Neurodevelopment 1

Question 1

What are the stages of brain development?

Answer 1

1. Cell birth/ Proliferation (neurogenesis and gliogenesis)- creation of neurons and glia that make up our brains
2. Cell migration- cells go to different places as they are programmed to
3. Cell differentiation and maturation
4. Synaptogenesis and synaptic pruning (cutting/ taking away synapsis)
5. Cell death
6. Myelination (myelogenesis)- slow process

Question 2

1. Cell birth/ Proliferation (Neurogenesis and Gliogenesis)
   - what is the process like?
   - initially, what is the neural tube like?
   - what happens structurally as the neural tube widens?

Answer 2

A massive process - at its peak, 250,000 neurons are born per minute. (Theres a lot of cell division/ mitosis to create the cells of the brain)

Initially, the neural tube is 1-cell thick touching on both ends

As the neural tube widens, the extensions of the cells elongate still holding on to the outer wall.

Question 3

1. Cell birth/ Proliferation
   What does neurogenesis not take place with?

Answer 3

Neurogenesis does not take place with neuronal division - neurons do not divide

Question 4

1. Cell birth/ Proliferation
   a) what are immature cells called?
   b) what do they divide to form?
   c) what can each progenitor cell be?

Answer 4

a) stem cells
b) progenitor (precursor cells)
c) neuroblast or a glioblast

Question 5

1. Cell birth/ Proliferation
   What did Santiago Ramon y Cajal observe in early observations?

Answer 5

Santiago Ramon y Cajal) observed that the cells undergoing mitosis (cells splitting) were always closer to the inner surface of the neural tube (hole), known as the ventricular zone (brain’s nursery)

ventricular zone- layer that produces all the new neurons

Question 6

1. Cell birth/ Proliferation
   - what does the neural tube give rise to?
   - what do the lining of the ventricles contain?
   - what will be created during early development?

Answer 6

• The neural tube gives rise to the ventricular system in a mature brain
• Even now, the lining of our ventricles contains stem cells
• An abundance of neurons will be created during early development, more than we will ever have as adults

Question 7

2. Cell migration
   What is it?

Answer 7

Refers to the movement of the newly formed cells towards the outer layers

Question 8

2. Cell migration
   a) how does the cortex develop?
   b) what is there of the cortex?
   c) what does it occur with the help of?

Answer 8

a) The cortex develops in an inside-out manner, and this is seen across species

b) There seems to be a primitive map of the cortex that predisposes cells born in a certain region to migrate to a certain cortical location (Rakic et al 2009)

c) Occurs with the help of (cues):

• chemical signals (immunoglobulins and cytokines)
• physical support (most use this) provided by radial glia
  • cells ‘climb’ along radial glia (look like wheel spokes) with the help of extensions

Question 9

Cortical development- cell migration

Answer 9

The green area starts off small but as neurons are being divided/ created and the neural tube begins to thicken and enlarge, the Radial glia are still holding on and elongate their extension so it becomes a long hole.

Radial glia main role is to provide support and guidance to immature neurons in order to find their way. They’re newly formed neurons climbing up a rope and migrating initially to a location closer to the ventricular zone and then the subsequent neurons move further out.

(Think of them as acrobats which stand on each other shoulder in order to reach further distances)

Important bit:
- most of them shimmy up glial poles
- some migrate from one vine to another like Tarzan (tangentially) and migrate to form areas such as the basal ganglia and amygdala

Question 10

Migration with the help of radial glia

Answer 10

Cells are being created around the ventricular zone (at bottom) then they move up and away towards the outer part of the cortex.

As it wraps itself its still immature but it still has extensions that allows it to climb and move away.

Question 11

Migration:
- what pattern do they follow?
- why is this important?

Answer 11

Immature neurons that migrate follow this specific pattern from inside to outwards.

This is important because areas of the cortex are layered in a specific way, so any disruption in this layering can have meaningful impact for the functioning of the brain later on.

Question 12

Cortical layers
Ventricular vs subventricular zone

Answer 12

Other areas/ layers are created and sometimes disappear.

Lining of ventricle/ neural tube can be referred to as ventricular zone

A lot of the neurons are created/ cell division occurs in the layer just above it. Its called the subventricular zone.

Both of these layers (ventricular zone and subventricular zone) are considered the nursery of the brain.

Question 13

Extensive migration of young neurons into the Infant Frontal Lobe:
- what is migrating and where?
- when is it most prominent?
- what will most of these become?
- what type of migration are they doing?

Answer 13

• A large wave of neurons are still migrating in the frontal cortex after birth
• Most prominent in the first few months of life (mostly up to 3m with some persisting up to 7m)
• Most of these will become inhibitory GABAergic interneurons (important in modulating excitation in neurons that are excitatory, fine tuning firing of neurons in different areas of the brain.)
• Some are doing the radial migration that we mentioned before but a lot of them move (Tarzan or tangentially) towards the cingulate cortex but there are other streams eg rostral (towards front) and medial (reach MPC)

Question 14

3. Differentiation and Maturation
   a) once arriving at their destination, what do immature neurons begins to express and what does this allow them to do?
   b) what do they start to form?
   c) dendritic development- 2 things?

Answer 14

a) Once they arrive at their destination,immature neurons begin to express particular genes that will allow them to become a particular type of cell.

b) They start to form an axon (mm/day) and dendrites (μm/day) that will give them their distinctive shape

c) Dendritic development:
- dendritic arborisation (branching)
- growth of dendritic spines

Question 15

Dendritic spines

Answer 15

Little swellings that a lot of the neurons have

These are providing neurons with a lot more space for other neurons to synapse on them

Visualise neurons a bit better

Question 16

Broca’s Area
- what is it associated with?
- other area?
- what does it become?
- what are differentiating between this time?

Answer 16

Brocas area was associated with expression of language to be able to articulate and use language as well as produce speech

Wernicke’s= understanding and comprehension- meaning behind words

Continues to become more and more developed

Cells are differentiating between this time- a lot of branching and maturing from newborn to 24 months

Question 17

Differentiation and Maturation
- explain induction
- if immature cells are removed from a given region what will they be replaced by?
- because of this characteristic of immature cells/ stem cells, what can these be used for?
- what happens once cells mature and differentiate?

Answer 17

• There are ongoing cell-cell interactions via the secretion of chemicals, where cells influence the fate of their neighbouring cells, a process known as induction.
• If immature cells are removed from a given region, they will be replaced by subsequent neurons that will arrive in this area and will acquire the same characteristics.
• Because of this characteristic of immature cells or stem cells (pluripotency- they can be any cell depending on what type of signal we offer), they can be used therapeutically to help tackle neurodegenerative conditions such as Parkinson’s disease etc.
• Once the cells mature and differentiate they lose that property.

Question 18

Morphology of neurons

Answer 18

Depending on what area of the brain the neurons are going to be, they are going to differentiate accordingly.

Question 19

4. Synaptogenesis and synaptic pruning
   a) what is synaptogenesis guided by?
   b) what is the growing end of the axon called?
   - how do the axons extend?
   c) what do growth cones develop, called?
   d) what are growth cones attracted to?
   e) What are chemicals called?

Answer 19

a) Synaptogenesis is guided by a variety of cues and signals

b) The growing end of the axon is called a growth cone (Santiago Ramon y Cajal, 1890), which he characterised as “a battering ram, endowed with exquisite chemical sensitivity, with rapid ameboid movements”

• The axons extend by adding microtubules to the tip of the axon

c) Growth cones develop thin extensions known as filopodia.

d) Growth cones are attracted to chemicals released from target sites (Roger Sperry, 1943)

e) Chemicals are called:
- Cell adhesion molecules (CAMs)
- Tropic molecules

They may be attracted or repelled depending on the type of signal that they detect

Question 20

Synaptogenesis
- what happens once a successful contact has been made?
- what happens once synapses are formed?
- when do the majority of our synapses take place?

Answer 20

• Once a successful contact has been made, axon and target induce each other to construct machinery to help them attach to one another (neurexins and neuroligins) and to form a synapse (postsynaptic density proteins, PSDs)
• Once synapses are formed, they are sluggish and slow in their firing compared to those in adults or more mature brains but they get faster with time
• The majority of our synapses take place after birth and continue to rearrange themselves throughout life

Question 21

The growth cone: image of cell with its axon

Answer 21

Flat ending called lamellipodium
Thin extensions called filopodium

eg. visualising growth cone with extensions as arm finding your phone in the night

Question 22

How do filopodia advance?

Answer 22

Adhering to other cells or by sensing their way around.

Question 23

Filopodia:
1- what can they make?
2- what do they have + function
3- what are used to detect and select among a wide range of guidance cues?
4- what can be either attractive or repulsive to the growth cone + elaborate

Answer 23

1- They can make physical contact with other cells (contact guidance) or they can be chemically guided (chemotropism)

2- They have proteins on their membrane which serve as receptors that ’recognise’ various molecules to which they will adhere or not

3- Thus, growth cones detect and select among a wide range of guidance cues

4- Both contact guidance and chemotropism can be either attractive or repulsive to the growth cone (these are changeable all of the time)

• The same cue may be attractive to one cone and repulsive to another or the nature of the relationship may change with time

Question 24

Synaptic pruning:
1- what are successful synapses?
2- what is synaptic pruning?
3- how is there plasticity?
4- what is “use it or lose it” principle?

Answer 24

1- Successful synapses are those who are active and thus are maintained and strengthened

2- Those that are not successful are eliminated - synaptic pruning

3- Due to the ability of the brain to constantly form new synapses and eliminate (prune) others there is plasticity

4- The determining factor is experience – “use it or lose it” principle. The more you use a particular area/ set of neurons and there is firing/ connections, they are going to be maintained and strengthened.

Question 25

Synaptic Rearrangement
Where does it occur and what is it related to?
What are there?
Process?

Answer 25

Occurs throughout life and it is related to learning or experience (Purves & Hadley, 1985)

We have physically different branches that are being redirected

Dynamic process that keeps changing depending on what goes on in the brain

Question 26

What is adolescence a period of?

Answer 26

Adolescence is a period of increased synaptic pruning

Question 27

Adolescence as a period of synaptic pruning:
1- what is still immature and what is better developed?
2- synaptic pruning sequence?
3- increase in?
4- second phase of ….
5- difference in process completion between girls and boys
6- what is overly important

Answer 27

1- The prefrontal cortex is still immature, while other areas are better developed, such as the limbic system

2- Synaptic pruning starting from the back to the front by early adulthood

3- Increase in white matter (myelination) which peaks in adulthood. It seems that adults are faster in their responses compared to adolescence.

4- Perhaps a second phase of “use it or lose it”

5- The process is completed earlier in girls than in boys

6- Environmental influence is overly important (similar to childhood)

Question 28

What did Gogtay et al 2004 do and find?

Answer 28

Gogtay et al 2004 (NIMH) did brain scans of 4-25y olds every 2 years and found that grey matter thickens in childhood but then it begins to thin out gradually (so we lose a lot of the grey matter)

Question 29

Adolescence (Gogtay et al 2004)
Grey matter, what happens?

Answer 29

There is a lot of grey matter at the start in early childhood then it seems that in adolescence and early adulthood it seems that we’re synaptically pruning a lot of our synapses.

Question 30

Cell death:
- who was it first noticed by?
- what did they notice
- what is now universally accepted?

Answer 30

• First noticed by Viktor Hamburger(1900-2001) in chicks but was initially dismissed
• Noticed that chick embryos had about 20,000 motor neurons shortly after the egg was laid but in the second week of incubation, they dropped to 12,000
• Subsequently verified in humans and now it is universally accepted that cell death is a normal part of development throughout the nervous system

Question 31

What was this types of cell death termed?

Answer 31

apoptosis (Kerr, Wyllie & Currie, 1972) - Programmed Cell Death (PCD)

Question 32

Apoptosis:
- what type of process in animals and plants
- webbing?
- what happens when axons initially reach their targets?
- what will many not form?

Answer 32

• Conserved process in animals and plants. For example, the separation of our fingers occurs through apoptosis of the cells of the webbing whereas in ducks the webbed feet remain
• so that webbing gets eliminated by apoptosis, so the cells that make up the webbing are removed by apoptosis.
• When axons initially reach their targets, they form synapses with several cells, there is overabundance. In fact, there are more neurons and more connections than we will eventually need, so some will have to go.
• Many will not form active synapses and will be eliminated - Neural Darwinism (survival of fittest idea, we have a lot of neurons and some of them will have to go because they cannot always be kept)

Question 33

Apoptosis vs Necrosis

Answer 33

Apoptosis is an active process:
Cells that undergo apoptosis are expressing genes that enable them to die – death genes (caspases)
Therefore, apoptosis is a quiet death, cells eliminate themselves with no disturbance

However, necronic death happens with disease/ injury where the cells are swelling and exploding their insides to the outside area and they cause a lot of inflammation and hurt the neurons in that area.

Question 34

From redundancy to refinement

Answer 34

We start with a lot of neurons but then the neurons have to make contact with other neurons and there is a degree of competition to make their synapses. Then the ones that perhaps haven’t been able to make connections are activating this programmed cell death and take themselves out of the picture.

Redundancy- lot of things going on- cells and synapses then we start to sculpt it out and end up with a more refined, efficient system.

Question 35

What is Rita Levi-Montalcini?

Answer 35

Proteins secreted by target cells promote the survival and growth of neurons – survival signals

Question 36

Which neurons will live and which neurons will die?

Answer 36

It soon became clear that there are several such proteins, a family of these factors named neurotrophic factors (Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3(NT-3) etc.

Sum:
The neurons which were lucky to make this attachment- synapse- if they start to talk to each other, the target secretes neurotropic factors. So they are maintained and they survive.

Where as other neurons perhaps haven’t been able to make a good attachment/ synapse, there will not be much growth factor secreted so would remove themselves from the area.

Question 37

In order to avoid apoptosis and survive, what will a neuron need?

Answer 37

A) neurotrophins (growth factors) from its target cells

B) active communication with other neurons which leads to the strengthening of the synapses (D.O. Hebb)

Question 38

6. Myelination
   1- what does it refer to?
   2- what does myeline do?
   3- where does it occur?
   4- what kind of process?

Answer 38

1- Refers to the process by which glia form the fatty sheath that covers the axons of neurons- increases efficiency of AP

2- Myelin speeds up the transmission of neural impulses

3- First occurs in the spinal cord and then in the hindbrain, midbrain and forebrain (back-to-front)

4- Slow process – it occurs gradually for decades, depending on the region i.e. in the cortex it continues until adulthood

Question 39

Difference between myelination in PNS and CNS?

Answer 39

In the PNS, Schwann cells (glial cells that provide myelin sheath) wrap themselves completely on one segment of the axon of one neuron. This creates the myelinated and unmyelinated segments to allow the cells to fire in an efficient, fast way.

In CNS, Oligodendroglia (glia that provide myelin for neurons) have a lot of extensions therefore they wrap themselves around as many axons as they can. There is no designated pathway for axons to grow and oligodendroglia secrete some chemicals that do not allow recovery after injury.

(implications for recovery following injury)

Question 40

Motor behaviour
- 2 months
- 4 months
- 10 months

Answer 40

Correlation between myelination and ability to grasp.

2 months- orients hand toward an object and gropes to hold it

4 months- grasps appropriately shaped object with entire hand

10 months- uses pincer grasp with thumb and index finger opposed

Question 41

summary:
1- what are created, migrate, differentiate and mature from synapses and compete for survival
2- what structures of a neuron are not fixed?
3- what is myelination a job for, and what type of process?
4- what do some process extend beyond and continue to do?

Answer 41

1- Immature neurons
2- Synapses and dendritic branches of a neuron are not fixed – they extend, retract or even disappear
3- glia and it is a slow process
4- Some processes extend beyond prenatal life and continue to shape our brains