Developmental Neuroscience Halo response of an embryonic chick ganglion after incubation with nerve growth factor. (Courtesy of Rita Levi- Montalcini)

Embryonic and Fetal Development of the Human Brain Actual Size

Lateral view of the human brain shown at one-third size at several stages of fetal development. Note the gradual emergence of gyri and sulci. Photographs of Human Fetal Brain Development

Nervous System Development in the Human Embryo (a) At 18 days after conception the embryo begins to implant in the uterine wall. It consists of 3 layers of cells: endoderm, mesoderm, and ectoderm. Thickening of the ectoderm leads to the development of the neural plate (inserts). (b) The neural groove begins to develop at 20 days.

Nervous System Development in the Human Embryo (c) At 22 days the neural groove closes along the length of the embryo making a tube. (d) A few days later 4 major divisions of the brain are observable – the telencephalon, diencephalon, mesencephalon, and rhombencephalon.

Eight Phases in Embryonic and Fetal Development at a Cellular Level 1.Mitosis/Proliferation 2.Migration 3.Differentiation 4.Aggregation 5.Synaptogenesis 6.Neuron Death 7.Synapse Rearrangement 8.Myelination 8 stages are sequential for a given neuron, but all are occurring simultaneously throughout fetal development

Eight Phases in Embryonic and Fetal Development at a Cellular Level 1. Mitosis 2. Migration 3. Aggregation and 4. Differentiation 5. Synaptogenesis 6. Death 7. Rearrangement 8. Myelination

1. Mitosis/Proliferation Occurs in ventricular zone Rate can be 250,000/min After mitosis “daughter” cells become fixed post mitotic

1. Mitosis/Proliferation: Neurons and Glia At early stages, a stem cell generates neuroblasts. Later, it undergoes a specific asymmetric division (the “switch point”) at which it changes from making neurons to making glia

2. Migration Note that differentiation is going on as neurons migrate.

2. Migration Radial glial cells act as guide wires for the migration of neurons Radial Glia

2. Migration Growth Cones Growth cones crawl forward as they elaborate the axons training behind them. Their extension is controlled by cues in their outside environment that ultimately direct them toward their appropriate targets. The fine threadlike extensions shown in red and green are filopodia, which find adhesive surfaces and pull the growth cone and therefore the growing axon to the right.

2. Migration Growth Cones Scanning electron micrograph of a growth cone in culture. On a flat surface growth cones are very thin. They have numerous filopodia Ramon y Cajal drew these growth cones showing their variable morphology

2. Migration: How Do Neurons “Know” Where to Go? There are extrinsic and intrinsic determinants of neurons’ fate. A.Extrinsic signals B.Different sources of extrinsic signals C.Generic signal transduction pathway D.Intrinsic determinants

3. Differentiation Neurons become fixed post mitotic and specialized They develop processes (axons and dendrites) They develop NT- making ability They develop electrical conduction

3. Differentiation Development of the cerebral cortex The ventricular zone (VZ) contains progenitors of neurons and glia. 1 st neurons establish the preplate (PP); their axons an ingrowing axons from the thalamus establish the intermediate zone (IZ). Later generated neurons establish layers II-VI. After migration and differentiation there are 6 cortical layers.

4. Aggregation Like neurons move together and form layers

5. Synaptogenesis Axons (with growth cones on end) form a synapse with other neurons or tissue (e.g. muscle)

5. Synaptogenesis: Attraction to Target Cells Target cells release a chemical that creates a gradient (dots) around them. Growth cones orient to and follow the gradient to the cells. The extensions visible in c are growing out of a sensory ganglion (left) toward their normal target tissue. The chemorepellent protein Slit (red) in an embryo of the fruit fly repels most axons.

6. Neuron Death Between 40 and 75 percent of all neurons born in embryonic and fetal development do not survive. They fail to make optimal synapses.

Neuron Death Leads to Synapse Rearrangement Release and uptake of neurotrophic factors Neurons receiving insufficient neurotropic factor die Axonal processes complete for limited neurotrophic factor

7. Synapse Rearrangement Active synapses likely take up neurotrophic factor that maintains the synapse Inactive synapses get too little trophic factor to remain stable

7. Synapse Rearrangement Time-lapse imaging of synapse elimination Two neuromuscular junctions (NM1 and NMJ2) were viewed in vivo on postnatal days 7, 8, and 9.

8. Myelination

Myelination Lasts for up to 30 Years

Brain Weight During Development and Aging

Critical Periods

Teratogens Greek – “teratos” – wonder or monster “genos” - birth 1.Physical agents (e.g., x-rays) 2.Chemicals (e.g., drugs) 3.Microorganisms (e.g., rubella)