NEURODEVELOPMENT AND NEUROREGENERATION Flashcards
1
Q
Which layer does neural tissue develop from?
A
The ectoderm (top layer of the embryo)
2
Q
What is the ectoderm responsible for giving rise to?
A
- Neural tissue, skin, hair
3
Q
Where about in the ectoderm do the cells become nueral tissue?
A
- Middle region of the ectoderm
4
Q
What is neurulation?
A
- The formation of the neural tube from the neural plate rolling up into a tube
5
Q
What is the centre of the nerual tube filled with?
A
- Lumen (centre of tube) is filled with fluid (CSF comes from here)
6
Q
Where does the CSF derive from?
A
Lumen of neural tube
7
Q
What occurs if the neural tube doesn’t close?
A
Spinobiphida as it is exposed to the external environment
8
Q
Where does the neural tube first join up?
A
- First joins up in the middle, then zippers up to closure points.
9
Q
What is neurogenesis?
A
- When progenitor cells proliferate to become neuroblasts
10
Q
Where do cells divide?
A
- Divide with the nucleus at the ventricular surface
11
Q
How to neuroblasts divide?
A
Assymetrically
12
Q
Why is nueroblasts division assymetric?
A
- To retain a pool of progenitor cells (APCs)
- Initially one cell thick but must form multiple layers
13
Q
Where are the newer cells found?
A
Further out to surface of brain
14
Q
What are the migrating cells controlled by?
A
- Cells that produce factors that tells cells when to stop migrating.
15
Q
What do parts of the neural tube swell to become?
A
- Vesicles that form different parts of the brain
16
Q
What do the growth factors control?
A
- The transcription factors
17
Q
How are cells differentiated into different cell types?
A
- Soluble growth factors are released from regions and affect cells around them by altering transcription factors ..so cells around them interact differently
18
Q
How do pyramidal neurons in cortex synapse on motor neurons in the spinal cord?
A
- Needs stimuli such as touch and smell (soluble things in body to guide neurons down spinal cord)
19
Q
How do neurons find their target?
A
They extend a growth cone at end of axon
20
Q
What (in genera) controls axon guidance?
A
Environmental signals
e.g. attraction/repulsion, guidance cues
21
Q
What can attractive and repulsive signals cause respectively?
A
- Attractive directs actin fibres to extend by encouraging polymerisation and repulsive signals cause actin filaments to retract (depolymerise)
22
Q
What are dividing cells called?
A
- Neural progenitors (progenitor cell)
23
Q
What are radial glial cells?
A
- Neural progenitors that give rise to all neurons and astrocytes of CEREBRAL CORTEX (most neurons of CNS)
24
Q
How do we give rise to billions of neurons in the brain?
A
- Symmetrical division to expand population of progenitors (both daughter cells remain in VZ)
- Assymetrical division occurs later in development
25
What occurs in assymetrical divison?
- Daughter cell migrates away to set position in cortex where it will NEVER DIVIDE AGAIN
- Other daughter cell stays in VZ to undergo more divisions
- Radial glial cells repeat pattern until all neurons and glia of cortex have been generated.
26
What is the fate of the migrating daughter cell determined by?
- Age of the precursor cell
- Position within VZ
- Environment at the time of division
27
How do daughter cells migrate?
- (neural precursor cells) follow path from VZ toward surface of brain
- Migrate along thin fibres emitted by radial glial cells
28
When do radial glia withdraw processes?
- Radial glia withdraw processes when migration is complete.
29
What does the architecture of cortical dendrites depend on?
INTERcellular signals
30
What 3 phases do differentiation of neurons differ in?
1. Pathway selection
2. Target selection (what to innervate)
3. Address selection (correct layer of LGN for example)
- neurons extend the axons as they differentiate
31
What are the different ways cells communicate ( in differentiation) ?
- Cell-cell contact
- Contact b/w cells and extracellular secretions of other cells
- Communication between cells over a distance with diffusable chemcials
32
When does a neuron differentiate?
- Once the neural precursor cell has migrated to take up its appropriate place in the NS
- After this, THEN IT EXTENDS PROCESSES (will eventually become axon and dendrite)
33
What is the growing tip of the neurite called?
- GROWTH CONE!
34
What does the growth cone contain on the inside?
Actin filaments and mitochondira and microtubules
35
What does the growth cone do?
- Identifies an appropriate PATH for neurite elongation (recognises it)
36
What is an important substrate for axonal growth?
- Extracellular matrix (growth only occurs if the matrix contains certain proteins)
37
What is the extracellular matrix?
- fibrous proteins deposited in spaces between cells
38
Which interaction promotes axonal elongation?
- Integrins (surface molecules that growing axons express) that bind LAMININ (glycoprotein)
39
What is fasciculation ?
- CAMs (cell adhesion molecules) are expressed
| - Causes axons growing together to STICK TOGETHER ( so the axons grow in unison)
40
What are pioneer axons?
- "stretch" as the nervous system expands and they guide developing neighbour axons to the same targets
41
How do pioneer axons grow in the correct direction?
- Axon trajectory (pathway) broken into segments (few 100 microns long)
- Finishes segment when it arrives at an intermediate target
- Like connecting the dots
42
What determines whether guidance cues are attractive or repusive?
- Receptor expressed by the axons
43
What is a chemoattractant?
- Diffusable molecule that acts over a distance to attract growing axons to their targets (to form spinothalmic tract e.g.)
44
Why don't our CNS axons regenerate?
- If axon is cut in CNS, severed tip initially forms growth cone but then aborted
- Due to 'nogo' which is molecule released when oligodendria are damaged- inhibits regeneration
45
What happens if a CNS alpha motor neuron axon is cut in the PERIPHERI?
- Grows back to its target (because severed IN Peripheri)
46
What is the detailed process of synapse formation?
- Growth cone approaches muscle fibre
- Agrin released to cause Ach to gather beneath the axon
- Neurotransmitters vesicles enter axon terminal
- Extracellular matric produced (connects neuron to muscle cell)
- Neurtrophin (survival factor) determines which axon remains at synapse
47
What is a more general process of synapse formation (lecture) ?
- Make contact
- Contact stabilisation (cell-cell interaction)
- Synaptic maturation: recruit synaptic machinery to site of immature synapse
- neural activity regulates synaptic connections
48
What do the pyramidal neurons extend?
- Apical dendrite and multiple basal dendrites
| - length increases postnatally
49
What occurs to dendritic spines in some neurodevelopmental disorders?
- Spine shape is altered (or not quite right)
50
Do the number of synapses increase or decrease with age?
- DECREASE! (peak at 5yrs)
| - Synapses are eliminated that aren't required
51
When do electrophysiological properties develop?
- Early in the embryo but undergo significant changes in maturation (production of ion channels changes response)
- Important in axon guidance
52
What can development in brain be influenced by?
- Genes and environmental factors both pre and postnatally
53
Where do astrocytes and oligodendrocytes (CNS) develop from?
- The neural plate
| - Important in synaptogenesis
54
When does gliogenesis begin?
After neurogenesis has finished
55
Where do microglia develop from?
- The immune system
56
What is used to try and study human brain development without killing animals and what is the process?
- Growing human organoids
1. human embryonic stem cells isolated
2. Then grow them in certain ways and expose to certain factors
3. This forms mini brain like strucutres
57
What range of cell types to brain organoids contain?
- Vesicles
- Neural retinal tissue
- Neuroepithelial cells
58
What are 2 examples of immunofluorescent markers?
- SOX2 - neuroepithelial marker
| - TUJ1- labelling differentiated neurons
59
What are the advantages of organoids?
- Different regions of the brain can be made
- Different neural cell types
- So good for studying evolution of the brain
- good for looking at patient mutations (pluripotent stem cells- can grow into organoid and compare to normal patient)
- Look at Glioma (cancer development in brain)
60
What are the disadvantages of organoids?
- NO good way of having blood cells supply organ in dish
- can only vasuclarise them by putting them in mouse brain
- Microglia (immune system) only come in AFTER vascularisation of brain
61
What type of models used for Zika virus?
Mouse
62
What type of models used for Austism
Also mouse models
63
What does sympathetic chain ganglion development involve?
- Multipolar neurons developing OUTSIDE the brain and spinal cord
64
Where do the sympathetic chain ganglia come from?
- Migrated out from neural crest (forming at border of neural plate and ectoderm)
65
Neural crest cells express........
- Different sets of genes to neural plate and other neural tissue bc of their position they are exposed to different combo of growth factors (induce expression of diff set of genes)
66
What does epithelial mesenchymal transition allow?
- Neural crest cells to transition to being more mesenchymal like and to break free from the neural tube to migrate (through body)
67
What can neural crest cells become/do in the PNS?
- neurons and glia (cranial ganglia)
- cartilage and bone (in face, neck, jaw)
- connective tissue
- sympatho adrenal cells
- sensory neurons and glia
- pigment cells
- ENTERIC NERVOUS SYSTEM
- SYMP AND PARASYMP GANLGIA
68
What changes must occur to neural crest cells in an epithelial-mesenchymal transition? (EMT)
- Cell-cell adhesion DECREASES (binding much less tightly to one another)
- Capable of changing direction but no polarity so doesn't know inside from out
- Can move a lot more
- cell-matrix adhesion DECREASES but still must interact to pull molecules along
69
What are epithelial cells like?
- round shape and conected to each other tightly
| - Know which way is inside and out
70
What are mesenchymal cells like?
- More polarised
| - Not joined together
71
When can EMT (Epithelial-Mesencymal transition) occur?
- A few times in development
- Occurs in wound healing (adults)--> new cells must migrate to fill the space
- interest in preocess in epithelial cancers
72
Where do the cells that form the sympathetic ganglia migrate to?
- The dorsal aorta
73
What do the neural crest cells in the trunk form?
- Dorsal root ganglia
- SYMPATHETIC CHAIN GANGLIA
- Pigment cells
- Adrenal medulla
74
What do somites do?
- Control migration ( so they only migrate in certain parts- segments- dorsal root)
- Sympathetic is chain
75
How is formation of smypathetic chain ganglia similar to axon guidance?
- Have attractive cues from dorsal aorta and repulsive cues in
76
What are the steps in formation of sympathetic chain ganglia?
1. nerual crest cells migrate to dorsal aorta
2. Cells DISPERSED along dorsal aorta
3. Cells aggregate into discrete ganglia (requires increase in cell-cell adhesion)
77
What happens once the sympathetic chain cells form?
- most send out axons and innervated by incoming pre ganglionic neurons
- send out neurites (axons) to reach targets (same mechanisms molecules in cell guidance migration)
78
What is co-located?
- Nerves and blood vessels
- Because nerves are using blood vessels to follow along or vice versa
OR using the same mechanisms to get to the same place
79
Where is sympathetic ganglia's final position?
- Towards the spinal cord
- Expression of attractive molecules by pre ganglionic neurons drive the migration
- Sympathetic ganglia express receptor for molecule
- Moves as group back towards s.c. (whole ganglia moves) - and is more DORSAL
80
Can preganglionic neurons in S.c synapse on neurons in one or more sympathetic ganglia? (T/F)
True! They can :)
81
What happens if synapses don't reach neuron target?
- They die via apoptosis
| - Makes too many neurons then culls the ones that aren't needed
82
What is sufficient for survival?
- Activation of receptors on growth cones
| - Survival depends on synpatic target- if enough neurotrophins are acting on growth cone it will LIVE
83
What do most sympathetic GC use as neurotransmitters?
- NORADRENALINE
- Some use Ach
- Some neurons can change phenotype ( adrengeric to cholonergic)
84
Where do Schwann and satellite cells (PNS) come from?
- The neural crest
85
What is a neuroblastoma?
- Originates from neuroblasts in adrenal medulla
- sympathetic ganglion cells can cause it to occur
- Most common tumor in childhood
86
What creates the 'sympathetic chain ganglia' chain?
- Preganglionic neurons in s.c synapsing on neurons in one or more sympathetic ganglia
87
The lower the organism is in the evolutionary chain the greater capacity it has to...
Regenerate
88
Can the liver regenerate in humans?
- YES a little bit
89
What are the three types of regeneration following nerve damage?
1. Axogenesis
2. Brain Plasticity/rewiring
3. Neurogenesis
90
What does regeneration of the CNS require?
- Progenitor cells to MIGRATE, RE-ESTABLISH cell contacts, SELF RENEW and undergo specification and spatial patterning to form neurons and glia that integrate into host tissue to replace damaged structures.
91
What is axogenesis?
- Axon regrowth from pre-existing injured neurons through the injury site to re-establish connections
92
Is axogenes likely to occur for a crush injury as opposed to sever injury?
NO! Axogenesis not likely for crush injury but is likely for sever injury
93
What is rewiring?
- New connections are formed to replace ones that are damaged to re-establish function of the neural pathway.
94
What is neurogenesis?
-Production of new neuronal cells from precursor populations that subsequently produce neurites to make connections with host cells.
95
Why do mammalian CNS axons tend to not reinnervate if damaged?
- Factors secreted by oligodendrocytes that inhibit growth (Nogo)
96
What is secreted from oligodendria cells to stop them from regenerating?
- Nogo e.g. in the neural pathways that perceive visual stimuli
97
What happens when you sever the axons of the retinal ganglion cells?
- RGCs apoptose (die)
- because they have no connections to visual cortex anymore
- Scar tissue formed which is physical barrier that stops axons from re-establishing contact with distal end
98
If the axons of the retinal ganglion cells are severed, does the optic nerve still have the ability to re-establish connection?
- YES!
- But when severed, the growth cone halts from not enough chemical being secreted to guide
- Or to prevent it from accidentally being mis-routed to another area (could go to next retina on contralateral side instead of LGN or superior colliculus)
99
Where do RGCs in visual system send connections to?
- LGN
- SUPERIOR COLLICULUS
- VISUAL CORTEX
100
What is the hearing pathway to the brain? (4 steps)
Inner ear--> Inferior colliculus--> Medial geniculate nucleus--> Auditory cortex
101
What happens if there is a lesion on the inferior colliculus?
- Visual neurons establish connection with MGN
| - Auditory cortex now processing visual information
102
In neurogenesis, when neuroepithelial cells proliferate, what do they become?
- Intermediate progenitor cells that then migrate and then aggregate and commit to being neurons
103
Can B cells also differentiate into neurons?
- YES! Can differentiate into neurons or oligodendrocytes
104
Where do progenitor cells originate from?
- Radial glial cells and B cells of brain
105
Where do stem cells come from in adult neurogenesis?
SVZ
106
What are totipotent stem cells?
- Can give rise to ALL embryonic somatic cells and germ cells. They can build a whole animal
- Zygote and few cells of morula are totipotent
107
What are pluripotent stem cells?
- Descendants of totipotent stem cells and give rise to cells of endo, meso and ectoderm
108
What are multipotent stem cells?
- Committed to fate
| - Produce cells of a particular lineage or closely related family
109
What does ectoderm comprise of ?
- Nervous system and skin
110
What does the mesoderm comprise of ?
- Skeletal muscle, vasculat lymphatics
111
What does the endoderm comprise of ?
- GI tract, glands
112
Why is it not likely to use totipotent stem cells for therapy? -
- Because they can give rise to a WHOLE organism (very few of them in development)
113
What are 3 different routes the cell could go to regenerate?
1. De-differentiation
2. Transdifferentiation
3. Reprogramming
114
What is de-differentiation AND exmaple?
- Cell committed to fate but can be reversed to precursor cell
e. g. Adult cardiomyocyte converted BACK into immature cardiomyocyte
- Immature cardiomyocytes then have the ability to proliferate
- Possilble to replace cells after heart attack
115
What is transdifferentiation?
- Families of cells (exocrine and beta cells e.g.)
- Exocrine cells secrete peptide hormones and can be encouraged to transdifferentiate into beta cells (which can form new neurons)
- does this by inserting transcriptional factors (cusing it to transdifferentiate)
116
What is reprogramming?
- Cause the cell to reprogram
- e.g. fibroblasts (skin cells)
- reprogrammed to become pluripotent stem cells by injecting transcriptional factors regulating genes and subsequent proteins
117
Where do we get pluripotent stem cells from?
- Embryonic stem cells from inner mass of blastocyst
- Embryonic germ cells from primordial germ cells
e. g. gPs--> germ-line derived pluripotent stem cells from spermatogonical stem cells of adult and neonatal fetus
118
What are the 3 major routes of somatic cell reprogramming to pluripotency?
- Fusion of somatic and ES cells (fuse adult with embryonic cell) --> hybrid cell
- Nuclear transfer of ESCs (put nucleus into somatic cell donor)
- Induced pluripotent stem cells ( inject transcription factors)
119
Why is Parkinsons a good candidate for stem cell therapy?
- Ability to generate/harvest large numbers of dopaminergic neurons for transplantation (detectable improvements in motor systems)
- Improvements when fetal mesencephalic neurons were transplanted (but grafts die-rejection of tissues)
120
What is the best stem cell option for the future?
- pluripotent ESCs or induced pluripotent stem cells (this overcomes issue of rejection as well)
121
What is memory?
- Knowledge of world is encoded, stored and later retrieved.
122
Can intelligence be taught?
- NO!
123
What is correlated with intelligence?
- Cortical volume (prefrontal cortex and temporal corticies--> hippocampus in this)
124
What is short term memory and where is it processed?
- Processed in hippocampus
- Memories last seconds to hour
- Vulnerable to disruption and readily lost
125
What is long term memory?
- Converted from short term memory via CONSOLIDATION (repitition)
- Lasts longer with re-consolidation (e.g. remembering parents/siblings birthdays)
- Can last for years (recall childhood memory)
126
What is WORKING memory and which structure takes place in this?
- PREFRONTAL CORTEX
- Temporary form of memory storage
- Limited in capacity & requires rehearsal
e. g. retention of telephone number that has just been given to you by reception (this then shifts into long term memory via consolidation)
127
What are two types of declarative memory?
- Episodic
| - Semantic
128
What is episodic (declarative memory)?
- Autobiographical info with temporal/spatial context e.g. nonna fell into the pool whilst carrying my birthday cake
- time/event association
129
What is semantic (declarative) memory?
- Mmemory for FACTS and events with no associations e.g. Kyoto is city in Japan
130
What are the types of nondeclarative memory? (3 types)
- Procedural memory
- Classical conditioning
- Non-associative
131
What is procedural (nondec) memory?
- Memory for skills and habits
| - e.g. learning to ride bike, using pair of chopsticks (things you don't forget)
132
What is classical conditoning (nondecl memory)?
- emotional response to stimulus generated by association e.g. ringing bell associated with food reward
133
What is non associative memory (nondecl) ?
- Habituation, sensitization e.g. person in foreign environment may be scared at first but then get used to it over time
134
What are the anatomical structures (4) responsible for declarative memory?
```
-TEMPORAL LOBE including the below:
Hippocampus
- Subiculum
- Parahippocampus
-Rhinal cortical areas
```
135
How do we know which lobes memory is involved in?
- Lesion studies
- H-M patient got anterograde amnesia.(from temproal lobe removal)
- Cant remember what he did but still has procedural memory (knows how to use knife and fork )
136
Which structure takes part in procedural memory?
- Striatum (caudate nucleus and putamen-part of basal ganlgia)
137
What is procedural memory?
- TYPE of long term memory of HOW to perform different actions and skills
- Happens from early in life where you begin to learn how to walk,talk etc. (so ingrained it is almost automatic)
138
What types of memory is the hippocampus important in?
- SPATIAL MEMORY! (like GPS function in brain)
- Hippocampus contains 'place' cells and the nuerons only fire when person is at particular location
e. g. taxi drivers in London have a larger hippocampus
- grid cells also us navigate
139
What is spatial memory and example of what it is required to navigate around?
- Part of memory responsible for recording information about ones environment and spatial orientation
- required to navigate around city
140
What occurs in system consolidation?
Where hippocampus dependent memories become independent of the hippocampus over period of weeks to years
141
When does snyaptic consolidation occur?
- Within the first few hours after learning or encoding
142
What does long-term potentiation allow for?
- A synapse to increase in strength
143
What occurs in the aquisition stage of memory and what is it influenced by?
- Sensory info perceived and acquired
- influenced by attention, motivation, ability to learn
e. g. going to remember less if distracted by someone talking
144
What occurs in the retention/encoding stage of memory?
- Crucial first step to creating a new memory
- Perceived item of interest to be converted into a construct that can be stored within the brain
- Requires consolidation to commit to longer term memory
145
Which stage of memory is the crucial first step to creating a new memory?
- Retention/encoding
146
What occurs in the consolidation process of memory ?
- Stabilisation of memory trace after acquisition
- Two specific processes
1. Synaptic consolidation
2. System consolidation
- Also uses long-term potentiation- increasing strength of synapse
147
What occurs in the retrieval stage of memory?
- Re-accessing of events or info from the past which have been previously encoded and stored within the brain
148
What is the Hebbian theory ?
- That memory results from synaptic modification
- "Neurons that fire together wire together"
- "Out of sync, lose their link"
- if partial stimulus comes in and is not as strong (so only a few neurons fire, Hebbian theory allows the whole circuitry to still fire (association-all fire together)
149
Where do learning and memory occur at the molecular level?
- At synapses
| - Results from modifications of synaptic transmission
150
What is synaptic plasticity?
- Ability of synapse to change strength in response to either use or diuse
- Important neurochemical function of learning and memory
151
What is Long Term Potentiation (LTP) of synaptic transmission in the hippocampus?
- Primary experimental model for investigating synpatic basis of learning and memory in vertebrates
152
In the context of LTP, what does tetanic stimulation of pre synaptic site cause?
- More release of glutamate (so strong response)q
153
What are sources of point-point contact between neurons?
- Dendritic spines
154
What is an example of structural correlation to memory?
- Dendritic spines
155
Can dendritic spines be altered by experience?
- YES!
- Structural plasticity of dendritic spines underlies learning and memory and cognition in cerebral cortex
- Induction of LTP causes shrinkage of spine heads
