Week 5a Slides
Wiring the Brain
Laura DeNardo, PhD
Page 1: Introduction
Title: Wiring the Brain
Author: Laura DeNardo, PhD
Page 2: Challenge of Wiring the Brain
Neuronal Connections
Approximately 1011 neurons in the brain
Each neuron forms about 103 synapses
Total: ~10^14 synapses to be established
Directions:
Dorsal, posterior, anterior, ventral orientations
Page 3: Organization of the Brain
Functional Areas in the Brain
Specialized organization necessary for function
Formation of synapses must be highly specific
Understanding begins at neural development stages
Page 4: Early Steps in Wiring
Patterning, Differentiation, and Migration
Essential precursors before neuronal connections
Identity acquisition and appropriate location migration required
Page 5: Embryonic Development in Frogs
Stages of Development
Fertilization leading to a genetically unique organism
Cleavage forms a blastula, a hollow ball of cells
Gastrulation forms a gastrula with three germ layers:
Ectoderm (future nervous system)
Endoderm
Mesoderm (signal sender for nervous system patterning)
Neurulation initiates nervous system construction; dorsal and ventral surfaces formed
Page 6: Neurulation Process
Neural Tube Formation
Neuroectoderm cells form a neural plate
Notochord (derived from mesoderm) signals to the neural plate
Neural plate center drops, edges form a neural fold
Edges fuse, forming the neural tube
Neural tube lumen develops into CNS ventricles (fluid-filled chambers)
Page 7: Patterning Along the Neural Tube
Anterior-Posterior (A-P) Axis
Five subdivisions of anterior neural tube
Telencephalon, Diencephalon, Mesencephalon, Metencephalon, Myelencephalon (forebrain, midbrain, hindbrain)
Posterior neural tube becomes the spinal cord
Page 8: Genetic Manipulation Insights
Emx2 and Pax6 Role
Emx2: Essential for developing posterior neural tube; absence leads to expansion of anterior regions (F/M and S1)
Pax6: Crucial for anterior neural tube development; absence leads to expansion of posterior regions (V1)
Functional organization includes:
F/M = Frontal/Motor Cortex
S1 = Somatosensory Cortex
A1 = Auditory Cortex
V1 = Visual Cortex
Page 9: Neuronal Identity and Migration
Identifying Neurons
After progenitor patterning, neurons need identity confirmation and correct migration to respective locations
Page 10: Structure of the Cerebral Cortex
Neuron Types and Layers
Comprised of glutamatergic and GABAergic neurons
Organized into discrete layers:
Deep layers
Superficial layers
Page 11: Birthplace Determines Neuron Identity
Origins of Cortical Neurons
Derived from telencephalon:
Glutamatergic cells (excitatory) from ventricular zone
GABAergic cells (inhibitory) from medial ganglionic eminence (MGE)
Page 12: Birthdate and Neuron Location
Autoradiography Findings
Neurons labeled at embryonic stages provide insights on layering by postnatal day 10
Early-born neurons (~E13) in deeper layers
Later-born neurons (~E17) in superficial layers
Page 13: Escape to Final Positions
Radial Glia Role
Newborn neurons utilize radial glia as scaffolds to reach cortical plate
Asymmetric division of radial glia results in neurons as offspring
Page 14: Summary of Neural Tube Development
Key Points
Fertilization leads to rapid proliferation and rearrangement into the neural tube
Subdivisions develop into brain and spinal cord parts
Morphogens assist in progenitor patterning along the A-P axis
Neuron identity linked to origin zone and birthdate influencing cortical layer residency
Newborns climb via radial glia to establish final positions
Page 15: Visual System Case Study
Visual Development
Retinal ganglion cell (RGC) axons form connections in visual thalamus (LGN) and superior colliculus
Correlates with visually guided movements
Page 16: Retinotopic Mapping in Visual System
Precise Connections Development
Visual system organized into retinotopic maps
Retinal neurons create an inverted world map
Connections reconstruct this in the tectum
Page 17: Chemoaffinity Hypothesis by Roger Sperry
Insights from Newts
Studied regeneration of visual connections in newts
Ability to restore vision after optic nerve damage provides insights into connection formation
Page 18: Nature vs. Nurture in Visual Wiring
Connection Formation Models
Functional Selection Model: Too many connections made, only useful ones retained
Predetermination Model: Axons predetermined to choose targets, disregarding activity
Page 19: Optic Nerve Regeneration Studies
Key Results from Sperry's Experiments
Severing one optic nerve and rotating eyeball leads to inverted vision upon regrowth
Suggests axons grow back to original targets, indicating predetermined connections
Page 20: Evidence for Chemical Signals
Stripe Assay Methodology
Tectum dissection and reassembly to observe axon growth patterns from retinal cells
Temporal retinal axons avoided posterior tectum, suggesting chemical repulsion
Page 21: Ephrin Gradients in Mapping
Role of Ephrins and Eph Receptors
Gradients along N-T and A-P axes guide axons
Axon guidance cues assist in establishing precise mapping connections
Page 22: Ephrin and Axon Connections
Findings in Fluorescent Dye Studies
Wildtype mice showed restricted axon innervation patterns consistent with ephrins' functions
Mice lacking EphA3 and ephrin-A5 showed disrupted mapping across colliculus
Page 23: Guidance Genes Overview
Cues for Axon Guidance
Long-range cues create natural gradients to attract/repel growing axons
Short-range cues interact directly with axon surface for effects
Page 24: Conclusion on Retinal Wiring
Activity's Influence on Visual Wiring
Previous experiments indicate wiring is predetermined, but activity may still play a role
Page 25: Hubel and Weisel's Contributions
Activity in Visual Systems
Explored role of neural activity in visual system wiring
Page 26: Visual Cortex Circuitry
Binocular Vision Circuits
Analysis of monocular and binocular cells in the visual cortex
Axons from different eyes connect to segregated cells in the LGN
Page 27: Hubel and Weisel's Neural Activity Recordings
Ocular Dominance in Neurons
Color-coded analysis of neuron response to visual stimuli
Spectrum of ocular dominance from strong preferences to neutrality
Page 28: Critical Period Monocular Deprivation
Impact of Experience on Wiring
Suturing one eye of kittens showed preference for the open eye post-surgery
Demonstrated experience shapes cortical circuits (V1 organization)
Page 29: Nobel Prize Recognition
1981 Nobel Prize in Physiology or Medicine
Shared by:
Roger W. Sperry for cerebral hemisphere specialization
David H. Hubel and Torsten N. Wiesel for visual system processing discoveries
Page 30: Summary of Visual System Wiring
Key Takeaways
Both molecular and activity-dependent mechanisms are crucial in developing visual systems
Chemoaffinity hypothesis and ephrins are pivotal for retinotectal mapping
Hubel and Wiesel emphasized visual experience's role in establishing binocular vision.