1. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neuroscience: Exploring the Brain, 3e Chapter 23: Wiring the Brain

2. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Neurons Example: Mammalian retinogeniculocortical pathway

4. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement Synaptic rearrangement –Change from one pattern to another –Consequence of neural activity/synaptic transmission before and after birth –Critical Period

5. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Elimination of Cells and Synapses Changes in Synaptic Capacity –Synapse elimination modeled in the neuromuscular junction

6. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Lateral Geniculate Nucleus (LGN)

7. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement 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. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement Segregation of Retinal Inputs to the LGN (Cont’d) –Plasticity at ‘Hebb’ synapses –“Winner-takes- all”

9. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement 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. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement Synaptic Convergence –Anatomical basis of binocular vision and binocular receptive fields –Monocular deprivation: Ocular dominance shift Plasticity of binocular connections Synaptic competition

11. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins

12. Activity-dependent Synaptic Rearrangement Critical period for plasticity of binocular connections

13. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement Effect of strabismus on cortical binocularity

14. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Activity-dependent Synaptic Rearrangement Modulatory Influences –Increasing age –Before and after birth –Enabling factors

15. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic Plasticity Two rules for synaptic modification –Wire together fire together (Hebbian modifications) –Out of sync lose their link –Correlation: heard and validated

16. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic Plasticity Excitatory Synaptic Transmission in the Immature Visual System –Focus on 2 glutamate receptors (Rs): AMPARs: glutamate-gated ion channels NMDARs: Unique properties

17. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic Plasticity Excitatory Synaptic Transmission –NMDA receptors have two unique properties Voltage-gated owing to Mg 2+ Conducts Ca 2+ Magnitude of Ca 2+ flux signals level of pre- and postsynaptic activation

18. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic 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)

19. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic Plasticity Lasting synaptic effects of strong NMDA receptor activation

20. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic 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

21. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Elementary Mechanisms of Cortical Synaptic Plasticity Brief monocular deprivation leads to reduced visual responsiveness –Depends on retinal activity, NMDA activation, postsynaptic calcium

22. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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

23. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Enriched environment: More complex brain structure. Increased dendritic branching and synaptic density Increased transmitter levels, total protein Better at solving maze problems

24. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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

25. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins End of Presentation

26. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Neurons Cell Proliferation –Neural stem cells give rise to neurons and glia

27. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Neurons Cell Proliferation (Cont’d) –Cleavage plane during cell division determines fate of daughter cells

28. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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

29. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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”

30. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Neurons Cell Differentiation –Cell takes the appearance and characteristics of a neuron after reaching its destination but programming occurs much earlier

31. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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

32. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Connections The three phases of pathway formation: –(1) pathway, (2) target, (3) address

33. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Connections The Growing Axon –Growth cone: Growing tip of a neurite

34. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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”

35. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Connections Axon Guidance –Guidance Cues: Chemoattractant (e.g., netrin), Chemorepellent (e.g., slit)

36. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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)

37. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Connections Axon Guidance –Establishing Topographic Maps

38. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins The Genesis of Connections Synapse Formation –Modeled in the neuromuscular junction

39. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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

40. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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