Brain Development

Key questions

1. Q1List the stages of brain development in order.

   Neural induction → neurulation → formation of brain divisions (vesicles) → neuronal proliferation and migration → circuit formation (axon generation and guidance) → neuronal competition → synaptogenesis → myelination → synaptic pruning → gray and white matter expansion → changes in healthy aging.
2. Q2What is neural induction, and what happens if it fails?

   Ectoderm cells differentiate to a neural fate because of external molecular signals/gradients (blocking BMP). Induction also means loss of potential. Failure → natural (spontaneous) abortion.
3. Q3Where do the neural-inducing signals come from, and what happens with two organizers?

   The organizer region secretes BMP inhibitors, turning nearby ectoderm neural. A second organizer region induces a second body axis → conjoined twins.
4. Q4What is neurulation, and when does it occur?

   The neural plate folds to form the neural tube, in weeks 3–4 of gestation; the tube zips closed from the middle outward toward both ends. (Gestational age counts from the last menstrual period, ~2 weeks before fertilization.)
5. Q5Name the neural tube defects.

   Anencephaly (much of the brain fails to form), encephalocele (brain protrudes through the skull), craniorachischisis (both brain and spinal cord stay open), and open or closed spina bifida (lower tube fails to close). Folate lowers risk; fortification has cut cases, but ~3,000 US pregnancies a year are still affected.
6. Q6Name the three signaling sources that pattern the neural tube.

   Roof plate, floor plate and somites. Floor plate → SHH; roof plate → BMPs (and retinoic acid); somites → BMPs.
7. Q7What is the five-vesicle stage?

   By gestational week 6: telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon — with folds, axes, differential growth and the optic vesicles.
8. Q8Where are cortical neurons born, and how do progenitors divide?

   In the ventricular zone. Symmetric division → two progenitors; asymmetric division → one progenitor + one non-dividing neuron.
9. Q9What do DCX and Reelin each do, and what does each mutant look like?

   DCX (doublecortin) drives neurons up along the radial glia; DCX mutants can form a double cortex (laminar heterotopia). Reelin tells neurons when to stop and detach at the right layer; Reelin mutants have disorganized layers. Either can cause lissencephaly.
10. Q10How do cortical neurons migrate, and in what order are layers built?

    Excitatory neurons climb radial glia toward the marginal zone (inhibitory neurons migrate tangentially). Layers form inside-out: deepest first, later neurons pass them. Cortical development spans gestational weeks 7–18. The neocortex has 6 layers.
11. Q11How does a neuron become polarized?

    The round cell sprouts neurites; one becomes the axon and the rest become dendrites, with different apical/basal markers.
12. Q12How do axons find their targets?

    A motile growth cone senses its environment and follows diffuse gradients (Eph receptors and their ephrin ligands) and non-diffuse extracellular signals; cues can attract or repel.
13. Q13Why do nasal retinal fibers cross at the optic chiasm but temporal fibers don't?

    Midline radial glia express ephrin-B. Temporal axons carry the receptor that is repelled by it, so they stay on the same side; nasal axons are not repelled and cross.
14. Q14What is the neurotrophic factor hypothesis?

    Target cells make limited neurotrophic factor; neurons that don't get enough undergo apoptosis. Factors: neurotrophins (NGF, BDNF, NT-3, NT-4/5), BMPs, hedgehogs, TGF-β, interleukins.
15. Q15Why does the cortex grow after birth?

    Mainly dendritic growth, spine formation and synaptogenesis — not new neurons. Between ~1 month and 6 years, neuron numbers stay flat while connections multiply. Synapse changes continue for life.
16. Q16Besides Fragile X and Rett, which disorders show spine changes?

    Alzheimer disease (reduced spine density), Down syndrome (smaller spines) and epilepsy (altered spine shape).
17. Q17What drives myelination, and what does it do?

    Oligodendrocytes in the CNS (Schwann cells in the PNS), interacting with signals from individual axons; myelin greatly speeds conduction. Myelination reflects stabilization of projections.
18. Q18Give the cortical maturation timeline.

    Rapid volume growth in the first 3 years, then leveling off and decline. Age 4: primary sensory, visual and motor cortex mature. Age 6: language early, prefrontal immature. Age 9: parietal and basal ganglia maturing. Age 11: limbic, parietal, prefrontal increasing. Age 15–18: association cortex matures by pruning. Age 21: most regions adult, but prefrontal and superior temporal still maturing.
19. Q19What changes in healthy aging?

    Gray matter loss (larger ventricles and sulci) and lower synaptic density. Working memory declines after the 7th decade while semantic memory (vocabulary) stays stable. Only some people develop severe degeneration (Alzheimer, other dementias, vascular).

Key questions

1. Q20What is a teratogen?

   An agent that causes abnormality after fetal exposure during pregnancy.
2. Q21Which environmental factors raise neural tube defect risk?

   Folate (folic acid) deficiency, maternal insulin-dependent diabetes and certain maternal anticonvulsants. About 3,000 US pregnancies a year are affected; rates are higher in Hispanic women.
3. Q22Which genes cause lissencephaly, and what happens?

   Recessive Reelin mutations and doublecortin (DCX) mutations disrupt neuronal migration → smooth brain (lissencephaly) or laminar heterotopia. Outcomes: abortion, seizures, early death; severe cases live ~10 years.
4. Q23Which gene is linked to agenesis of the corpus callosum?

   DCC (an axon-guidance receptor). Often diagnosed in the first 2 years; may cause intellectual disability, subtler psychosocial problems, or nothing. A seizure may be the first sign.
5. Q24How do Fragile X and Rett differ at the synapse?

   Fragile X: increased dendritic spine density. Rett: decreased spine density. Subnormal intellect tracks spine morphology.
6. Q25Why can one signaling defect cause broad abnormalities?

   The same signaling molecules (e.g., BMPs) are reused at many stages and in many systems.
7. Q26Why does the timing of exposure matter?

   The time of interference determines which developing function is hit. Fetal alcohol: heavy 1st-trimester drinking → facial dysmorphology, CNS dysfunction, very low IQ; heavy 3rd-trimester drinking → poor coordination, impaired cognition and memory, emotional problems.
8. Q27What does excess vitamin A (retinoic acid) do to the neural tube?

   Large amounts (e.g., isotretinoin/Accutane) cause neural tube and other CNS defects; retinoic acid is one of the neural tube's own patterning signals.
9. Q28What is the most common infectious cause of birth defects in the US, and its effects?

   Cytomegalovirus (CMV). ~1 in 200 babies are born with it (higher in African Americans); 1 in 5 of those have symptoms: hearing loss, developmental and motor delay, microcephaly. Rubella and Zika also affect brain development.

Key questions

1. Q29What is the outcome of failed neural induction?

   Natural (spontaneous) abortion.
2. Q30What is the outcome of failed neurulation?

   Neural tube defects — e.g., spina bifida / myelomeningocele (caudal) or anencephaly (cranial).
3. Q31What is the outcome of failed neuronal migration?

   Lissencephaly (smooth brain) or laminar heterotopia: seizures, intellectual disability, early death.
4. Q32What is the outcome of failed axon guidance of crossing fibers?

   Agenesis of the corpus callosum: from no symptoms to seizures and intellectual disability.
5. Q33What is the outcome of abnormal synaptogenesis / spine regulation?

   Intellectual disability and autism-spectrum features — Fragile X (too many spines), Rett (too few).
6. Q34Why are earlier failures usually worse?

   Early stages build the foundation every later stage depends on, so failures cascade; later failures hit narrower functions.