Neurodevelopment 2

Question 1

stages of brain development

Answer 1

1. Cell birth/proliferation (Neurogenesis and Gliogenesis) - the creation of neurons that make up our brains
   
   2. Cell migration
   3. Cell differentiation and maturation
   4. Synaptogenesis and synaptic pruning - cutting or taking away synapses
   5. Cell death
   6. Myelination (myelogenesis) - slow and long process

Question 2

cell birth/proliferation (neurogenesis and gliogenesis

Answer 2

• A massive process - at its peak, 250,000 neurons are born per minute - rapid process - a lot of cell division
  
  • 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.
  • Neurogenesis does not take place with neuronal division - neurons do not divide.
  • Immature cells called stem cells divide to form progenitor (precursor) cells - undergo mitosis
  • Each progenitor cell can be a neuroblast or a glioblast.
  • In early observations (Santiago Ramon y Cajal) observed that the cells undergoing mitosis were always closer to the inner surface of the neural tube, known as the ventricular zone (brain’s nursery).
  • 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.
  • Mitosis - the process by which a cell replicates its chromosomes and then segregates them, producing two identical nuclei in preparation for cell division

Question 3

cell migration

Answer 3

• Refers to the movement of the newly formed cells towards the outer layers - move in an outward motion - move from the ventricular zone to outer layers.
  
  • The cortex develops in an inside-out manner, and this is seen across species.
  • There seems to be a primitive map of the cortex that predisposes cells born in a certain region to migrate to a certain corticol location (Rakic et al, 2009)
  • Occurs with the help of:
    a. Chemical signals - immunoglobulins and cytokines - being secreted by the target cells to guide the neurons to the location
    b. Physical support - provided by radial glia (provide support and guidance to the immature neurons for them to find their way)
  • Cells ‘climb’ along radial glia (look like wheel spokes) with the help of extensions
    · Most of them shimmy up glial poles - migrate from the ventricular zone to the outer layers, known as the marginal zone
    · Some migrate from one vine to another like Tarzan (tangentially), and migrate to form areas such as the basal ganglia and amygdala - how they populate other areas of the brain.

Question 4

migration with the help of radial glia

Answer 4

· Shows where the cells are being created and move away to the outer layers.

Question 5

migration

Answer 5

· Neurons that migrate follow the specific patter by moving outwards (inside-out)
· Any disruption in the layering can have an impact in the functioning of the brain later on.

Question 6

Extensive migration of young neurons into the infant frontal lobe:

Answer 6

· There is still massive migration that takes place in newborn babies, with traces still being there when they are 7 months - takes place mainly in 1-3 months after born.
· 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 - very important.

Question 7

differentiation and maturation

Answer 7

· Once they arrive at their destination, immature neurons begin to express particular genes that will allow them to become a particular type of cell - start to differentiate and mature.
· They start to form an axon and dendrites that will give them their distinctive shape.
· Dendritic development:
- Dendritic arborization (branching)
- Growth of dendritic spines - providing the neurons with a lot more space, so other neurons can synapse on them
· Broca’s area - language production - cells differentiate during the first 24 months in broca’s area
· 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 used therapeutically to help tackle neurodegenerative conditions such as Parkinson’s disease etc.
· Once the cells mature and differentiate they lose that property.

Question 8

Synaptogenesis and synaptic pruning:

Answer 8

· Synaptogenesis is guided by a variety of cues and signals - chemical cues that are being secreted by the target cells.
· 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” - gets longer and longer to find the target
- The axons extend by adding microtubules to the tip of the axon.
· Growth cones develop thin extensions known as filopodia - has receptors which can detect chemicals
· Growth cones are attracted to chemicals released from target sites (Roger Sperry, 1943) - can be repelled or attracted depending on the signal they get
- Cell adhesion molecules (CAMs)
- Tropic molecules

Question 9

synaptogenesis

Answer 9

· 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 - continue to create synapses across our lifetime

Question 10

Filopodia advance by adhering to other cells or by sensing their way around:

Answer 10

· They can make physical contact with other cells (contact guidance) or they can be chemically guided (chemotropism).
· They have proteins on their membrane which serve as receptors that ‘recognise’ various molecules to which they will adhere or not.
· Thus, growth cones detect and select among a wide range of guidance cues
· Both contact guidance and chemotropism can be either attractive or repulsive to the growth cone
- The same cue may be attractive to one cone and repulsive to another or the nature of the relationship may change with time.

Question 11

synaptic pruning

Answer 11

· Successful synapses are those who are active and thus are maintained and strengthened
· Those that are not successful are eliminated - synaptic pruning
· Due to the ability of the brain to constantly form new synapses and eliminate (prune) others there is plasticity.
· The determining factor is experience - “use it or lose it” principle
· It continues to change - the more you use it the more they are maintained and strengthened

Question 12

synaptic rearrangement

Answer 12

· Occurs throughout life and it is related to learning or experience (Purves and Hadley, 1985)
· Image of mouse brain

Question 13

Adolescence is a period of increased synaptic pruning (Powell, 2006)

Answer 13

· Adolescence is a time where most parts of the brains are matured but the cortex is still immature, will can lead to impulsivity.
· The prefrontal cortex is still immature, while other areas are better developed, such as the limbic system.
· 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 - start to lose a lot of grey matter.
- Synaptic pruning starting from the back to the front by early adulthood
- Increase in white matter (myelination) which peaks in adulthood - adults a bit more efficient in their answers compared to adolescents
- Perhaps a second phase of “use it or lose it”
- The process is completed earlier in girls than in boys
· Environmental influence is overly important (similar to childhood)

Question 14

cell death

Answer 14

· Necessary component of our brain development
· 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 15

apoptosis

Answer 15

· This type of cell death was termed apoptosis (Kerr, Wyllie and Currie, 1972) - Programmed Cell Death (PCD) - useful in shaping the organism
· Conserved process in animals and plants, e.g., the separation of our fingers occurs through apoptosis of the cells of the webbing whereas in ducks the webbed feet remain.
· 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 - a bit of competition, survival of the fittest

Question 16

apoptosis vs necrosis

Answer 16

· Apoptosis is an active process - cells that undergo apoptosis are expressing genes that enable them to die - death genes (caspases)
· Necrosis - happens with injury or infections, cause inflamation and hurt in the near by cells

Question 17

which neurons will live and which will die

Answer 17

· Rita Levi-Montalcini - proteins secreted by targeted cells promote the survival and growth of neurons - survived signals
· Nerve Growth Factor (NGF) - Levi-Montalcini and Stanley Cohen were awarded the Nobel Prize in Physiology or Medicine in 1986 for their discovery.
· It soon became clear that there are several such proteins, a family of these factors named neurotrophic factors (Brain-Derived Neurotrophic Factor (BDNF), Neurothrophin-3 (NT-3), etc.
· In order to avoid apoptosis and survive a neuron will need:
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 18

myelination

Answer 18

• Refers to the process by which glia form the fatty sheath that covers the axons of neurons.
  
  • Myelin speeds up the transmission of neural impulses.
  • First occurs in the spinal cord and then in the hindbrain, midbrain and forebrain (back-to-front).
  • Slow-process - it occurs gradually for decades, depending on the region i.e., in the cortex it continues until adulthood.

Question 19

myelination in PNS and CNS

Answer 19

• PNS - schwann cells are dedicated glial cells, and wrap themselves completely around one neuron - allowed the cells to fire in an efficient way
  
  • CNS - oligodendroglia have a lot of extensions, and wrap themselves around a lot of different axons - which has implications on injury

Question 20

motor behaviour

Answer 20

• Correlation between myelination and ability to grasp.
  
  • Become more refined with our movements.

Question 21

Does the brain produce new neurons in adulthood?:

Answer 21

• Originally it was believed that no new neurons were formed after early development
  
  • Early findings in rats were dismissed or highly criticized (Altman, 1962; Bayer, 1982; Kaplan, 1981)

Question 22

major impact

Answer 22

• In songbirds - there is a steady replacement (seasonal) of neurons in the ‘singing’ area (Nottebohm 70s and 80s)
  
  • “What we found…was a huge pool of labeled cells - and many of the cells were new neurons. Every bird, young or old, was producing thousands of them each day” (Specter, 2001)
  • Generated in the lining of the ventricles, migrated to their final destination, differentiated and then responded to auditory stimuli.

Question 23

what about in humans

Answer 23

• There are a few ‘neurogenic’ regions in the adult human brain.
  
  • Olfactory epithelium contains cells that continuously divide to provide new olfactory sensory neurons, and replace damaged ones (Bedard and Parent, 2004) - e.g., nose and sense of smell.
  • But also, cells produced in the subventricular zone (SVZ) of the lateral ventricles migrate to replace interneurons in the adult olfactory bulb.
  • This long path of migration towards the olfactory bulb is called the Rostral Migratory Stream (RMS) (Altman, 1969; Curtis et al, 2007).

Question 24

the rostral migratory stream (RMS)

Answer 24

• Newborn cells from the subventricular zone (SVZ) migrate to the olfactory bulb and become interneurons.
  
  • Astrocytes wrap around the migrating neurons to create a ‘pipeline; and keep them on the right path.
  • This occurs throughout life.

Question 25

the hippocampus

Answer 25

• The granular layer of the dentate gyrus of the hippocampus, was the first neurogenic area to be discovered (Altman & Das, 1965).
  
  • New neurons are created and added to the dentate gyrus throughout life.
  • Continues throughout life

Question 26

What about the cerebral cortex?

Answer 26

• There seem to be very few adult-born neurons in the cortex, which are created in the SVZ but still not much is known.
  
  • Neurogenesis can be induced by injury but it depends on the extent of the injury.

Question 27

Recovery following injury

Answer 27

• Recovery is better in younger brains than in older brains and it is better in the periphery than it is in the brain.
  
  • The mechanisms of recovery mainly involve new branching of axons and dendrites, a process known as collateral sprouting:
  • New branches formed by non-damaged axons attach to vacant spots of dendrites and cell bodies.
  • The cells secrete neurotrophins that allow collateral sprouting to occur.
  • Especially in the first 2 weeks after damage, the rate of new synapses forming is very fast.

Question 28

collateral sprouting

Answer 28

• Injury and we lose an axon, so there is space, and neurons detect this and they grow a branch into this area

Question 29

Brain adaptations occur throughout life:

Answer 29

• In people blind since infancy there is enhanced tactile (finger sensitivity) and auditory ability.
  
  • People who are deaf have a better sense of touch and vision.
  • In cases of amblyobia or lazy eye we can intervene (i.e., wear an eye patch) and reinstate good vision.
  • So, the brain adapts accordingly to the environmental stimuli, known as neuroplasticity (synaptic plasticity).

Question 30

Recognition in the monkey cortex:

Answer 30

• Found that the areas of the brain that corresponded to the missing finger, where taken over by the area of the brain next to the space.

Question 31

Blindness (Burton et al, 2002)

Answer 31

• Researchers asked sighted and blind people to feel Braille letters or other items and say whether they were the same or different.
  
  • Blind people performed better
  • PET and fMRI scans indicated substantial activity in the occipital cortex of blind people while they perform these tasks.
  • Auditory stimuli also produced increased responses in visual areas of the cortex.

Question 32

Music training:

Answer 32

· Musicians have larger brain areas responsible for hearing and finger control
· MRI scans reveal:
- The temporal cortex of professional musicians in the right hemisphere is 30% larger than in non-musicians
- Thicker grey matter in the part of the brain responsible for hand control and vision of professional keyboard players
- Larger than normal area of the postcentral gyrus in the right hemisphere for the movements of the left hand (string control)

Question 33

More vs fewer experiences:

Answer 33

· Rats raised in an enriched environment develop a thicker cortex and have increased dendritic branching (Rosenzweig and Benner, 1980).
· Much of the enhancement was due to physical activity.
· Increased dendritic branching was correlated with improved ability to learn.

Question 34

Critical periods:

Answer 34

· A period during which the brain is most sensitive to a specific experience (Konrad Lorenz (1930s) – imprinting)
· Absence of visual stimuli can lead to blindness, or lack of exposure to language at an early age may lead to the inability to use language
· The same goes for other abilities or skills such as motor development, musical development etc.
· Bateson, 1979: Sensitive periods could be conceived of as a brief opening of a window of vulnerability, of need, and also of opportunity.

Question 35

Richard Tees - ‘train ride’

Answer 35

· Depiction of the different critical periods, when they are opening or shutting
· More flexibility in higher cognition

Question 36

Blakemore and Cooper, 1970:

Answer 36

· Kittens were kept in darkness at all times and taken away from there mums.
· Put in a cage with black and white stripes of light, and had a cone one for 3 months
· When the kitten was looking at the vertical lines they were firing, but not with horizontal lines - don’t recognise them

Question 37

The case of Genie:

Answer 37

· Social and experiential deprivation and chronic malnutrition
- Point of birth - 13, kept in a room in the dark, in a cage, not allowed to walk, poorly fed

Question 38

Many conditions can be traced back to early development:

Answer 38

· Epidemiological studies show evidence for environmental factors that lead to pathology later in life such as epilepsy, autism spectrum disorders, schizophrenia etc.
· Activation of the mother’s immune system (MIA) - season of birth, viral epidemics, population density
· Prenatal malnutrition (folic acid, thiamine deficiency, etc)
· Substance abuse
· Complications during pregnancy and delivery particularly anoxia or hypoxia