CASE 1: Development of the nervous system
donderdag 2 november 2023 15:36
1. Nervous system (general)
Central nervous system (CNS) = brain and spinal cord (integration)
Has nucleus between neurons
Peripheral nervous system (PNS) = all other neurons (sensory & motor)
Has ganglia between neurons
And are made up of:
Neurons: send out input, one & long (cell body = soma), wrapped in myelin
Dendrites: receive input, many & short
Synapses = a place between two neurons where information is transferred -->
Glial cells support neurons
In the CNS
Macroglia
- Astrocytes: BBB, regulate blood flow
- Oligodendrocytes: produce myelin
Microglia: scavenger cells that remove dead cells and debris
Ependymal cells: circulation of cerebrospinal fluid
In the PNS
- Schwann cells: produce myelin (same as oligodendrocyte but then in PNS)
- Satellite cells: protective barrier
2. Development of the nervous system
Neurodevelopment = a term referring to the brain's development of neurological
pathways that influence performance or functioning (e.g. intellectual functioning,
reading ability, social skill memory)
By 8 weeks the brain and nervous system are already in place. With birth the
structure of the brain is already there, but the brain is much smaller than an adult
brain.
- In preschool the brain already has grown 4x its size
- At the age of 6 90% of the adult brain is there
This has to do with connections. Basics are there, but connections need to be formed.
This happens during/after birth. This is time dependent, smile talk etc. and can
change by experience. You learn, practise something this has to be maintained.
How does the prenatal brain develop? -> Embryogenesis
The embryo begins as a flat disc with 3 layers of cells
- Endoderm
- Mesoderm
- Ectoderm -> nervous system development
During neurulation (week 3) the neural plate will form a neural tube (hollow) and this
will become the brain and spinal cord (CNS).
After neural tube formation the forerunners of major brain areas become apparent,
these are the successive stages in the development of the neural tube.
- Three-vesicle stage: at early stages of development only three brain vesicles
are present
- Five-vesicle stage: at a later stage two additional vesicles form, one in the area
of the forebrain (Ia and Ib) and the other in the hindbrain (3a and 3b).
In these ventricles the brain cell starts to develop.
How do brain cells develop? -> Neurogenesis
Starts with embryonic stem cells (ESC) which are specialized for neurons and glial
cells
Neuronal structure develops in three major stages:
- Cell proliferation
- Cell migration
- Cell differentiation
The brain develops from the walls of the fluid-filled vesicles, in the early stages
consisting of two layers
- The ventricular zone
- The marginal zone (with as top layer the pial surface)
And is associated with 5 positions
1. Cell extends a process (precursor) to the pial surface of the marginal zone
TENTAMEN PREP 2 Pagina 1
, - The ventricular zone
- The marginal zone (with as top layer the pial surface)
And is associated with 5 positions
1. Cell extends a process (precursor) to the pial surface of the marginal zone
2. At the pial surface the cell's DNA is copied
3. Cells retract back as it has 2 completed copies of DNA
4. Cell divides in two
Cell proliferation
Cell division under the influence of Notch and Numb. Very early in development we
see symmetrical cell division. With the split 2 identical copies came into place. These
are radial glial cells, this is done because a lot of cells are needed that can generate
brain cells. Later on the split occurs asymmetrically meaning the daughter cells are
not equal. 1 cell remains in the ventricular zone and is still a stem cell. This cell will
divide again. The other daughter cell prepares to migrate to become an actual brain
cell, a neuron. To be more specific a neural precursor cell.
Cell migration
Daughter cells migrate along the thin fibres emitted by the radial glial cells that span
the distance between the ventricular zone and the pial surface. The immature
neurons (neural precursor cells) follow this radial path from the ventricular zone
toward the surface of the brain. Initial cells migrate to the cortical plate are those
that will form the subplate.
The development of the cortex is inside-out and the precursor cells keep migrating
until all layers of the cortex have differentiated. Then the subplate neurons
disappear. The first layer to be formed is VII, VI etc. and the intermediate zone and
the ventricular zone become white matter. The closer to the white matter the older.
When all layers are filed the subplate, ventricular zone and the intermediate zone
disappears into the white matter.
Cell differentiation
1st Neuronal differentiation (primarily pre-natal) by asymmetrical division.
2nd Astrocyte differentiation (peaks around time of birth)
3rd Oligodendrocyte differentiation
The fate of the cells is determined by Notch signalling in the cerebral cortex.
Notch is a cell surface receptor that interacts with ligand (Delta). Notch has various
functions in different stages of neurodevelopment. During pre-natal development
Notch signalling regulates self-renewal of developing and adult neural stem cells.
During (mostly) post-natal development Notch promotes gliogenesis and inhibits
neuronal differentiation.
3. Neuronal elongation
The growth cone identifies the appropriate path for neurite elongation. To make
contact with other brain cells. Growth cone can be found at the end of a neurite,
probing the environment for attractive cues: nutrients that the neuron needs to
survive.
Why do some neurons survive, while others do not?
The neurotrophic factor hypothesis (cues that the neurons need)
Neurons extend their axons to target cells which secrete low levels of neurotrophic
factors. The neurotrophic factor binds to specific receptors and is internalized and
transported to the cell body, where it promotes neuronal survival. But there are not
enough nutrients. Neurons that fail to receive adequate amounts of neurotropic
factor die through programmed cell death -> apoptosis. Nerve growth factor is a
trophic factor promoting neuronal survival. Trophic factor is part of a family called
neurotrophins.
Neurotrophins (like neuron growth factor) act on cell surface receptors, mostly
tyrosine kinase (Trk) receptors. Which regulate synaptic strength and plasticity in the
mammalian nervous system.
Synapses: neurons communicate using electrochemical signals. They are not
connected directly, but via a junction, a synapse.
When the growth cone comes in contact with its target, a synapse is formed.
1) A dendritic filopodia,that is a spike on the lamellipodia contacts an axon
2) Contact leads to the recruitment of synaptic vesicles and active zone proteins
to the presynaptic membrane
3) Neurotransmitter receptor accumulate post-synaptically
This is the same in the CNS and PNS
The difference is the connection they make:
CNS: neuron - neuron
PNS: neuron - muscle
TENTAMEN PREP 2 Pagina 2
,PNS: neuron - muscle
The formation of a peripheral synapse = neuromuscular synapse
The neuromuscular junction. The postsynaptic membrane, known as the motor end
plate contains junctional folds with numerous neurotransmitter receptors.
Analogies of CNS and PNS synapses
- Structurally similar
- Bi-directional signalling
- Clustering of neurotransmitter receptors
- Synaptic vesicles have similar components
- Synapse elimination during development
Differences
- Central synapses have no basal lamina (ECM)
- Central synapses have no junctional folds, but dendritic spines
- Different neurotransmitters
○ In CNS (+) use glutamate
○ In PNS (+) use Ach
- Different neurotransmitter receptors
4. Synaptic plasticity
This happens as synapses strengthen or weaken over time.
Action potential travels through the presynaptic cell. The synaptic vesicles at the axon
terminal contain neurotransmitters (inhibitory/ excitatory) receptors are present on
the post-synaptic cell (ligand-gated ion channels)
1) Action potential reaches axon terminal and depolarizes membrane
2) Voltage-gated Ca++ channels open and Ca++ flows in
3) Ca++ influx triggers synaptic vesicles to release neurotransmitters
4) Neurotransmitters bind to receptors on target cell
The depolarisation will fire an action potential.
Normal synaptic transmission
AMPA receptor: Na+ efflux, K+ influx
NMDA receptor is blocked by Mg++
Both have a glutamate receptor
Induction of long-term potentiation (high frequency tetanus)
A lot of stimulation at the same time will start to depolarize the post synaptic
membrane. Mg++ block is removed from the NMDA receptor and Ca++ can flow into
the cell. Ca++ starts a cascade in which the activation of the post-synaptic membrane
is enhanced
- Upregulation of AMPA receptors
- Upregulated neurotransmitter release at the pre-synaptic membrane
The expression of long-term potentiation has two main effects on synaptic
transmission
- Activation of protein kinases enhances current through AMPA receptors
- Retrograde messengers that activate protein kinases (in presynaptic terminal
enhances subsequent transmitter release)
In long term depression, the exact opposite occurs and AMPA receptors are removed.
NEURONS THAT FIRE TOGETHER WIRE TOGETHER, NEURONS THAT FIRE OUT OF SYNC
LOSE THEIR LINK
5. Functional brain development
First overproduction of synapses as a lot of connections need to be made to have a
baseline in order to have the functions you need for brain development.
1. Visual & auditory cortex
2. Language & speech
3. Higher cognitive functions up until 2.5 years
Why is there overproduction?
The connections that you use become stronger and the connections not used can
eventually be removed by long term depression
Why don't we keep them all?
There is only so much energy in the brain, why waste it on connections that you do
not use
(green line in the figure you can ignore)
TENTAMEN PREP 2 Pagina 3
, not use
(green line in the figure you can ignore)
Neuronal stem cells in the adult brain
Neural stem cell are progenitor cells that generate neurons and glial cells, but
themselves remain in the cell cycle. Proliferating neural cells use themselves up
during development so sources of new neurons in an adult are extremely limited.
-> damage to the CNS is more serious than other organs (like skin or liver) as those
tissues persist stem cells into adulthood
In adult mammals neural stem cells persist in the hippocampus
6. Regeneration of the nervous system
Axotomy affects the injured neuron and its synaptic partners
Axon damage in the cell will degenerate but axons in the periphery regenerate better
than those in the CNS, as they are myelinated -> Schwann cells
Peripheral and central nerves differ in their ability to support axonal regeneration. In
the peripheral nervous system, severed axons regrow past the site of injury. In the
central nervous system, severed axon typically fail to regrow past the site of injury.
Schwann cells can promote regeneration. In the CNS oligodendrocytes fall apart and
the myelin debris is an attractive point for the astrocytes to clean and form a glial
scar, that further inhibits the regeneration.
Differences
- Environmental factors: peripheral cells provide growth-promoting factors to
the injured areas; factors normally absent from the brain
- Components of myelin inhibit neurite outgrowth fragments of central myelin
are potent inhibitors of neurite growth.
- Injury-induced scarring hinders axonal regeneration: astrocytes become
activated and proliferate following injury, acquiring features of reactive
astrocytes that generate scar tissue at sites of injury.
- An intrinsic growth program promotes regeration. Environmental differences
cannot completely account for the poor regeneration of central axons. Even
though they can regenerate in peripheral nerves, central axons grow much less
well than peripheral axons when navigating the same path. Thus adult central
axons may be less capable than peripheral axons of regeneration.
Stimulating questions
Stimulating question for concept 1: Neural development
- What do you see in figure 1 of the case; how is the brain formed before birth?
- What is meant by the term "neurulation"?
- Try to explain the different stages of prenatal development.
Stimulating question for concept 2: Brain cell formation
- Which different cells are present in the brain and how are they formed?
- Is there a role of stem cells in this process and is Notch signaling involved? See
figure
2 of the case.
- What does Claire mean when she indicates that brain cells proliferate, migrate, and
TENTAMEN PREP 2 Pagina 4
donderdag 2 november 2023 15:36
1. Nervous system (general)
Central nervous system (CNS) = brain and spinal cord (integration)
Has nucleus between neurons
Peripheral nervous system (PNS) = all other neurons (sensory & motor)
Has ganglia between neurons
And are made up of:
Neurons: send out input, one & long (cell body = soma), wrapped in myelin
Dendrites: receive input, many & short
Synapses = a place between two neurons where information is transferred -->
Glial cells support neurons
In the CNS
Macroglia
- Astrocytes: BBB, regulate blood flow
- Oligodendrocytes: produce myelin
Microglia: scavenger cells that remove dead cells and debris
Ependymal cells: circulation of cerebrospinal fluid
In the PNS
- Schwann cells: produce myelin (same as oligodendrocyte but then in PNS)
- Satellite cells: protective barrier
2. Development of the nervous system
Neurodevelopment = a term referring to the brain's development of neurological
pathways that influence performance or functioning (e.g. intellectual functioning,
reading ability, social skill memory)
By 8 weeks the brain and nervous system are already in place. With birth the
structure of the brain is already there, but the brain is much smaller than an adult
brain.
- In preschool the brain already has grown 4x its size
- At the age of 6 90% of the adult brain is there
This has to do with connections. Basics are there, but connections need to be formed.
This happens during/after birth. This is time dependent, smile talk etc. and can
change by experience. You learn, practise something this has to be maintained.
How does the prenatal brain develop? -> Embryogenesis
The embryo begins as a flat disc with 3 layers of cells
- Endoderm
- Mesoderm
- Ectoderm -> nervous system development
During neurulation (week 3) the neural plate will form a neural tube (hollow) and this
will become the brain and spinal cord (CNS).
After neural tube formation the forerunners of major brain areas become apparent,
these are the successive stages in the development of the neural tube.
- Three-vesicle stage: at early stages of development only three brain vesicles
are present
- Five-vesicle stage: at a later stage two additional vesicles form, one in the area
of the forebrain (Ia and Ib) and the other in the hindbrain (3a and 3b).
In these ventricles the brain cell starts to develop.
How do brain cells develop? -> Neurogenesis
Starts with embryonic stem cells (ESC) which are specialized for neurons and glial
cells
Neuronal structure develops in three major stages:
- Cell proliferation
- Cell migration
- Cell differentiation
The brain develops from the walls of the fluid-filled vesicles, in the early stages
consisting of two layers
- The ventricular zone
- The marginal zone (with as top layer the pial surface)
And is associated with 5 positions
1. Cell extends a process (precursor) to the pial surface of the marginal zone
TENTAMEN PREP 2 Pagina 1
, - The ventricular zone
- The marginal zone (with as top layer the pial surface)
And is associated with 5 positions
1. Cell extends a process (precursor) to the pial surface of the marginal zone
2. At the pial surface the cell's DNA is copied
3. Cells retract back as it has 2 completed copies of DNA
4. Cell divides in two
Cell proliferation
Cell division under the influence of Notch and Numb. Very early in development we
see symmetrical cell division. With the split 2 identical copies came into place. These
are radial glial cells, this is done because a lot of cells are needed that can generate
brain cells. Later on the split occurs asymmetrically meaning the daughter cells are
not equal. 1 cell remains in the ventricular zone and is still a stem cell. This cell will
divide again. The other daughter cell prepares to migrate to become an actual brain
cell, a neuron. To be more specific a neural precursor cell.
Cell migration
Daughter cells migrate along the thin fibres emitted by the radial glial cells that span
the distance between the ventricular zone and the pial surface. The immature
neurons (neural precursor cells) follow this radial path from the ventricular zone
toward the surface of the brain. Initial cells migrate to the cortical plate are those
that will form the subplate.
The development of the cortex is inside-out and the precursor cells keep migrating
until all layers of the cortex have differentiated. Then the subplate neurons
disappear. The first layer to be formed is VII, VI etc. and the intermediate zone and
the ventricular zone become white matter. The closer to the white matter the older.
When all layers are filed the subplate, ventricular zone and the intermediate zone
disappears into the white matter.
Cell differentiation
1st Neuronal differentiation (primarily pre-natal) by asymmetrical division.
2nd Astrocyte differentiation (peaks around time of birth)
3rd Oligodendrocyte differentiation
The fate of the cells is determined by Notch signalling in the cerebral cortex.
Notch is a cell surface receptor that interacts with ligand (Delta). Notch has various
functions in different stages of neurodevelopment. During pre-natal development
Notch signalling regulates self-renewal of developing and adult neural stem cells.
During (mostly) post-natal development Notch promotes gliogenesis and inhibits
neuronal differentiation.
3. Neuronal elongation
The growth cone identifies the appropriate path for neurite elongation. To make
contact with other brain cells. Growth cone can be found at the end of a neurite,
probing the environment for attractive cues: nutrients that the neuron needs to
survive.
Why do some neurons survive, while others do not?
The neurotrophic factor hypothesis (cues that the neurons need)
Neurons extend their axons to target cells which secrete low levels of neurotrophic
factors. The neurotrophic factor binds to specific receptors and is internalized and
transported to the cell body, where it promotes neuronal survival. But there are not
enough nutrients. Neurons that fail to receive adequate amounts of neurotropic
factor die through programmed cell death -> apoptosis. Nerve growth factor is a
trophic factor promoting neuronal survival. Trophic factor is part of a family called
neurotrophins.
Neurotrophins (like neuron growth factor) act on cell surface receptors, mostly
tyrosine kinase (Trk) receptors. Which regulate synaptic strength and plasticity in the
mammalian nervous system.
Synapses: neurons communicate using electrochemical signals. They are not
connected directly, but via a junction, a synapse.
When the growth cone comes in contact with its target, a synapse is formed.
1) A dendritic filopodia,that is a spike on the lamellipodia contacts an axon
2) Contact leads to the recruitment of synaptic vesicles and active zone proteins
to the presynaptic membrane
3) Neurotransmitter receptor accumulate post-synaptically
This is the same in the CNS and PNS
The difference is the connection they make:
CNS: neuron - neuron
PNS: neuron - muscle
TENTAMEN PREP 2 Pagina 2
,PNS: neuron - muscle
The formation of a peripheral synapse = neuromuscular synapse
The neuromuscular junction. The postsynaptic membrane, known as the motor end
plate contains junctional folds with numerous neurotransmitter receptors.
Analogies of CNS and PNS synapses
- Structurally similar
- Bi-directional signalling
- Clustering of neurotransmitter receptors
- Synaptic vesicles have similar components
- Synapse elimination during development
Differences
- Central synapses have no basal lamina (ECM)
- Central synapses have no junctional folds, but dendritic spines
- Different neurotransmitters
○ In CNS (+) use glutamate
○ In PNS (+) use Ach
- Different neurotransmitter receptors
4. Synaptic plasticity
This happens as synapses strengthen or weaken over time.
Action potential travels through the presynaptic cell. The synaptic vesicles at the axon
terminal contain neurotransmitters (inhibitory/ excitatory) receptors are present on
the post-synaptic cell (ligand-gated ion channels)
1) Action potential reaches axon terminal and depolarizes membrane
2) Voltage-gated Ca++ channels open and Ca++ flows in
3) Ca++ influx triggers synaptic vesicles to release neurotransmitters
4) Neurotransmitters bind to receptors on target cell
The depolarisation will fire an action potential.
Normal synaptic transmission
AMPA receptor: Na+ efflux, K+ influx
NMDA receptor is blocked by Mg++
Both have a glutamate receptor
Induction of long-term potentiation (high frequency tetanus)
A lot of stimulation at the same time will start to depolarize the post synaptic
membrane. Mg++ block is removed from the NMDA receptor and Ca++ can flow into
the cell. Ca++ starts a cascade in which the activation of the post-synaptic membrane
is enhanced
- Upregulation of AMPA receptors
- Upregulated neurotransmitter release at the pre-synaptic membrane
The expression of long-term potentiation has two main effects on synaptic
transmission
- Activation of protein kinases enhances current through AMPA receptors
- Retrograde messengers that activate protein kinases (in presynaptic terminal
enhances subsequent transmitter release)
In long term depression, the exact opposite occurs and AMPA receptors are removed.
NEURONS THAT FIRE TOGETHER WIRE TOGETHER, NEURONS THAT FIRE OUT OF SYNC
LOSE THEIR LINK
5. Functional brain development
First overproduction of synapses as a lot of connections need to be made to have a
baseline in order to have the functions you need for brain development.
1. Visual & auditory cortex
2. Language & speech
3. Higher cognitive functions up until 2.5 years
Why is there overproduction?
The connections that you use become stronger and the connections not used can
eventually be removed by long term depression
Why don't we keep them all?
There is only so much energy in the brain, why waste it on connections that you do
not use
(green line in the figure you can ignore)
TENTAMEN PREP 2 Pagina 3
, not use
(green line in the figure you can ignore)
Neuronal stem cells in the adult brain
Neural stem cell are progenitor cells that generate neurons and glial cells, but
themselves remain in the cell cycle. Proliferating neural cells use themselves up
during development so sources of new neurons in an adult are extremely limited.
-> damage to the CNS is more serious than other organs (like skin or liver) as those
tissues persist stem cells into adulthood
In adult mammals neural stem cells persist in the hippocampus
6. Regeneration of the nervous system
Axotomy affects the injured neuron and its synaptic partners
Axon damage in the cell will degenerate but axons in the periphery regenerate better
than those in the CNS, as they are myelinated -> Schwann cells
Peripheral and central nerves differ in their ability to support axonal regeneration. In
the peripheral nervous system, severed axons regrow past the site of injury. In the
central nervous system, severed axon typically fail to regrow past the site of injury.
Schwann cells can promote regeneration. In the CNS oligodendrocytes fall apart and
the myelin debris is an attractive point for the astrocytes to clean and form a glial
scar, that further inhibits the regeneration.
Differences
- Environmental factors: peripheral cells provide growth-promoting factors to
the injured areas; factors normally absent from the brain
- Components of myelin inhibit neurite outgrowth fragments of central myelin
are potent inhibitors of neurite growth.
- Injury-induced scarring hinders axonal regeneration: astrocytes become
activated and proliferate following injury, acquiring features of reactive
astrocytes that generate scar tissue at sites of injury.
- An intrinsic growth program promotes regeration. Environmental differences
cannot completely account for the poor regeneration of central axons. Even
though they can regenerate in peripheral nerves, central axons grow much less
well than peripheral axons when navigating the same path. Thus adult central
axons may be less capable than peripheral axons of regeneration.
Stimulating questions
Stimulating question for concept 1: Neural development
- What do you see in figure 1 of the case; how is the brain formed before birth?
- What is meant by the term "neurulation"?
- Try to explain the different stages of prenatal development.
Stimulating question for concept 2: Brain cell formation
- Which different cells are present in the brain and how are they formed?
- Is there a role of stem cells in this process and is Notch signaling involved? See
figure
2 of the case.
- What does Claire mean when she indicates that brain cells proliferate, migrate, and
TENTAMEN PREP 2 Pagina 4
