1. Lecturer: Dr Lucy Patston lpatston@unitec.ac.nz

2.  www.youtube.com/watch?v=2MKNsI5CWoU www.youtube.com/watch?v=2MKNsI5CWoU  Girl living with half her brain

3.  Lundy: Chapter 4  Tortura: PDF provided on Moodle Lundy-Ekman. Neuroscience: Fundamentals for Rehabilitation, 4th Edition. W.B. Saunders Company, 2013. Kandel et al. Principles of Neural Science, 5 th Edition. McGraw Hill, 2012. Tortura & Derrickson. Principles of anatomy and physiology, 13 th Edition. Wiley. 2012.

4.  What is neuroplasticity  Central chromatolysis and Wallerian degeneration  Axonal injury in the PNS  Mechanisms for recovery in CNS

5.  Be able to discuss cellular processes after injury (central chromatolysis & Wallerian degeneration)  Be able to name and discuss two mechanisms of sprouting in the PNS  Be able to name and discuss four mechanisms for synaptic recovery in the CNS  Be able to explain why there is no repair of damaged axons in the CNS

6.  Capacity of nervous system to adapt to change ◦ Learning ◦ Injury  Old thinking – cortical representations static upon reaching adulthood, then:  1992: Canadian researchers discovered epidermal growth factor (EGF) stimulated cells from adult mice brains to proliferate into neurons and astrocytes  1998: Human hippocampus seen to show significant number of new neurons

7.  Now we know – brain is dynamic structure, changing constantly through experience ◦ Use it or lose it!  Changes: sprouting new dendrites, synthesis of new proteins, changes in synaptic contacts  Despite this, neurons have limited ability to regenerate (replicate and repair themselves)  Change can be anatomical, physiological or pharmacological

8.  Anatomical ◦ Studies showing cortical motor maps change upon learning new skill – piano ◦ Recovering from stroke with interventions aimed at motor movement etc. (fMRI studies)  Physiological ◦ Refinement of synaptic connections by experience ◦ E.g., music, doing stuff (dancing, swimming), emotional or social development  Pharmacological ◦ Adaptation of synapses after damage, injury or toxic insult  Forms basis of addiction/withdrawal

9.  Injuries damaging or severing axons may be recoverable  Injuries to cell bodies, however, usually cause death of the neuron  In PNS damage to dendrites and myelinated axons may be repaired in cell body remains intact and if Schwann cells remain active  In CNS little or no repair of damage occurs (even when cell body intact, a severed axon cannot be repaired or regrown) ◦ NB: This is not to say that new neurons/synapses do not grow

10.  24-48 hours after injury, cell body undergoes central chromatolysis ◦ parts of the cell body break down/dissolve (Nissl bodies); nucleus moves toward periphery of soma; presynaptic terminals retract  Apoptosis (cell death) may then occur

12.  By Day 3-5 after an axon is severed, ◦ part connected to cell body is called proximal segment ◦ Part isolated from cell body is called distal segment  Cytoplasm leaks out and segments retract from each other  Distal segment then undergoes process called Wallerian degeneration

13.  Axon swells, breaks, terminal buttons degenerate  Myelin sheath pulls away (but neurolemma remains intact)  Glial cells tidy up debris  Schwann cells multiply (mitosis) and grow toward each other and may form a regeneration tube

14.  Regeneration tube acts as protection and guidance for axon to regrow across injury site (if small enough)

15.  Common due to long-range axons not sheltered by skull or vertebral column  Axons may be severed by knives, machines etc.  Axons may undergo repair if: ◦ 1. cell body is intact ◦ 2. Schwann cells are functional ◦ 3. Scar tissue has not occurred  Regrowth of damaged axons called sprouting 1.Collateral (presynaptic death) 2.Regenerative (postsynaptic death)

18.  Functional regeneration of axons occurs more frequently in PNS than CNS  Nearly complete lack of neurogenesis in CNS due to ◦ (1) inhibitory influences from glial cells (oligodendrocytes)  Possibly mechanism that stops axonal growth in development once target region is reached? (see Development lecture) ◦ (2) absence of nerve growth factor (NGF) by Schwann cells  1-1.5mm growth per day  Problematic when new innervation is inappropriate (e.g., wrong muscle) ◦ Unintended movements named synkinesis usually short- lived

19.  Same processes after SCI and TBI ◦ Axonal retraction ◦ Wallerian degeneration (WD) ◦ Central chromatolysis  In CNS most damage occurs hours/days afterwards, due to cellular cascade: ◦ Increased permeability of axons ◦ Dysregulation of Na + -Ca 2+ channels  causing influx of Ca 2+  Ca 2+ influx -> swelling/breaking/chromatolysis/WD  This causes diffuse axonal injury/disconnection SCI: Spinal cord injury TBI: Traumatic brain injury

20.  Glial scars form physically preventing axonal regeneration  Astrocytes and microglia release growth- inhibiting factors (Nogo)  Oligodendrocytes have no NGF, but Nogo instead!  Animal tests have shown that administering a Nogo inhibitor after injury improves sprouting and functioning

21.  Mechanisms for recovery in CNS: 1.Recovery of synaptic effectiveness 2.Denervation hypersensitivity 3.Synaptic hypereffectiveness 4.Unmasking of silent synapses

22.  Swelling that produced pressure on presynaptic cell resolves and normal transmission is resumed

23.  Increased sensitivity to other, nearby, presynaptic cells due to additional receptors

24.  Larger than normal amounts of neurotransmitter released to remaining synapse

25.  Unused synapses are lurched into action!

26.  Cortical maps can be modified by experience ◦ E.g., violinists have enlarged finger representations for the left hand  fMRI studies document functional recovery after stroke. ◦ Activity in somatosensory cortex shifts to more bilateral after stroke and then back to lateralised as recovery progresses  Reorganisation seen in deaf and blind individuals. ◦ Cochlear implants after age 7 activate non-usual cortical areas. ◦ Congenitally blind ppl use occipital cortex for reading Braille and memory

27.  Intensity and time between injury and rehab influence recovery  Prolonged inaction promotes adjacent loss of cells/function ◦ Rat study: “rehab” 5 or 30 days post lesion ◦ 5 day group used impaired forelimb twice as well as 30 day group  Task-specific rehab better ◦ Constraint-induced movement therapy (functional arm constrained in sling) shown to be better behaviourally and through imaging