Wiring the Brain: Development and Plasticity

1. Neuroscience: Exploring the Brain, 3e Chapter 23: Wiring the Brain

2. Introduction • Operation of the brain • Precise interconnections among 100 billion neurons • Brain development • Begins as a tube • Neurogenesis, synaptogenesis, pathway formation, connections formed and modified • Wiring in brain • Establishing correct pathways and targets • Fine tuning based on experience

3. The Genesis of Neurons • Example: Mammalian retinogeniculocortical pathway

4. Activity-dependent SynapticRearrangement • Synaptic rearrangement • Change from one pattern to another • Consequence of neural activity/synaptic transmission before and after birth • Critical Period

5. The Elimination of Cells and Synapses • Changes in Synaptic Capacity • Synapse elimination modeled in the neuromuscular junction

6. The Lateral Geniculate Nucleus (LGN)

7. Activity-dependent SynapticRearrangement • Synaptic segregation • Refinement of synaptic connections • Segregation of Retinal Inputs to the LGN • Retinal waves (in utero) (Carla Shatz) • Activity of the two eyes not correlated -> segregation in LGN • Process of synaptic stabilization • Hebbian modifications (Donald Hebb)

8. Activity-dependent SynapticRearrangement • Segregation of Retinal Inputs to the LGN (Cont’d) • Plasticity at ‘Hebb’ synapses • “Winner-takes- all”

9. Activity-dependent SynapticRearrangement • Segregation of LGN Inputs in the Striate Cortex • Visual cortex has ocular dominance columns (cat, monkey) - segregated input from each eye • Synaptic rearrangement is activity-dependent • Plastic during critical period • Effects of congenital cataracts (if not removed early)

10. Activity-dependent SynapticRearrangement • Synaptic Convergence • Anatomical basis of binocular vision and binocular receptive fields • Monocular deprivation: • Ocular dominance shift • Plasticity of binocular connections • Synaptic competition

13. Activity-dependent SynapticRearrangement • Critical period for plasticity of binocular connections

14. Activity-dependent SynapticRearrangement • Effect of strabismus on cortical binocularity

15. Activity-dependent SynapticRearrangement • Modulatory Influences • Increasing age • Before and after birth • Enabling factors • Basal forebrain & LC must be intact for plasticity

16. Elementary Mechanisms of CorticalSynaptic Plasticity • Two rules for synaptic modification • Wire together fire together (Hebbian modifications) • Out of sync lose their link • Correlation: heard and validated

17. Elementary Mechanisms of CorticalSynaptic Plasticity • Excitatory Synaptic Transmission in the Immature Visual System • Focus on 2 glutamate receptors (Rs): • AMPARs: glutamate-gated ion channels • NMDARs: Unique properties

18. Elementary Mechanisms of Cortical Synaptic Plasticity • Excitatory Synaptic Transmission • NMDA receptors have two unique properties • Voltage-gated owing to Mg2+ • Conducts Ca2+ • Magnitude of Ca2+ flux signals level of pre- and postsynaptic activation

19. Elementary Mechanisms of CorticalSynaptic Plasticity • Long-Term Synaptic Potentiation • Monitor synaptic strength before and after episodes of strong NMDA activation • Accounting for LTP • AMPA insertion (“AMPAfication”) • Splitting synapses (doubling)

20. Elementary Mechanisms of CorticalSynaptic Plasticity • Lasting synaptic effects of strong NMDA receptor activation

21. Elementary Mechanisms of CorticalSynaptic Plasticity • Long-Term Synaptic Depression (LTD) • Neurons fire out of sync • Synaptic plasticity mechanism opposite of LTP • Loss of synaptic AMPARs • Loss of synapses? (unknown) • Mechanism for consequences of monocular deprivation

22. Elementary Mechanisms of CorticalSynaptic Plasticity • Brief monocular deprivation leads to reduced visual responsiveness • Depends on retinal activity, NMDA activation, postsynaptic calcium

23. Why Critical Periods End • Why do critical periods end? • Plasticity diminishes: • When axon growth ceases • When synaptic transmission matures • When cortical activation is constrained • Intrinsic inhibitory circuitry late to mature • Understanding developmental regulation of plasticity may help recovery from CNS damage

24. Enriched environment: More complex brain structure. • Increased dendritic branching and synaptic density • Increased transmitter levels, total protein • Better at solving maze problems

25. Concluding Remarks • Generation of brain development circuitry • Placement of wires before birth • Refinement of synaptic infancy • Developmental critical periods • Visual system and other sensory and motor systems • Environment influences brain modification throughout life

26. Barn Owl : Space Map in Inf. Colliculus This is a computational map!

27. ‘Supervised’ learning / plasticity Prism goggles experiment: ‘eye instructs the ear’ A V After 8 weeks w/ Prism goggles A V

28. End of Presentation

29. The Genesis of Neurons • Cell Proliferation • Neural stem cells give rise to neurons and glia

30. The Genesis of Neurons • Cell Proliferation (Cont’d) • Cleavage plane during cell division determines fate of daughter cells

31. The Genesis of Neurons • Cell Migration • Pyramidal cells and astrocytes migrate vertically from ventricular zone by moving along thin radial glial fibers • Inhibitory interneurons and oligodendroglia generate from a different site and migrate laterally

32. The Genesis of Neurons • Cell Migration • First cells to migrate take up residence in “subplate” layer which eventually disappears • Next cells to divide migrate to the cortical plate • The first to arrive become layer VI, followed V, IV, and so on: “inside out”

33. The Genesis of Neurons • Cell Differentiation • Cell takes the appearance and characteristics of a neuron after reaching its destination but programming occurs much earlier

34. The Genesis of Neurons • Differentiation of Cortical Areas • Adult cortical sheet is a “patchwork quilt • Cortical “protomap” in the ventricular zone replicated by radial glial guides • But some neurons migrate laterally • Thalamic input contributes to cortical differentiation

35. The Genesis of Connections • The three phases of pathway formation: • (1) pathway, (2) target, (3) address

36. The Genesis of Connections • The Growing Axon • Growth cone: Growing tip of a neurite

37. The Genesis of Connections • Axon Guidance • Challenge in wiring the brain • Distances between connected structures • But in early stages nervous system is a few centimeters long • Pioneer axons stretch as nervous system expands • Guide neighbor axons to same targets • Pioneer neurons grow in the correct direction by “connecting the dots”

38. The Genesis of Connections • Axon Guidance • Guidance Cues: Chemoattractant (e.g., netrin), Chemorepellent (e.g., slit)

39. The Genesis of Connections • Axon Guidance • Establishing Topographic Maps • Choice point; Retinal axons innervate targets of LGN and superior colliculus • Sperry (1940s): Chemoaffinity hypothesis • CNS axons regenerate in amphibians, not in mammals • Factors guiding retinal axons to tectum • Ephrins/eph (repulsive signal)

40. The Genesis of Connections • Axon Guidance • Establishing Topographic Maps

41. The Genesis of Connections • Synapse Formation • Modeled in the neuromuscular junction

42. The Genesis of Connections • Synapse Formation • Steps in the formation of a CNS synapse: • Dendritic filopodium contacts axon • Synaptic vesicles and active zone proteins recruited to presynaptic membrane • Receptors accumulate on postsynaptic membrane

43. The Elimination of Cells and Synapses • The mechanisms of pathway formation • Large-scale reduction in neurons and synapses • Development of brain function • Balance between genesis & elimination of cells and synapses • Apoptosis: Programmed Cell Death • Importance of trophic factors, e.g., nerve growth factor