Adult Nervous System What is the capacity of the PNS and CNS for repair? WHY? Why discuss this now? Potential for repair depends on cellular properties of nerve and glial cells. http://neuroscience.uth.tmc.edu/s1/chapter09.html Chris Cohan, Ph.D. Dept. of Pathology/Anat Sci University at Buffalo 2017
Objectives 1. Understand the process of PNS regeneration, the importance of intact epineurium, and the time it takes for recovery of function. 2. Understand the differences in regenerative capabilities between PNS and CNS and the reasons for it. 3. Describe strategies for repair of the CNS. 4. Understand how recovery of CNS function can occur in the absence of neuronal growth.
Regeneration CASE 1: A 35 year-old woman involved in a car accident compressed the ulnar nerve against the humerus crushing it, paralyzing digits 4/5 of her right hand. Will she ever regain use of her fingers? If so, how long will it take to recover?
Regeneration CASE 2: A 16 year-old boy on summer vacation jumped head-first off a dock into water he did not realize was only 2 ft deep. On impact with the ground, vertebrae C3 and C4 were crushed, compressing the spinal cord, severing all tracts at this level. All sensory and motor function below his neck was lost. Will he ever regain use of his upper and lower limbs?
Limitations of Repair Once differentiated, neurons do not divide BUT neuronal stem cells exist in few locations: Primary olfactory neurons (smell) Hippocampus (memory consolidation)
Reactions To Injury Peripheral nerve axon chromatolysis Wallerian degeneration If an peripheral nerve is crushed or cut, axons in the nerve will be severed. Axons distal to the crush undergo Wallerian degeneration. The cell body exhibits chromatolysis.
Regeneration In the PNS: proximal axons can regrow connections can be restored endoneurium epineurium perineurium Peripheral nerve axon
Regeneration in PNS Distal severed axons degenerate as well as surrounding myelin, but endoneurium is intact. Schwann cells Schwann cells survive / crucial role proliferate for structural repair remove myelin; remyelinate Nerve fibers sprout from end of axon. Penetrate tunnels remaining in endoneurium; grow towards target Axons contact target; remyelinated.
endoneurium Distal nerve with degenerated axons
Regeneration in PNS Condition of Nerve Trunk Important CRUSH best efficiency/accuracy to guide growing axons CUT gap in severed ends; axons lose guidance epineurium must be reconnected surgically nerve sheath implants also helpful Spinal cord Peripheral nerve injury sheath implants
Regeneration in PNS Time for recovery: about 1 mm/day for functional recovery Case: Accident crushes ulnar nerve 50 cm from hand. How long to recover? 50cm=500mm 1mm/day 500 days or about 1.5 years
Regeneration in CNS Is there recovery from spinal cord damage or brain injury? Little or None WHY? No axonal regeneration WHY? Is it the neurons themselves or their environment?
Regeneration in CNS The extracellular environment of the adult CNS does not support axon growth Albert Aguayo, McGill Univ Stopped Sciatic nerve graft
Regeneration in CNS CNS does not support new growth because: 1. Growth-inhibitory molecules are present on mammalian CNS myelin; damaged myelin releases growth inhibitory molecules 2. The CNS has little extracellular matrix 3. Astrocyte proliferation can block growth physically and via secreted molecules (4. Developmental signals no longer present)
Potential for CNS Regeneration Axons can grow in some regions - corpus callosum. Neuronal proliferation occurs in some CNS locations throughout life: hippocampus, olfactory epithelium Glial regeneration astrocytes and oligodendrocytes must be available and continue to function
Strategies for CNS Repair Growth factors rescue dying neurons - which ones Stem cells and transfection provide new source of neurons or new capabilities Antibodies to CNS myelin antigens - animal models recent study in rats showed recovery of motor function after stroke. Required: 1) antibodies to growth inhibitory receptors on nerve cells 2) training/rehab following period of new growth.
Recovery in the Absence of Growth Limited capacity for structural repair so: Limit area of injury restore circulation quickly (stroke) decrease inflammation/edema hypothermia Brain can remap function of cortex greatest potential at birth; declines with age, BUT brain circuitry is ALWAYS changing. Remapping depends on: motivation, training, effort importance of rehab and attitude