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Embryology of the Nervous System: Week-by-Week Development

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Week 3 - Neural Induction and the Neural Plate

• The neural plate appears around day 17-18 as a slipper-shaped thickening of dorsal ectoderm in the midline
• The notochord and paraxial mesenchyme induce the overlying ectoderm to form the neural plate (neural induction) via TGF-β family members, Wnts, SHH, and BMPs
• The lateral edges of the neural plate elevate to form neural folds flanking a central neural groove
• By day 20, the neural groove is deepening and somites are beginning to appear alongside it

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Week 4 - Neural Tube Closure and Primary Brain Vesicles

• Neural folds elevate and fuse to form the neural tube, beginning in the cervical region (~day 22) and proceeding both cranially and caudally
• Rostral (anterior) neuropore closes on day 25 (18-20 somite stage)
• Caudal (posterior) neuropore closes on day 27-28
• The cephalic end dilates into three primary brain vesicles:
  1. Prosencephalon (forebrain)
  2. Mesencephalon (midbrain)
  3. Rhombencephalon (hindbrain)
• Two brain flexures form: the cephalic flexure (in the midbrain region) and the cervical flexure (at the hindbrain-spinal cord junction)
• Neural crest cells delaminate from the edges of the closing neural folds and begin migrating. They will give rise to dorsal root ganglia, cranial sensory ganglia, autonomic ganglia, Schwann cells, chromaffin tissue, and many craniofacial structures
• The remainder of the neural tube caudal to the brain vesicles becomes the spinal cord; the lumen becomes the central canal
• The walls of the spinal cord differentiate into three zones: ventricular zone (neuroepithelium), mantle (intermediate) zone (future gray matter), and marginal zone (future white matter)
• The sulcus limitans divides the mantle layer into a dorsal alar plate (sensory) and ventral basal plate (motor)

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Week 5 - Secondary Vesicles and Cerebral Hemisphere Primordia

• The three primary vesicles differentiate into five secondary vesicles:

• A pontine flexure develops, thinning the roof of the hindbrain (future 4th ventricle)
• The rhombencephalic isthmus separates the mesencephalon from the metencephalon
• Cerebral hemispheres begin as bilateral evaginations from the lateral wall of the telencephalon at the start of week 5
• Sympathetic ganglia begin forming as neural crest cells migrate lateral to the aorta during week 5
• The pituitary gland begins forming: Rathke's pouch (oral ectoderm upgrowth) meets the infundibulum (neuroectodermal downgrowth from the diencephalon floor) around week 5-6

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Weeks 6-8 - Cortical Zones, Basal Ganglia, Cerebellum

• By the middle of the second month (week 6-7), the basal part of the cerebral hemisphere expands, forming the corpus striatum; fibers later divide it into caudate nucleus and lentiform nucleus (internal capsule formation)
• Choroid plexuses form in the lateral ventricles (week 6-7)
• The hippocampus thickens in the medial wall of the hemisphere
• The cerebellar plate (rhombic lips from the alar plates of the metencephalon) begins developing; midline fusion gives rise to the vermis
• Cortical zones of the cerebral wall are present: ventricular, subventricular, intermediate, subplate, and marginal zones

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Weeks 8-20 - Neuronal Proliferation, Migration, and Cortical Layering

• Radial migration: Neurons born in the periventricular germinal matrix (ventricular and subventricular zones) migrate outward along radial glial fibers to form the cortical layers in an inside-out pattern (deep layers form first, superficial layers last)
• Cortical layers VI to I are laid down progressively from approximately weeks 8-20
• At peak activity, neurogenesis adds approximately 100,000 cells and 400,000 synapses per minute
• The cortex is initially smooth (lissencephalic); sulci and gyri begin appearing from around week 20 onwards, greatly increasing surface area
• The insula (buried cortex) becomes overgrown as the hemisphere expands, becoming hidden in the lateral sulcus

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Weeks 8-12 - Spinal Cord, Meninges, and Peripheral Nervous System

• Spinal meninges differentiate from mesenchyme surrounding the neural tube (pia and arachnoid from neural crest-derived mesenchyme; dura from paraxial mesoderm)
• The spinal cord at this stage occupies the full length of the vertebral canal; it begins to lag behind vertebral column growth from about week 8 onward
• At birth, the conus medullaris is at the level of L3; in adulthood it rises to L1-L2
• This creates the cauda equina (roots of L2 and below) and the filum terminale
• Cranial nerves are organized and functional by the end of the embryonic period (week 8)

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Weeks 16-24 - Gyri, Myelination Begins, Cerebellum Expands

• Primary sulci appear from about week 16-20 (central sulcus, lateral sulcus); secondary and tertiary sulci follow
• The corpus callosum begins forming by week 12 and is fully formed by week 20: the anterior commissure forms first, followed by the hippocampal commissure, then the corpus callosum proper (genu first, then body, then splenium)
• Myelination begins in the spinal cord around weeks 14-16 (motor pathways before sensory), then progressively ascends through the brainstem and into the cerebral hemispheres
• The cerebellum expands rapidly, and the external granule cell layer (from the rhombic lip) forms, then migrates inward to become the internal granule layer

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Late Fetal and Postnatal - Myelination

• Myelination continues to be the dominant process in the late fetal and early postnatal period
• Peripheral nervous system myelin (by Schwann cells) begins around week 15
• CNS myelin (by oligodendrocytes) begins around week 18-20 and proceeds in a predictable sequence: spinal cord > brainstem > cerebellum > cerebrum
• The corticospinal tracts are not fully myelinated until the end of the second postnatal year, which explains the Babinski sign being normal in infants
• Cerebral cortex myelination is not complete until well into the second decade of life

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Quick Reference Summary Table

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• The Developing Human: Clinically Oriented Embryology, Moore & Persaud (9th ed.), Ch. 17 - Nervous System, pp. 1017-1108
• Langman's Medical Embryology, Sadler (14th ed.), Ch. 18 - Central Nervous System, pp. 333-355