NEUR30003: PRINCIPLES OF NEUROSCIENCE NOTES LECTURE 4: Development of the Nervous System Microscopy and Staining - ~1011 neurons making ~1014 synaptic connections; precise connectivity with regional specialization - Watch neurons developing rather than mature - Easier to observe developing brain rather than mature brain - Santigao Ramon-y-Cajal found it easier to study: “the young wood … rather than the … impenetrable … full grown forest” Integrated Steps - Neural induction: Assigning neural potential to a region of early embryo - Neurulation: Forming the rudimentary nervous system - Morphogenesis and patterning of neural tube - Neurogenesis: Production of neurons and glia from precursor cells - Neuronal migration: Neurons move from sites of production to their positions in the mature brain - Axon growth and path finding: To find appropriate targets and dendritic arborization - Synaptogenesis: Making and refining synaptic connections - Gliogenesis/Myelination Neural Induction - Assigning neural potential to a region of early embryo - A region of the dorsal embryonic ectoderm acquires neural fate; the potential to form the nervous system - The entire central nervous system (CNS) is formed from the neural plate while the remainder of the ectoderm acquires epidermal fate - Epidermal fate is determined by local bone morphogenetic protein (BMP) signaling - Signals from ‘organizer’ region (Ng-Noggin, Chd- Chordin) block the BMP signal inducing neural fate Ø Organizer tissue is derived form the developing mesoderm tissue - In chick embryo, the organizer is called Hensen’s node, in human embryo: the node - The node later becomes the brain and CNS of the organism 2017 SEMESTER I 10 NEUR30003: PRINCIPLES OF NEUROSCIENCE NOTES Neurulation: Formation of the Neural tube - Neural plate olds up, side push up and forms neural folds - Neural folds fuse in the dorsal midline and pinches off from the epidermis - Epidermis fuses over the top • Neural Tube Defects - Failure for the neural folds to push up or for the neural tube to fuse - The neural tube zips up bidirectional from initial points of closure to the cranial and caudal neuropore - Neural tissue protrudes in newborn or brain tissue gets degraded if exposed to amniotic fluid • Neural Crest Cells - Cells at the neural plate margin differentiate into neural crest cells - When the dorsal margins of tube fuse, the neural crest cells migrate from this region - Neural crest gives rise to peripheral and enteric nervous ganglia, melanocytes, Schwann cells, cartilage and bone (face, jaw) - Only found in the embryo Morphogensis - Following neural tube closure, primary and secondary brain vesicles form: Ø Wall: Neurocepithelium Ø Fluid-filled central cavity: Ventricular system - At the rostal end of the neural tube 3 distinct vesicles form: Ø Prosencephalon (forebrain) Ø Mesencephalon (midbrain) Ø Rhomencephalon (Hindbrain) - Further segmentation: 5 vesicle stage Ø Prosencephalin splits into the Telencephalon and diencephalon Ø Rhombencephalon splits into the Metencephalon and Myelencephalon 2017 SEMESTER I 11 NEUR30003: PRINCIPLES OF NEUROSCIENCE NOTES Patterning of the Neural Tube - Gradients of morphogens from patterning centers or organizing regions provide different positional cues for specifying cell fate - Overlying ectoderm induces roof plate (RP): Ø Secretes dorsalizing morphogens (BMPs, FGF, Wnts) - Underlying notochord induces floor plate (FP): Ø Secretes ventralizing morphogen (Sonic hedgehog) - If cells are closer to the RP it is more likely to become an interneuron where as cells closer to the FP it is more likely going to become a motor neuron The Neuroepithelium - A primary germinal zone lining the ventricular system of the developing CNS - The brain vesicle/neural tube initially consists of a single layer of neuroepithelial cells - Appears multi-layers because the nucleus and cell body move to different positions along the apical-basal axis with different phases of the cell cycle - Symmetric divisions at the start to expand the neuroepithelium pool 2017 SEMESTER I 12 NEUR30003: PRINCIPLES OF NEUROSCIENCE NOTES - Single neuroepitheial neuron nucleus moves towards the cortical space to divide to become radial galia cells - The cell is a precursor; able to turn into any type of cell within the brain - Asymmetrical division of radial glia cells give rise to neurons and a copy of itself Ø Radial glia cells can give rise to neurons or intermediate progenitors that become new neurons via symmetrical division Ø Radial glia also provides a scaffold for radial migration of their post-miotic neuron progeny - New cells move along the radial glia cells to the surface of the developing brain - Around birth, radial glia cells disappear and transform into astrocytes Cortical Layer Formation - The earliest neurons to be born undergo terminal division from the preplate - The preplate is split into the marginal zone (MZ) and the subplate (SP) as the first wave of cortical plate (CP) neurons arrives - Neurons of the CP assemble into layers II-IV in an inside-out sequence: Ø The deepest cellular layers are assembled first and the closest to the surface last Ø Subplate are first to be born - Subplate neurons split into Cajal-retzius (CR) cells that secrete proteins that attract migrating neurons; telling some neurons to keep migrating through the layers - Besides guidance from glia cells, there are also attracted to specific molecules - Cortical interneurons are produced in the basal forebrain (MGE: Medial ganglionic eminence) - Olfactory bulb neuroblasts (new neurons) migrate along the rostal migratory stream (red arrow) - Cerebellar grandule cell precursors migrate from rhombic lip (green arrows) - Where and when the terminal (neurogenic) divisions occurs specifies cell fate - Inhibitory and excitatory neurons are developed in separate locations Ø Inhibitory: Basal forebrain (MGE) Ø Excitatory: Dorsal end 2017 SEMESTER I 13 NEUR30003: PRINCIPLES OF NEUROSCIENCE NOTES Neurogenesis - Production of neurons and glia is controlled by separate transcriptional programs, each blocks the other - Neuronal program is turned on to make subtypes of neurons - Neural stem cells can undergo no change and become adult neuronal stem-cell Neurons - Neurons in the mature cortex exhibit great morphological and functional diversity - Pyramidal neurons (80%) are excitatory long-range projection neurons Ø Axons project to other cortical hemisphere or sub-cortical targets like spinal cord - Interneurons (20%) are mainly locally-projecting neurons that modulate cortical excitatory output 2017 SEMESTER I 14 .