Development and refinement of CNS

1. Development and refinement of CNS Earliest form of neuroplasticity

2. Stages of NS development • Induction of neural plate • Birth or proliferation of neurons and glia • Migration of cells to their eventual locations in NS • Axon growth and formation of synapses between neurons • Death of particular neurons and rearrangement of neural connections

3. Neuralization, or Induction of the Neural Plate

5. Cell Proliferation • Cells in the neural tube begin to proliferate (multiply, divide and increase in number) • Most of cell division occurs in ventricular zone of neural tube • Cell division occurs through mitosis • After about 7 weeks of development one daughter cell will remain in ventricular zone and one will migrate outward and become a neuron or glial cell

6. Types of Cell Migration

7. Methods of Cell Migration

8. Cell Migration con’t • The layers of the cerebral cortex develop at different times • Cells in outermost layers must migrate through innermost layers first • Development proceeds in an inside-out fashion • Cells in the neural crest will develop into neurons and glial cells of the peripheral nervous system

9. Formation of axons and dendrites • Growth cones: structures that form at the end of developing axons and dendrites • 3 main features: main body; filipodia; lamellipodia • Filipodia and lamellipodia can move and pull the growing processes along with them • Chemoaffinity hypothesis • Guidance molecules

10. Axon formation, con’t • First axons to reach their target have pioneer growth cones, and use guidance molecules to guide them • Later axons use trail blazed by pioneer growth cones • Fasciculation: tendency for developing axons to stick together and grow along established pathways • Cell adhesion molecules (CAMs): on surface of growing axons that cause axons proceeding in the same direction to stick together

12. Synaptogenesis • Formation of new synapses • Requires coordinated activity of at least 2 neurons • Requires presence of glial cells, particularly astrocytes • Structures of the synapse must form (receptors, neurotransmitters etc) • Many processes promote or inhibit synapse formation so that best connections are made

13. Neuron Death • Cell death can be necrotic or apoptotic • Necrosis: passive cell death, results in inflmmation • Apoptosis: programmed cell death (cell suicide), much neater • Cell death during NS development is apoptotic • Failure to get adequate NGF leads to apoptosis

14. Synapse Rearrangement • When neurons die they leave space on postsynaptic membrane • Sprouting axons of surviving membranes will take over space • Rearrangement seems to focus output of each neuron on a smaller number of post-synaptic cells and increases selectivity of synaptic transmission.

15. Time course of development • Most neurons in adult brain are present by 7 months post conception • Volume of brain quadruples after birth • Due to synaptogenesis, myelination of axons and increased branching of dendrites • Primary visual cortex, auditory visual cortex undergo burst of synpatogenesis at 4 months of age until a maximum is reached at 7 months, synapses in prefrontal cortex develop steadily up to age of 2

16. Myelination • Sensory cortex gets myelinated first (first few months of life) • Motor areas are next • Prefrontal cortex is last, continues into adolescence • Myelin is composed of 15% cholesterol, which is why doctors recommend milk for babies

17. Dendritic Branching • Deeper layers of cortex develop their branches earlier than outer layers • Just like time frame of migration of neurons in cortex (inside-out manner) • This pattern of development occurs the same way in all cortical regions

18. Plasticity • If the nervous system is still being formed after birth then that means our brain’s connections are plastic (can be rearranged) • Environment influences which neurons survive and which ones are lost • “Use it or lose it”: can be good and bad. Enriched environments can be helpful, deprivation can have permanently damaging effects • Period of plasticity appears to be limited in some cases (critical period) and unlimited in some cases

19. End points to plasticity? • Critical periods imply that the brain is not always going to be plastic • What ends critical periods? End of period of axon growth? Maturation of synaptic connection? Beginning of inhibitory input? Presence or absence of neurotrophins (nerve growth factors)? • Mature neurons maintain nearly all of the machinery necessary for restructuring their synaptic connections (e.g. recovery after motor nerve injury involves axonal sprouting at neuromuscular junction)

20. End points to plasticity? • Now there is evidence of neuroplasticity in adult brains in olfactory cortex and hippocampus • Goldman and Nottebohm (1980s) show neurogenesis in bird brains. In 1990s evidence of neurogenesis in adult rats and primates

21. Neural stem cells: originate in ependymal layer of brain’s ventricles Cells migrate to olfactory bulb Hippocampal cells come from neural stem cells near their final location

22. “Recovery” of function

23. Neuroplasticity and brain damage • CNS damage can trigger 4 neuroplastic responses: • Degeneration • Regeneration • Reorganization • Recovery of function

24. Neural Degeneration • Anterograde degeneration: degeneration of the distal segment of an axon that has been cut (the section between the cut and the synapse). Occurs quickly • Retrograde degeneration: degeneration of the proximal segment (the section between the cell body and the cut). Progresses gradually and • Damage can spread to neurons that are linked to damaged neurons: transneuronal degeneration (can be retrograde or anterograde)

26. Neural Regeneration • Regrowth of damaged neurons • Does not progress very well in mammals and higher vertebrates • Virtually nonexistent in the CNS Of adult mammals • Does occur in the PNS of adult mammals

27. Three possibilities • If Schwann cell myelin sheaths remain intact, regenerating neurons grow through them to original targets • If nerve is severed and cut ends are separated by a small space regrowth can be directed to incorrect targets • If severed ends are far apart or long section of nerve is damaged functional regeneration may not occur

28. Schwann cells • Promote regeneration in the mammalian PNS by producing neurotrophic factors and cell adhesion molecules (CAMs) • Neurotrophic factors stimulate growth of new axons and CAMs on membranes of Schwann cells provide the paths along which regenerating axons grow • In CNS oligodendroglia do not stimulate or guide regeneration; actually release factors that block regeneration

29. Neural Reorganization • Could result from (1) strengthening of existing conditions possibly through release from inhibition and (2) establishing new connections by collateral sprouting.

30. Treatment of NS Damage • Neuroprotection: e.g. reducing brain damage by blocking neurodegeneration • Promoting CNS regeneration • Neurotransplantation (fetal tissue, stem cells) • Rehabilitation training

31. Neuroprotection • Brain injury is a complex cascade of biochemical and structural changes of varying duration each of which may contribute to neuronal death or repair and regeneration • One therapeutic approach involves administering compounds to protect neural tissue from cytotoxic and excitotoxic effects of the injury cascade

32. Inhibiting Cytotoxicity • Neuroprotective agents that reduce cytotoxicity tend to absorb damaging molecules such as free radicals • Free radicals can interact with cell membranes, DNA and proteins, changing their conformation and affecting their function • Free radical scavengers have not been very effective in clinical trials

33. Inhibiting Excitotoxity • Another approach is to try to prevent the excitotoxic loss of neurons after injury • Blocking hyperexcitation of receptors for glutamate • Treatments must target several pathways in the injury cascade. Highly selective compounds may lose their beneficial effect or become toxic by pushing the injury cascade into alternative pathways, which may be just as destructive

34. Neuroprotection • Both the timing and the type of the pharmacologic agent to be given can have a significant impact on the success of therapy. • With neuroprotective agents the general rule is that the earlier they are given the better, especially if the mode of action is increasing inhibitory tone in the brain. • Increased levels of inhibition that may be needed to block excitotoxicity in the damaged area may disrupt the subsequent recovery if treatment is maintained throughout the course of rehabilitation

35. Neural Regeneration • How can the regeneration of neural tissue be stimulated after injury? • Trophic factors: agents that can stimulate the repair, regeneration, elongation, and reconnection of damaged axons or dendrites • We are only beginning to understand the multiple interactions that guide or block regenerating axons to their targets, and how behavioral experience can affect functional outcomes in injury models

36. Reorganization through training • Can physical therapy or exercise be used to stimulate the brain to reorganize after a TBI? • A good limb can be restrained, forcing use of impaired limb, so that the impaired limb ‘relearns’ how to perform tasks • Critical periods may exist for this type of reorganization because brain will be differentially sensitive to increased levels of activity following injury