2.2 Development

Question 1

Why study NS Development? (3)

Answer 1

<ol> <li>Complexity: The human brain is the most complex structure known in our universe</li> <li>Learning: The processes that shape the brain during development are continually involved in adapting the function of the brain to changing environments</li> <li>Repair:Harnessing developmental mechanisms is a potentially useful strategy to repair the brain or to slow neurodegenerative disease</li></ol>

Question 2

How many neurons and synapses? (1)

Answer 2

<ul> <li>100 billion neurons; 100 trillion synapses</li></ul>

Question 3

Neuronal connectivity and brain speciality? (1)

Answer 3

Precise connectivity of neurons, but regional specialisation

Question 4

NS Development Step 1 (1)

Answer 4

Neural Induction: Assigning neural potential to a region of early embryo

Question 5

NS Development:Neural Induction Process (4)

Answer 5

“<ul> <li> <div>Region of the dorsal embryonic ectoderm acquires <strong>neural fate</strong>(potential to form nervous system)</div> </li> <li> <div>Entire CNS is formed from the <strong>neural plate</strong></div> </li></ul><div><img></img><b><br></br></b></div><ul> <li> <div>Remainder of the ectoderm acquires epidermal fate by local bone morphogenetic protein <strong>(BMP)</strong> signalling.</div> </li> <li> <div>As the neural fold forms, the embryo is a neurula</div> </li></ul>”

Question 6

If BMP determines epidermal fate, how is neural fate induced? (1)

Answer 6

“Signals from “organizer” region (e.g. Ng‐Noggin, Chd ‐ Chordin) <span>block the BMP</span> signal, inducing <span>neural fate</span><div><span><br></br></span></div><div><img></img><br></br></div>”

Question 7

NS DevelopmentStep 2

Answer 7

Neurulation: Forming the rudimentary nervous system

Question 8

Neurulation:Process? (4)

Answer 8

“<ol> <li>Neural plate folds elevates, forming neural groove</li> <li>Neural fold fuses in dorsal midline, forming neural tube</li><li>Neural tube is pinched off from epidermis, which remodels over the neural tube</li><li>Neural tube “zips up” bidirectionally from initial points of closure (Cranial: Brain; Caudal: Spine)<br></br></li></ol><div><img></img><br></br></div><div><img></img><img></img><br></br></div>”

Question 9

Neurulation defect 1: anencephaly? (1)

Answer 9

“Cranial neuropore fails to close, exposing primitive brain cells to amniotic fluid where it degenerates<div><img></img><br></br></div>”

Question 10

Neurulation defect 2: Spina Bifida? (1)

Answer 10

“Caudal neuropore fails to close, exposing spinal cord to amniotic fluid where it is damaged<div><img></img><br></br></div>”

Question 11

NS Development:Step 3 (2)

Answer 11

Morphogenesis (Development) and Patterning of Neural Tube.

Question 12

Morphogenesis (Development) and Patterning of Neural Tube. What are the 2 patterns?

Answer 12

1.Anterior-Posterior Patterning<br></br>- Caudal and Rostal End<br></br><div>2. Dorsal-Ventral Patterning<br></br></div>

Question 13

Morphogenesis (Development) and Patterning of Neural Tube.Anterior-Posterior: Caudal End (3)

Answer 13

<ul> <li>Forms primary and secondary brain vesicles</li> <li>Wall: Comprised of neuroepithelium</li> <li>Fluid-filled central cavity: Forms ventricular system</li></ul>

Question 14

Morphogenesis (Development) and Patterning of Neural Tube.Anterior-Posterior: Rostral End (3)

Answer 14

“Formation of 3 distinct vesicles and further segmentation into 5 vesicles<div><br></br></div><div>1. Prosencephalon (Forebrain)</div><div>- Telencephalon (becomes cerebral cortex)</div><div>- Diencephalon (becomes thalamus, hypothalamus, retina)</div><div><br></br></div><div>2. Mesencephalon (Midbrain)</div><div>Remains the same</div><div><br></br></div><div>3. Rhombencephalon (Hindbrain)</div><div>- Metencephalon (becomes pons and cerebellum)</div><div>- Myelencephalon (becomes medulla)</div><div><br></br></div><div><br></br></div><div><img></img><div><br></br><br></br></div></div>”

Question 15

Morphogenesis (Development) and Patterning of Neural Tube. Dorsal-Ventral Patterning? (2)

Answer 15

Neural tube receives patterning signals from organizing centres<div><br></br><div>Morphogens from patterning/organizing centres provide different positional cues for specifying cell fate (2)<br></br></div></div>

Question 16

InNS Development, what are the 5 apoptosis factors that occurs simulatenously?

Answer 16

1. Neurogenesis<div>2. Neuronal migration<br></br></div><div>3. Gliogenesis/myelination<br></br></div><div>4. Axon growth and pathfinding to find appropriate targets for dendritic arborisation (Dendritic arborisation = Neurons form new dendritic trees and branches)<br></br></div><div>5.Synaptogenesis</div>

Question 17

What is neurogenesis in NS development? (1)

Answer 17

Production of neurons and glia from precursors (Neuroepithelium?)

Question 18

Neuroepithelium:What is it? (1)

Answer 18

Neuroepithelium is a primary germinal zone lining the ventricular system (CSF) of the developing CNS

Question 19

Neuroepithelium:Where is it in the developing NS? (2)

Answer 19

<ul> <li>Brain vesicles/neural tube initially consists of a single layer of neuroepithelial cells</li> <li>Appears multi-layered because nucleus and cell body move to different positions along the apical-basal axis with different phases of the cell cycle</li></ul>

Question 20

Neuroepithelium:What do they do?

Answer 20

“<ul> <li>Neuroepithelial cells and radial glia are multipotent neural progenitor (““ancestor””) cells</li> <li>Layer becomes thicker as cell divides</li></ul><div>1. Neuroepithelial > Radial Glia (Neuroepithelial can’t give rise to tissue)</div><div><br></br></div><div>2. Radial glia > New neurons / Intermediate progenitors (and to new neurons)</div><div><br></br></div><div>3. Radial glia > Astrocytes / Stem Cells of adult brain<br></br></div><div><br></br></div><div><img></img><br></br></div>”

Question 21

Neuroepithelium: Symmetric vs Asymmetric Divison (2+2)

Answer 21

“<ul> <li> <div>Symmetric division</div> <ul> <li>Produce 2 identical daughter cells</li> <li>Used in NS development to expand the neuroepithelial cell pool or give rise to 2 neurons</li> </ul> </li> <li> <div>Asymmetric divison</div> <ul> <li>Produce 2 different daughter cells</li> <li>Used in NS development for radial glia to divide, thereby producing another radial glia cell and a differentiated neuron</li> </ul><div><img></img><br></br></div><div><br></br></div> <div><br></br></div> </li></ul>”

Question 22

Neuronal migration (2)

Answer 22

Neurons move from sites of production to their positions in the mature brain (Always generated at remote locations and need to migrate into place)<div><br></br></div><div>Where and when the terminal division occurs specifies cell fate<br></br></div>

Question 23

Cortical Layer Formation (4)

Answer 23

“<ul> <li>Earliest neurons to undergo terminal division (Cajal-Retzius) form the Preplate <ul> <li>As the 1st wave of cortical plate neurons (CP) arrive, the preplate is split into the marginal zone (MZ; Cajal-Retzius cells) and subplate (SP; 6 cortical layers)</li> </ul> </li> <li>CP neurons assemble into layers II-VI in an <strong>inside out manner</strong> (deepest cellular layers are assembled first, and superficial cellular layers are assembled last)</li> <li>As new layers of cells are formed, they migrate past previous layers on the RG scaffolding<br></br><img></img><br></br>Preplate: From Pia to VZ</li></ul>”

Question 24

Gliogenesis/myelination (1). When does it occur?

Answer 24

“Occurs after neurogenesis because production of neurons and glia, controlled by separate transcriptional programmes, block one another.<div><img></img><br></br></div>”

Question 25

Types of neurons in the mature cortex?

Answer 25

<ul> <li>Pyramidal neurons (80%) are <strong>excitatory long‐range</strong> projection neurons. Axons project to other cortical hemisphere or sub‐cortical targets like spinal cord.</li> <li>Interneurons (20%) are mainly locally‐projecting inhibitory neurons that modulate cortical excitatory output</li></ul>

Question 26

Development of the dendritic arbour? (3)

Answer 26

<ul> <li>Basic plan is genetically specified (Programs of gene transcription)</li> <li>Growth and branching is influenced by environmental factors (e.g., local signals; active synapses)</li> <li>A factor that repels an outgrowing axon may in fact attract an outgrowing dendrite</li></ul>

Question 27

Development of the axon. Where and precision? (2)

Answer 27

• Axon growth takes place at the growth cone (Highly mobile neurite tip)<div>- Axons grow along a precisely defined path. How? (1)<br></br></div>

Question 28

Axon growth takes place at the growth cone (Highly mobile neurite tip). How is it regulated?

Answer 28

<ul> <li><strong>Actin filaments</strong> regulate the shape and directed growth of the growth cone. Important in extension and retraction</li> <li><strong>Microtubules</strong> provide structural support to the axon shaft. Important for axon extension</li></ul>

Question 29

Axons grow along a precisely defined path. How? (1)

Answer 29

“Growth cone senses and integrates attractive and repulsive signals in the environment, steering axon growth<div><img></img><br></br></div>”

Question 30

Synaptogenesis (1)

Answer 30

Making and refining synaptic connections

Question 31

Prefrontal Synapse Development Timeline (2 + 1)

Answer 31

“<u>Excitatory prefrontal synapse</u><div>Density increases dramatically in early post-natal years and falls off around age 5<br></br></div><div><u>Inhibitory prefrontal synapse</u><br></br></div><div>Density increases at around age 15<u><br></br></u></div><div><br></br></div><div><img></img><br></br></div>”

Question 32

Refinement of synaptic connectivity (2). How?

Answer 32

• Refinement is activity-dependent (Input match output)<div>-Connections are usually originally overproduced. Performance is improved by adjusting the number, boundaries and strength of connections through a competitive process</div>

Question 33

Refinement of synaptic connectivity: NMJ

Answer 33

“<ul> <li>Pre-refinement <ul> <li>Each motor neuron innervates many muscle fibres, and each muscle fibre is innervated by many motor neurons</li> </ul> </li> <li>Post-refinement </li><ul> <li>Each motor neuron innervates many muscle fibres, but each muscle fibre is innervated by a single motor neuro</li> </ul><li><img></img><br></br></li> </ul>”

Question 34

Refinement of synaptic connectivity: Competition for V1 ‘territory’ occurs after eye opening (4)

Answer 34

“<ul> <li>If 1 eye is closed at birth, axon terminals relaying signals from the open eye occupy 100% of the cortical area in layer 4</li> <li>If 1 eye is closed at 2-3 weeks, there is a progressively weaker effect</li><li>If 1 eye is closed at 6 weeks, there is no effect<br></br></li><li>This defines the critical period where sensory input from L and R eyes rearranges developing circuits into ocular dominance columns<br></br></li></ul><div><img></img><br></br></div>”