Neural Plasticity

1. Neural Plasticity • Damage to the nervous system can induce remodeling of neural pathways • Such remodeling reflects plasticity • CNS is much more plastic than once believed • Plasticity greatest in the developing brain • Young child • some degree of plasticity remains in the adult brain

2. Plasticity • Critical period • Alteration of connections in visual cortex in visually deprived neonates • Amblyopia (reduced visual capacity) • Sprouting of new axons does occur in the damaged CNS

3. Neurotrophic factors • Target tissues play a critical role in regulating the # of surviving neurons by secreting a variety of neurotrophic factors • Neurotrophin class • nerve growth factor (first one discovered) • protein with 3 subunits (MW 130,000) • beta subunit is biologically active • bind to specific receptors • promote neuronal survival

4. Neurotrophic factors • Elimination of neurotrophic factors & their receptors lead to neuronal death • sensory and sympathetic neurons require trophic support from neurotrophins secreted by their targets • target cells secrete limited amounts of neurotrophic factors • deprivation of neurotrophic factors activates a cell death program in neurons • apoptosis

5. Apoptosis • Cell death characterised by 4 features • cell shrinkage • condensation of chromatin • cellular fragmentation • phagocytosis of cellular remnants • Process prevented by neurotrophins • The cell death program is the cause of neuronal cell loss that normally occurs in the first year of life • Caspase- enzyme that cleaves COOH (protein)

6. Damage in the nervous system • Most injuries involve damage to axons • axotomy- transection of the axon • dooms the distal segment • glial cells degenerate (Wallerian degeneration) • proximal portion also affected probably due to lack of trophic factors from target cell • postsynaptic neurons can also atrophy and die • inputs to injured neuron can withdraw “synaptic stripping” & replaced with Schwann cells (PNS) or Microglia or Astrocytes (CNS) • neuronal degeneration can propagate through a circuit in both antro and retrograde directions

7. Regeneration in the nervous system • New neural connections can reform following injury • Regenerative capacity is • > PNS • < CNS • Axonal Sprouting • Chemotropic factors secreted by Schwann cells attract axons to distal stump

8. PNS regeneration • Once they return to their targets regenerated axons can form functional nerve endings • regeneration of neuromuscular junctions • re-innervation of glands, blood vessels, & viscera by ANS • sensory axons can re-innervate muscle spindles • In all three divisions of PNS (motor, sensory & autonomic the effects of axotomy are reversible (but not necessarily perfect)

9. CNS regeneration • Little regeneration occurs in CNS after injury (short stumps) • long distance regeneration of axons is rare • may have a latent regenerative capacity that can be exploited via therapeutic interventions • environment • growth promoting factors (laminin, cell adhesion molecules) • central myelin is an inhibitor of axon outgrowth

10. Regeneration (cont) • Restoration of function requires synaptic regeneration • Central axons may retain capacity to form synapses even in adult

11. Minimizing damage in nerve trauma • Antioxidants • methylprednisone • lipid peroxidation • Preventing excitotoxicity • NMDA receptor antagonists • MD 801

12. Regeneration in the nervous system • New neural connections can reform following injury • Regenerative capacity is • > PNS • < CNS • Axonal Sprouting • Chemotropic factors secreted by Schwann cells attract axons to distal stump

13. PNS regeneration • Once they return to their targets regenerated axons can form functional nerve endings • regeneration of neuromuscular junctions • re-innervation of glands, blood vessels, & viscera by ANS • sensory axons can re-innervate muscle spindles • In all three divisions of PNS (motor, sensory & autonomic the effects of axotomy are reversible (but not necessarily perfect)

14. CNS regeneration • Little regeneration occurs in CNS after injury (short stumps) • long distance regeneration of axons is rare • may have a latent regenerative capacity that can be exploited via therapeutic interventions • environment • growth promoting factors (laminin, cell adhesion molecules) • central myelin is an inhibitor of axon outgrowth

15. Regeneration (cont) • Restoration of function requires synaptic regeneration • Central axons may retain capacity to form synapses even in adult

16. Focal hand dystonia • Pt. is unable to independently control digits of the hand. • Happens when fingers are moving together at a high rate of activity for long periods of time. • Pianists practicing certain pieces for up to 8 hours/day • Somatosensory representation in cortex of affected digits are fused • In monkeys when two adjacent digits sewn together (sydactyly) the cortical representations of both digits become one

17. The newborn brain • Contains about 100 billion nerve cells • Each neuron connects to anywhere from a few thousand to 100,000 other neurons • At birth each neuron averages about 2500 synapses • By age 3-4 this has risen to about 15,000 synapses and then you start to lose synapses • Process called “pruning” • Adult brain 100-1000 trillion synapes • Humans have about 35,000 genes • So what governs the connections in the brain? • NOT THE GENES

18. Plasticity in Brain Development • The final wiring of the brain occurs after birth & is governed by early experience • Neurons that fire together wire together • A protein called MAP2 ( microtubule-associated protein 2) • Map2 molecules form bridges between neurofilaments and microtubules • Part of internal skeleton that affects neurons growth and structure • May mediate the formation of new neural pathways • (Scientific Am, Dec 1988, p56-64.)

19. Plasticity • Even in adults the sensory cortex is constantly remodeling • The existence and importance of brain plasticity are no longer in doubt • “Some of the most remarkable observations made in recent neuroscience history have been on the capacity of the cerebral cortex to reorganize itself in the face of reduced or enhanced afferent input.” (Edward Jones UCD, center for neuroscience, 2000)

20. The wiring of the brain • Is governed by the neuronal activity • Synaptogenesis governed by activity • Patterns of stimulation • Neurons that wire together fire together • Its survival of the busiest