2022-03-03 11:44:31

Prelude 8:01

Today’s topic

  • How the human brain develops

Timeline of milestones

  • Brain ~ 2.5% of body mass
  • CNS among earliest-developing, last to finish organ systems
    • Prolonged developmental period (==childhood) makes CNS especially vulnerable

Neurons

  • ~ 86 billion neurons in adult CNS
    • similar # of glia
  • In cortex, about 16 (14-32) billion
    • 80/20% Glu/GABA
  • Development generates millions neurons/hr

Synapses

Axons

Prenatal period

  • 38 weeks from conception/fertilization on average
  • Embryonic period (weeks 1-8), fetal period (weeks 9+)
  • Divided into 3 12-13 week trimesters

Insemination

  • Can occur 3-4 days before or up to 1-2 days after…ovulation
  • Some animals signal ovulation; humans do not

Fertilization

  • Within ~ 24 hrs of ovulation

Implantation

  • Fertilized ovum implants in wall of uterus
  • ~ 6 days after fertilization

Early embryogenesis

Formation of neural tube (neurulation)

  • Embryonic layers: ectoderm, mesoderm, endoderm
    • Neural tube forms ~ 23 pcd (postconceptual days)
  • Neural tube closes in middle, moves toward rostral & caudal ends, closing by 29 - 30 pcd.
  • Failures of neural tube closure
    • Anencephaly (rostral neuraxis)
    • Spina bifida (caudal neuraxis)

Spina bifida

Neural tube becomes…

  • Ventricles & cerebral aqueduct
  • Central canal of spinal cord

Differential growth of vesicles

  • Rostro-caudal patterning via differential growth into vesicles
    • Forebrain (prosencephalon)
    • Midbrain (mesencephalon)
    • Hindbrain (rhombencephalon)

Neurogenesis and gliogenesis

  • Neuroepithelium cell layer adjacent to neural tube
    • creating ventricular zone (VZ) and subventricular zone (SVZ)
  • Pluripotent stem and progenitor cells divide, produce new neurons & glia

Neurogenesis

  • Neurogenesis (of excitatory Glu neurons) observed by 27 pcd (7 pcw; post-conceptual week)
  • Most cortical and striatal neurons generated prenatally, but
    • Cerebellum continues neurogenesis ~ 18 mos postnatal mos

Old (adult) brains new neurons?

  • Some animals, yes == songbirds, birds that store food caches
  • Humans, on much more limited scale
    • hippocampus
    • striatum
    • olfactory bulb (minimally)
    • not much, if any, in cerebral cortex
  • Most neurogenesis occurs near ventricles

Neural progenitor/stem cells

  • Undergo symmetric & asymmetric cell division
  • Generate glia, neurons, and basal progenitor cells

Radial glia and cell migration

Axon growth cone

Growth cones guided by

  • Chemoattractants
    • e.g., Nerve Growth Factor (NGF)
  • Chemorepellents
  • Receptors in growth cone detect chemical gradients

Glia migrate, too

Differentiation

  • Neuron vs. glial cell
  • Cell type
    • myelin-producing vs. astrocyte vs. microglia
    • pyramidal cell vs. stellate vs. Purkinje vs. …
  • NTs released
  • Where to connect

Infancy & Early Childhood

Synaptogenesis

  • Begins prenatally (~ 18 pcw)
  • Peak density ~ 15 mos postnatal
  • Spine density in prefrontal cortex ~ 7 yrs postnatal
  • 700K synapses/s on average

Proliferation, pruning

  • Early proliferation (make many synapses)
  • Later pruning
  • Rates, peaks differ by area

Apoptosis (programmed cell death)

  • 20-80%, varies by area
  • Spinal cord >> cortex
  • Quantity of nerve growth factors (NGF) influences

Synaptic rearrangement

  • Progressive phase: growth rate >> loss rate
  • Regressive phase: growth rate << loss rate

Myelination

  • Neonatal brain largely unmyelinated
  • Gradual myelination, peaks in mid-20s
  • Non-uniform pattern
    • Spinal cord before brain
    • Sensory before motor

Gyral development (12-19 pcw)

20-27 pcw

28-35 pcw

36-44 pcw

Structural/morphometric development

Myelination across human development

Changes in brain glucose use

Gene expression across development

Summary of developmental milestones

Prenatal

  • Neuro- and gliogenesis
  • Migration
  • Synaptogenesis begins
  • Differentiation
  • Apoptosis
  • Myelination begins

Postnatal

  • Synaptogenesis
  • Cortical expansion, activity-dependent change
  • Then cubic, quadratic, or linear declines in cortical thickness
  • Myelination
  • Prolonged period of postnatal/pre-reproductive development (Konner, 2011)

Timeline of milestones

References

Baumann, N., & Pham-Dinh, D. (2001). Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiological Reviews, 81(2), 871–927. https://doi.org/10.1152/physrev.2001.81.2.871

carlsagandotcom. (2009, February). Carl sagan - COSMOS - evolution. Youtube. Retrieved from https://www.youtube.com/watch?v=gZpsVSVRsZk

Chi, J. G., Dooling, E. C., & Gilles, F. H. (1977). Gyral development of the human brain. Ann. Neurol., 1(1), 86–93. https://doi.org/10.1002/ana.410010109

DeFelipe, J., Alonso-Nanclares, L., & Arellano, J. I. (2002). Microstructure of the neocortex: Comparative aspects. Journal of Neurocytology, 31(3-5), 299–316. https://doi.org/10.1023/a:1024130211265

Götz, M., & Huttner, W. B. (2005). The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol., 6(10), 777–788. https://doi.org/10.1038/nrm1739

Hagmann, P., Sporns, O., Madan, N., Cammoun, L., Pienaar, R., Wedeen, V. J., … Grant, P. E. (2010). White matter maturation reshapes structural connectivity in the late developing human brain. Proceedings of the National Academy of Sciences, 107(44), 19067–19072. https://doi.org/10.1073/pnas.1009073107

Kang, H. J., Kawasawa, Y. I., Cheng, F., Zhu, Y., Xu, X., Li, M., … Šestan, N. (2011). Spatio-temporal transcriptome of the human brain. Nature, 478(7370), 483–489. https://doi.org/10.1038/nature10523

Kety, S. S., & Schmidt, C. F. (1948). The Nitrous OXIDE METHOD FOR THE QUANTITATIVE DETERMINATION OF CEREBRAL BLOOD FLOW IN MAN: THEORY, PROCEDURE AND NORMAL VALUES. The Journal of Clinical Investigation, 27(4), 476–483. https://doi.org/10.1172/JCI101994

Knickmeyer, R. C., Gouttard, S., Kang, C., Evans, D., Wilber, K., Smith, J. K., … Gilmore, J. H. (2008). A structural MRI study of human brain development from birth to 2 years. J. Neurosci., 28(47), 12176–12182. https://doi.org/10.1523/JNEUROSCI.3479-08.2008

Konner, M. (2011). The Evolution of Childhood. Belknap Press of Harvard University Press. Retrieved from http://www.hup.harvard.edu/catalog.php?isbn=9780674062016

Kuzawa, C. W., Chugani, H. T., Grossman, L. I., Lipovich, L., Muzik, O., Hof, P. R., … Lange, N. (2014). Metabolic costs and evolutionary implications of human brain development. Proc. Natl. Acad. Sci. U. S. A., 111(36), 13010–13015. https://doi.org/10.1073/pnas.1323099111

Marner, L., Nyengaard, J. R., Tang, Y., & Pakkenberg, B. (2003). Marked loss of myelinated nerve fibers in the human brain with age. The Journal of Comparative Neurology, 462(2), 144–152. https://doi.org/10.1002/cne.10714

Silbereis, J. C., Pochareddy, S., Zhu, Y., Li, M., & Sestan, N. (2016). The cellular and molecular landscapes of the developing human central nervous system. Neuron, 89(2), 248–268. https://doi.org/10.1016/j.neuron.2015.12.008