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
• gt PNS
• lt 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
• gt PNS
• lt 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