Nervous System Development PDF

**Case 1 -- How does the nervous system develop?** **[1. How does neurulation work? (general, Notch)]** **Neurulation** Neurulation is the early embryonic process that leads to the formation of the neural tube, the precursor to the central nervous system (which includes the brain and spinal cord)...

**Case 1 -- How does the nervous system develop?** **[1. How does neurulation work? (general, Notch)]** **Neurulation** Neurulation is the early embryonic process that leads to the formation of the neural tube, the precursor to the central nervous system (which includes the brain and spinal cord) in vertebrates. It is a crucial developmental stage that involves coordinated cellular movements, changes in cell shape, and gene expression patterns to form this foundational structure. 1. **Neural plate formation :** the ectoderm (outer layer) thickens in response to signals from the underlying **notochord**, forming the neural plate. 2. **Neural plate folding:** the neural plate bends to form neural folds on either side of a neural groove. Cell shape changes, particularly at the edges, help this folding process. 3. **Neural tube formation:** The neural folds fuse at the midline, forming the neural tube, which later separates from the ectoderm to allow skin formation over it. 4. **Closure and neural crest cells:** the tube "zips" closed from specific points along its length. Neural crest cells, which emerge from the neural folds, migrate to form strcture like peripheral nerves and facial cartilage. When 3/4th week Germ layers give rise to: - Endoderm - Mesoderm - Ectoderm [Molecular signals] **Sonic Hedgehog (Shh)**: secreted by the notochord, it plays a significant role in patterning the neural tube, especially in determining ventral (front) and dorsal (back) cell fates. [Notch signaling] While Notch signaling is not central to the initial formation of the neural tube, it does have regulatory roles neurulation, particularly in later stages of neurogenesis (the differentiation of neurons). The Notch pathway helps to balance progenitor cell proliferation and differentiation, ensuring an adequate supply of neural progenitor cells for proper central nervous system development. This pathway is also involved in regulating the neural tube's boundaries and cell fate decisions. **[2. What are the different stages of embryonic development? (cell migration)]** During the third week after fertilization, gastrulation starts and 3 germ layers are formed from the **epiblast**. The ectoderm, mesoderm and ectoderm. The ectoderm will eventually form the nervous system. Neurulation takes place during the folding of the embryo. The enural tube is formed at the place where the mesoderm has formed the notochord. The notochord induces development of the neural plate and the neural groove, and thus the whole nervous system. The ectoderm expresses BMP, which blocks the differentiation into the neural plate but the notochord inhibits BMP and the neural plate is formed in this region. Thickening of the neural plate will form the neural groove, which will then close to form the neural tube. After the neural tube forms, it will be subdivided into the forebrain (prosencephalon), midbrain (mesencephalon), hindbrain (rhombencephalon) and the spinal cord. After closure of the neural tube, the **3 brain vesicles** are marked by expansions of the neural tube called **primary brain vesicles**. During the 5th week, the mesencephalon becomes larger and the prosencephalon and the rhombencephalon both divide in 2 portions, forming the **5 secondary brain vesicles**. Prosencephalon telencephalon and diencephalon Mesencephalon mesencephalon Rhombencephalon -- metencephalon and myelencephalon. The PNS is formed from the neural crest cells which is neural ectoderm lateral of the neural tube. **Neurogenesis** After the vesicle formation, the brain cells start to develop. The initial step in the formation of brain cells, is the recruitment of small clusters of ectodermal cells that acquire the potential to become neuronal precursors. Those cells can either develop into **non-neural support cells** or **neuronal cells**. The cells that have this potentail are **neural stem cells. The neural stem cells (NSCs)** are restricted to the fate of becoming either **glia** or **neurons**. Neural structures develop in three major steps: 1. Proliferation 2. Migration 3. Differentiation Those steps happen within the walls of the five fluid-filled vesicles, in the early stages consisting of two layers: - **Ventricular zone (VZ)** - **Marginal zone** **Cell proliferation** **Cell proliferation** is the process of amplifying the number of cells via undergoing the cell cycle (mitosis). It begins as soon as the neural tube closes. The cells that need to proliferate are the **neural stem cells** and they are located within the **ventricular zone**. Their proliferation is characterized by five steps that differ from a normal cell cycle. These steps can be differentiated by the position of the nucleus: 1. The cell extents a process to the Pial surface the nucleus is located at the VZ within this stage. 2. The cell's DNA starts to replicate the nucleus starts to travel towards the Pial surface. 3. Two complete copies of the cell's DNA are present the nucleus travels back to the VZ. 4. Cell retracts its arm from the Pial surface nucleus arrives at the bottom of the VZ. 5. The cell can now start to divide into two daughter cells. The faith of the two daugther cells depends on the way and the plane the stem cell divides in. there are two options: **Symmetric cell division** **Radial glia cells** = progenitor stem-like cells that generate both neurons and glia cells. Those cells help with migration and differentiation of the brain cells. They have not only two division outcomes, but three: - **Symmetric division** production of 2 new **radial glia cells** which expand the population of the proliferative progenitor cells. - **Early asymmetric division** production of 1 new **radial glia cells** and 1 new **neuron** which promotes the increase of neuron population. - **Late assymetric division** production of 1 new **neuron** and 1 new **astrocyte/oligodendrocyte** which promotes the increase of nonneural support cell population. **Cell migration** The daugther cells that are destined to migrate out of the VZ and start to differentiate, travel along thin fibers emitted by radial glia cells that span the distance between the ventricular zone and the pial surface **intermediate zone**. The immature neurons (also called **neural precursor cells**) follow this radial path from the VZ to the surface of the brain where they start to form the cortex and the **cortical plate.** The organisation of the cerebral cortex is done in an **outside-last-manner**: Cells that migrate from the VZ and leave the cell cycle at **early stages** those are neurons that settle in the **deepest layers** of the cortex and form layer IV. Cells that migrate from the VZ and leave the cell cycle at progressively later stages migration over a longer distance across layer VI those cells settle in more superficial laers of the cortex, startin from layer V and ending with layer I. When layer I is developed, the **subcortical neurons** will disappear. The result are six cortical neuron cell layers. The white matter will build up underneath the sixth layer. [Development of the zones] The ventricular zone (zone of proliferation) and the intermediate zone (zone of migration) will both become the **white matter** underneath the cerebral cortex. The cortical plate (zone of differentiation) will diseappear once the layers are formed, and the neurons are matured. **[3. Neuronal cell differentiation. (Notch, 3 types)]** **Cell differentiation** There are three phases of cell differentiation. Those phases are overlapping and go hand in hand with each other: **1st differentiation** neural differentiation it happens primarily pre-natal. **2nd differentiation** astrocyte differentiation peaks around the time of birth. **3rd differentiation** oligodendrocyte differentiation. The cell differentiation is regulated by **notch** and **delta**. Notch signaling regulates the fate of cells within the developing cerebral cortex. Notch is a cell surface receptor that interacts with a ligand called Delta. When delta binds to notch, the intracellular domain of notch dissociates and travels into the nucleus to activate transcription factors. Notch has variou functions during different developmental stages of the nervous system: - **Pre-natal development** notch signaling regulates self-renewal of developing stem cells as well as adult stem cells. - **Post-natal development** notch signaling promotes the generation of glia cells. **Mechanism of action** Activation of notch within cell A via the Delta expression on cell B intracellular signaling cascade proteolytic cleavage of cytoplasmic notch domain it translocates into the nucleus activation of the transcription factor '**suppressor of hairless**' which are encoded by proneural genes activation of the expression of the inhibitory proteins '**enhancer of split'** repression of '**achaete-scute**' gene expression leads to a decrease in expression of Delta on the cell surface of cell A notch in cell B is not activated, because cell A does not express delta cell A = destined to be a glia cell, while B = destined to become a neuronal precursor cell. A diagram of a diagram Description automatically generated Other ways to regulate notch: - Cytoplasmic protein '**numb**' the protein numb binds to the cytoplasmic domain of notch and inhibits its signalling. Only one of two daugther cells after a cell cycle inherit the numb protein and becomes a neuron. The other daugther cell will become a glia cell to support the neuron. Oligodendrocyte function responsible for myelin sheaths forming. Astrocyte function Satellite cells support cell body Schwann cells in myelin sheaths **[4. How does synaptic plasticity work? (potentiation/depression, Neurotrophic signaling, Neurotrophic factor hypothesis) ]** **Synapse formation** When a migrated and differentiated stem cell is destined to become a neuron, the cell needs to undergo further **maturation** processes to become a mature neural cells. A neuron is dependent on its connections towards other cells which are determined by their axon and dendrites. Therefore, an immature neural cell needs to develop those extensions to interact with its neighbours and targets. This maturation is supervised by the **growth cone**. The growth cone identifies the appropriate path of **neurite elongation**. The dendrite- and the axon-formation are dependent on this growth cone. The growth cone searches the environment for appropriate targets or pathways to form a connection with. The axon will develop as a long extension to form connections with target cells, while the dendrites become smaller extensions to form connections to receive information. This formation is subdivided into four major steps: 1. **Lamellipodia** and **filopodia** start to form with the help of microtubules. They will search the environment for possible targets. 2. Once a target is found, the **neurites** start to form out the lamellipodia. 3. One neurite is destined to become the **axon**. It will start to proliferate into a long neurite. 4. The other remaining neurites stay as small extensions and become the **dendrites.** Synaptic plasticity refers to the ability of synapses to strengthen or weaken over time in response to activity. This is often regulated by mechanisms such as **potentiation** and **depression**, as well as through signaling by **neurotrophic factors**. **Synaptic plasticity** sensitivity of the synapses **Structural plasticity** amount of synapses. More related with long-term potentiation **Long-term potentiation** **Long-term potentiation** is a **strengthening** of a synaptic connection that happens when the synapse of one neuron repeatedly fires and excites another neuron. It is a long-lasting enhancement in signal transmission between two neurons. **AMPA and NMDA receptors** There are two types of receptors involved in the LTP. On the one hand you have **AMPA receptors** and on the other hand the have the **NMDA receptors**. Both are excited by **glutamate/glycine**. AMPA receptors are excited by glutamate (and glycine) and they open up Na^+^ channels on the postsynaptic membrane. NMDA receptors are excited by glutamate, but they won't open just because it is bind to the receptor. NMDA receptors are *dependent* on the membran potential. **MG^2+^** is bound to those receptors and blocks the entrance of Ca^2+^ ions. If the membrane potential is depolarised by the AMPA receptors and the influx of Na^+^ ions, then the Mg^2+^ is released and Ca^2+^ can flow into the cell. Ca^2+^ is a very important second messenger in the long-term potentiation. It activates a protein called **CaMKII** (alfa-calcium-calmodulin dependent protein kinase II), which migrates to the synapse and activates new AMPA receptors via phosphorylation. Long-term potentiation can be subdivided into two phases: - **Early phase** - More AMPA receptors are activated and produced to create a stronger depolarization and produced to create a stronger depolarization. - Nitric oxide synthesis forming a **retrogade signal** to the pre-synaptic cell to activate protein kinases which enhance the neurotransmitter release positive feedback loop. - **Late phase** - Additional activation of tyrosine kinases and PKC activation of transcription factors and coding of new synapses. **Long-term depression** **Long-term depression** (LTD) is the opposite of LTP. LTD is the **weakening of synapses** when they are not active anymore or the timing between pre-synaptic cell and post-synaptic cell is wrong. This causes the **loss of AMPA receptors** and eventually the loss of the synapse. Neurons that fire together wire together (LTP) Neurons that fire out of sync lose their link (LTD) G-protein coupled receptor NMDA Transmitter gated ion channels AMPA **Neurotrophic factor hypothesis** Due to the growth cone (specialized and highly motile tips of growing axons), immature neurons extend their axons to find target cells. Those target cells are found because they secrete low levels of **neurotrophic factors** (e.g. **nerve growth factor (NGF)**). The neurotrophic factor can bind to a specific receptor (mostly **tyrosine kinases**) on a developing axon. This factor is then internalized and transported towards the cell body (soma), where it promotes the neural survival by forming a connection. The new forming neuron is dependent on the neurotrophic factor because it inhibits the process of apoptosis. Without the neurotrophic factor, the newly formed neuron will die. So, neurons that fail to receive adequate amounts of neurotrophic factors in addition to their growth cone will undergo apoptosis. The enurons which formed the connection to their target and survived, can start to communicate with each other. Neurons communicate via either electrical signals or electrochemical signals. This communication does not happen via direct contact but via junction in between the neurons synapses are formed. TRKA (tyrosine kinase) binds to NGF (nerve growth factor) **[Differences central and peripheral (GABA, neuromuscular junctions, glutamate)]** **Peripheral transmission** An AP travels from the CNS via a somatic motor neuron (PNS) to the muscle, where in the end of the axon it branches many times and forms neuromuscular junctions (**end plates**). Used neurotransmitted: **acetylcholine** (Ach) it is synthesized and stored in vesicles in the neuron and released via **exocytosis**. The sacrolemma of the receiving muscle fiber has a lot of junctional folds which contain a lot of Ach receptors. When the stimulation is over, an enzyme called **acetylcholinesterase** breaks Ach down into acetic acid and choline. The sacrolemma needs to have a normal resting potential with the Sodium-Potassium pump (inside negative; outside positive). An action potential arrives at the axonal terminal of the motor neuron. The pre-synaptic terminal gets depolarized and voltage gated Ca^2+^ channels open. The positive charged calcium drags the transmitter filled vesicles to the active zone of the pre-synaptic membrane. The vesicles fuse with the membrane and release acetylcholine into the cleft. Ach binds to the receptors in the junctional folds and open op ligand-gated Na^+^ acetylcholine channels. More sodium influx than potassium efflux and the end-plate potential is created depolarization of the sacrolemma. After the AP moved over the sacrolemma an **excitation-conctraction coupling (EC coupling)** occurs. +-----------------------------------+-----------------------------------+ | **Similarities CNS and PNS | **Differences CNS and PNS | | synapses** | synapses** | +===================================+===================================+ | - Structurally similar but not | - Central synapse have no | | identical | **basal lamina** a strucutred | | | form of extracellular matrix | | - **Bi-directional** signaling | while PNS synapses have | | | those. | | - Cluster of neurotransmitter | | | receptors | - Central synapse have no | | | junctional folds but | | - Synaptic vesicles have | **dendritic spines** | | similar components | | | | - Difference in | | - Synapse elimination during | neurotransmitters: | | development | | | | - **Excitatory:** Glutamate | | | (CNS), acetylcholine | | | (PNS) | | | | | | - **Inhibitory:** GABA and | | | glycine (CNS), GABA | | | (PNS). | | | | | | - Different neurotransmitter | | | receptors. | +-----------------------------------+-----------------------------------+ Calcium is a basal lamina factor (target tissue signal calcium to synapses) **[5. When do the functions in figure 4 develop? (explain figure 4: when and where)]** **Sensorimotor stage** This stage starts right **after birth** and last until the second year of the child. The baby comes in contact with the world depending on movements and sensations. The basic actions of the visual and auditory functions are developed. visual (occipital lobe) and auditory (temporal lobe) cortices are developed and form their synapses.  **Preoperational stage** The preoperational stage happens during the **2nd-7nd** year of the child. It begins to think symbolically and learns how to use words and pictures for the representation of those thoughts. The child is getting better with language and thinking, but higher cognitive functions still lack. The child tends to think egocentric and struggles to see things from another perspective. the **angular gyrus** (parietal lobe) and the **Broca's region** (frontal lobe) are developed and form their synapses. **Concrete operation stage** This stage includes the **7th** to the **11th** year of the child. Logical thinking starts to develop, and concepts of conversation can be understood. The child starts to think reasonable and logical. **prefrontal cortex** starts to form connections and develops higher cognitive functions. **Formal operation stage** This stage is from the age **12** and onwards. The prefrontal cortex normally takes up until the age of **25** to be fully developed. The older the child will get, the more it can supress its instincts and act logically. The ability to care about others in spite of one's own interest will develop. maturation of **prefrontal cortex**. The brain forms much more synapses in our early development than we need as an adult. This overproduction results in the dying of a lot of synapses that we don't need and only the essential synapses remain intact **pruning.** **[6. Regeneration/damage of peripheral and central neuronal cells.]** **Neural regeneration** The most common damage within the nervous system is done to the axons. This is because the axons are really long compared to the cell body and they are more easily targeted. **Axotomy** affects the injured neuron and its synaptic partners. When an axon is damaged, the axon terminals will degrade and lose their function as pre-synaptic cells. This will trigger an event called **Wallerian degradation** the complete endplate of a neuron will be degraded and the connection to the target cell will be lost. The myelin sheaths around the axons will lose their grip and dissociate. This will lead to the degradation of the **oligodendroytes/Schwann cells**. The fragmentation of those myelin sheaths will trigger macrophages which will cause a **local inflammation**. Neutrophils, macrophages and glial cells will be attracted and form a **glial scar**. This glial scar prevents the renewal of the damaged axon. This event leads to the degradation of the whole axon. It will affect the neuron prior and posterior to the damaged axon. The regeneration of this event is different within the CNS and the PNS: Axons within the periphery regenerate better than those in th CNS. Peripheral and central nerves differ in their ability to support **axonal regeneration**. In the PNS severed axons regrow past the site of injury, while the CNS severed axons typically fail to regrow past the site of injury. This has to do with the **myelination** of the axons. **Schwann cells** within the PNS only produce one myelin sheath while **oligodendrocytes** within the CNS produce several myelin sheaths. Schwann cells maintain their shape when axotomy occurs. This promotes the regrowth of the axon past the still resistant Schwann cells. When axotomy happens within the CNS, oligodendrocytes lose the myelin sheaths of the injured axon part and they are degraded. The axon has no pathway or direction to start regrowing and is therefore a target for macrophages and glial cells = **glial scar**. The glial scar prevents the regrowth of the axon. More differences in CNS and PNS regeneration: - **Environmental factors:** peripheral cells provide growth-promoting factors to the injured areas, while those factors are normally absent from the brain. - **Components of myelin inhibits neurite outgrowth:** fragments of central myelin sheaths are potent inhibitors of neurite outgrowth. - **Injury-induces scarring** **induces axonal regeneration:** astrocytes become activated and proliferate following injury, acquiring features of reactive astrocytes that generate scar tissue at site of injury. - **An intrinsic growth program** promotes regeneration Neurogenesis in adult brain: **Subventricular zone** of lateral ventricle; subgranular zone of the **dentante gyrus** (hippocampus).