covid, pneumonia, severe lung disease, heart attack
  • Cerebral edema ⇒ trauma or altitude
  • Cerebral compression ⇒ hydrocephalus making clogged CSF/blood in SSS (could be local)
  • Altitude ⇒ >26,000 ft/8,000 meters leads to death
  • Carbon monoxide poisoning
  • Drowning
70
Q

Neurotoxins

A

toxins that kill you by interfering with the nervous system or kill nerve cells themselves

71
Q

toxins that kill by interference? (5)

A
  • Nerve gas
  • botulinum toxin
  • curare
  • tetanus toxin
  • tetrodotoxin
72
Q

nerve gas

A

blocks breakdown of acetylcholine

73
Q

Botulinum toxin

A

blocks neurotransmitter release

74
Q

Curare

A

blocks nicotinic acetylcholine receptor

75
Q

Tetanus toxin

A

blocks release of inhibitory neurotransmitters

76
Q

Tetrodotoxin

A

from puffer fish and blocks voltage gated sodium channels

77
Q

toxins that kill neurons (6)

A
  • ethanol
  • fetal alcohol syndrome
  • Excitotoxins (glutamate agonists)
  • lead
  • mercury
  • arsenic
78
Q

ethanol (def + 5)

A

brain tends to shrink and have neural loss
- Apoptosis of cerebral cortical neurons
- Mitochondrial dysfunction
- Vitamin deficiencies ⇒ particularly thiamine?
- Acetaldehyde: reactive ethanol metabolite
- Ethanol encourages inflammation

79
Q

fetal alcohol syndrome

A

interferes with myelination so Glia may die
- Unclear if neurons die

80
Q

Excitotoxins (glutamate agonists)

A

if you take in an agent that acts like glutamate it causes cells to fire more ⇒ not necessarily a good thing => shellfish poisoning
- Domoic acid

81
Q

Domoic acid

A

produced by algae and accumulated by shellfish, sardines, etc. ⇒ red tide is produced by the algae that produce domoic acid
- Glutamate (AMPA and NMDA) agonist ⇒ excites neuron and depolarizes it which removes the magnesium block from the NMDA receptor and the agonist allows calcium in which kills the cell

82
Q

what happens when you ingest Domoic acid? (3)

A
  • Damage to hippocampus and amygdala
  • Loss of short term memory
  • Kidney damage at lower doses than cause brain damage
83
Q

lead

A

directly inhibits NMDA receptors and substitutes for Ca++ (controls many enzymes) ⇒ can decrease normal cell functions without calcium
- Lead water pipes and lead paint (leaded gasoline)
Induces apoptosis
- Unclear to what extent it kills neurons rather than disabling them
- Significantly fewer hippocampal microglia after low level lead exposure in mice

84
Q

mercury

A

different forms of toxicity depend on the chemical form
- Hg+ and Hg++ ⇒ Either ionic form can damage the kidney
- Elemental metallic Hg and organic Hg go to the brain

85
Q

organic Hg

A

(still a hazard) methyl mercury; dimethyl mercury and is an important environmental hazard
- Coal burning ⇒ atmosphere ⇒ rain ⇒ lakes
- Concentrated up the food chain such as in fish ⇒ found in MN fish
- 50 year half life in the body

86
Q

methyl mercury

A

for industrial use and inhibits Na+/K+/ATPase as well as ATP production by mitochondria
- Minamata Disease in japan
- Lab accidents ⇒ Karen Wetterhahn and now its regulated different by US FDA

87
Q

Arsenic

A

poisons mitochondria and induces release of inflammatory agents (cytokines) and results in widespread apoptosis in the cerebral cortex, cerebellum, etc.
- Sourced from groundwater
- Serious problem in Bangladesh and problem in parts of the US including parts of MN

88
Q

disease types that kill neurons or glia (5)

A
  1. Metabolic
  2. Psychiatric diseases
  3. Infectious diseases
  4. Immunological diseases
  5. Neurodegenerative diseases
89
Q

Diabetes mellitus

A

diabetic neuropathy which kills axons in peripheral nerves ⇒ lose vasculature that supplies blood to nerves in the periphery
- Distal regions (hands, feet) are affected more than proximal regions (upper arms, thighs, chest)
- Affects sensory and motor axons
Very common in half of people with type 2 diabetes

90
Q

how does pathology of diabetes work?

A

Vascular damage ⇒ ischemia ⇒ axon death
- Long axons are harder to regenerate

91
Q

functional losses of diabetes (motor [2] and sensation [2])

A
  1. Motor function:
    - decreased conduction velocities
    - decreased Na+/K+/ATPase
  2. Sensation:
    - loss of touch, vibration, pain
    - Loss of sensation ⇒ vulnerable to injury due to loss of blood supply
    Note: Untreated injuries ⇒ amputation
92
Q

Psychosocial stress

A

depression in rat models
- Increased inflammatory markers in brian
- Reduced neurogenesis in hippocampus
- Apoptosis in hippocampus

93
Q

infectious diseases that kill neurons (3)

A
  • Polio
  • rabies
  • herpes simplex
94
Q

Poliomyelitis (polio)

A

caused by poliovirus
- Epidemics through the 1950’s in the US
- Nearly eliminated by vaccination
- Still exists in some countries
- Transmitted through fecal contamination of water
- Most infections lead to minimal effects but 1% lead to CNS involvement

95
Q

how does polio kill neurons?

A

infected neurons die from the virus
- Spinal motoneurons
- Brain stem neurons
- Can be fatal if respiratory control is lost
- Iron lung is used to help people breath during acute viral phase
- Cases in older individuals likely to be more severe

96
Q

Rabies

A

caused by the rabies virus and transmitted through bites/scratches by infected animals
- Relatively long incubation ⇒ 1 week-6 years after exposure but typically 1-2 months
- Virtually always fatal

97
Q

2 forms of rabies

A
  1. Encephalitic (furious) form: hyperactivity, agitation, aggression with a terrifying presentation in ⅔ of cases
  2. Paralytic form: hypoactive in ⅓ of cases
98
Q

how does rabies kill neurons?

A

The virus is retrogradely transported from periphery to CNS and replicated in the CNS killing neurons ⇒ likely overwhelms cellular metabolism
- Apoptosis can occur but may be a protective reaction
- Death of cell ⇒ loss of axonal transport ⇒ decreased infection in neurons innervated by cell (we don’t know for sure)

99
Q

herpes simplex

A

cause varying degrees of encephalitis in
- Type 1 is cold sores and Type 2 is genital sores

100
Q

encephalitis

A

inflammation in the brain
- This is rare and mostly in immunocompromised people

101
Q

when does each type of herpes cause encephalitis

A
  • HS1 And HS2 can cause encephalitis in neonates
  • HS1 can cause severe encephalitis in adults
102
Q

how does herpes kill neurons?

A
  • Reported to induce apoptosis in neurons and microglia
  • Higher fever from infection can also kill neurons
103
Q

Guillain-Barre syndrome (kills glia)

A

in the PNS as an autoimmune attack on peripheral myelin
- PNS myelin are composed of Schwann cells
- Macrophages phagocytose and eat myelin
- Demyelination ⇒ poor axonal function ⇒ death by respiratory arrest in severe cases

104
Q

neurodegenerative diseases (4)

A
  • Amyotrophic lateral sclerosis ⇒ Lou Gherigs disease
  • Huntington disease
  • Parkinson disease
  • Alzheimer disease

Neuroscience (18 decks)

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