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Neural Injury and Repair Noam Y. Harel, MD, PhD 12 November 2013 Brain and Behavior

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Disclosures I do not have any financial or other conflicts of interest to disclose for this learning session. I do not affirm that all discussions of drug use will be consistent with either FDA or compendia-approved indications. Off-label and experimental drugs may be discussed.

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Learning Objectives 1.Recognize differences between axonal injury and repair in the PNS versus CNS. 2.Understand levels of neural plasticity from subcellular to network plasticity. 3.Recognize approaches and targets for improving neural repair. 4.Understand principles of neurorehabilitation essential in conjunction with any other drug, cellular, or engineering-based treatments.

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Injury: soma or nerve? Scenery: PNS or CNS? Machinery: intrinsic, extrinsic Strategery: Targets for repair and recovery

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Injury: Soma Excitotoxicity (may be acute or chronic) Ischemia, trauma, etc Decreased ATP Inc intracellular Na +, Ca ++ Membrane Depolarization Increased action potentials Glutamate release Decreased glutamate reuptake Increased extracellular glutamate Cell death SPREADING EXCITOTOXICITY Doble 1999 NECROSIS INFLAMMATIONAPOPTOSIS NO INFLAMMATION

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Injury: Soma DP Agamanolis Chromatolysis

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Injury: Nerve Ray Jurewicz Deumens et al. Focal demyelination Axon disrupted Endo. disrupted Peri. disrupted Epi. disrupted Prognosis Good (weeks) Fair (mos) Poor (surgery may help).... NERVE CONDUCTION STUDIES/ELECTROMYOGRAPHY: Demyelination: Decreased conduction velocity Axonal loss: Decreased action potential amplitude

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Intra-axonal organelle and microtubule breakdown (minutes-hours) Schwann cells begin axon breakdown and recruit more cells (hrs-days) Macrophages enter, accelerate process (1-2 weeks) Path cleared for axons to regrow proximal-->distal (weeks-months) Injury: Nerve Wallerian Degeneration

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Scenery: Peripheral vs Central PNSCNS Ramon y Cajal

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Scenery: Peripheral vs Central Wallerian Degeneration Wallerian Degeneration PNS yes CNS fail

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Scenery: Peripheral vs Central PNS yes CNS fail Schwanns help Oligodendrocyte debris, astrocytes, scarring hurt

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Machinery: Intrinsic vs Extrinsic Akbik et al., 2012 CNS EXTRINSIC Inhibitors CNS Cell Type Inhibitory Product Oligo- dendrocytes Myelin- associated inhibitors AstrocytesChrondoitin sulfates Astrocytes+Fibr oblasts Glial/fibrous scar tissue

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Scenery: Peripheral vs Central Intrinsic growth potential (1-3 mm/d) Sluggish growth potential (0.1 mm/d) PNS yes CNS fail

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Machinery: Intrinsic vs Extrinsic Seo & Kiyama, 2011 PNS INTRINSIC Advantages Regeneration-Associated Genes PNS neurons possess receptors and signal transduction machinery allowing them to grow in response to neurotrophins, retrograde injury signals cAMP

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Machinery: Intrinsic vs Extrinsic Letourneau What does regeneration look like? Growth Cones

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Machinery: Intrinsic vs Extrinsic What does regeneration look like? Ramesh 2004Dickson 2002 Growth Cones Dynamic growth through regulation of actin and microtubule polymerization/depolymerization Hammarlund et al., 2009

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Machinery: Intrinsic vs Extrinsic What does FAILED regeneration look like? Ramon y Cajal Retraction Bulbs (of Cajal)

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Synapse regulation Receptor regulation Transmitter regulation Network adaptation Sprouting CNS PLASTICITY: A more realistic term than CNS regeneration Short-term, Long-term Long-term

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Synapses, receptors, transmitters Lesch, Waider 2012 Xu et al., 2009 Dendritic spines Axonal bouton Dendritic spine Glial cell

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Network adaptation

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Sprouting: Use What You Got Uninjured 1.Direct regeneration 1 2 3 5 4 7 6 7.Retargeting 2.Itinerant regeneration 4.Direct proximal sprouting 3.Sprouting from neighbor 5.Sprouting to neighbor 6.Indirect rerouting

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Complexity Redundancy VJ Wedeen Redundancy PlasticityRecovery through Rerouting, not Regeneration

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Recovery through Rerouting, not Regeneration

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Strategery: Repair and Recovery Targets anyone? *class to fill-in*

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Improve cleanup macrophages instead of oligos? Reduce inflamm & scarring steroids; chondroitinases; etc Add guidance scaffold Schwanns; olfactory ensheathing glia; etc Replace growth factors but can CNS neurons respond? gradients? Trigger RAGs cAMP modulators (rolipram); direct gene therapy Activate growth cones calcium; microtubule stabilizers (eg taxol) Block extrinsic inhibitors Mabs; receptor decoys; RhoA inhibitors Excite circuits transmitter agonists; K + blockers; electrical stim; etc Replace neurons Stem cells Remyelinate axons Stem cells Rehabilitate!! Strategery: Repair and Recovery Targets anyone? ESSENTIAL IN CONJUNCTION WITH ALL THE ABOVE

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ANY kind of activity/nerve stimulation: exercise, electrical stim, magnetic stim, etc Leads to increases in: growth factors, especially BDNF neurogenesis glial cell support angiogenesis synaptogenesis Activity Plasticity Wu et al., 2008

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Circuits need Pruning Shore, 1997 14 yo6 yobirthconsolidationregrowthinjury Plasticity isnt just Growth

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Education > Exertion Specificity > Sweaty Learning (or re-learning) a variety of skilled, task-specific, repetitive tasks is more beneficial than general exercise alone. Skilled: Better stimulates cortical networks Task-specific: Real-life skills more motivating; prune unneeded circuits Repetitive: to maintain gains/consolidate circuits, need to overlearn

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Education > Exertion Specificity > Sweaty Learning (or re-learning) a variety of skilled, task-specific, repetitive tasks is more beneficial than general exercise alone. Rigorous, CONTROLLED clinical rehabilitation studies are woefully lacking, sorely needed

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In both animals and humans, repetitive training in a specific task leads to improved performance in that task, without benefit in other tasks From the spinal cord injury field Cats trained to stand can stand but not walk better Cats trained to walk can walk but not stand better Rats trained to swim can swim but not walk better Rats trained to reach can reach but not climb better Humans trained on treadmill can walk better on treadmill but not over ground De Leon et al, 1998; Smith et al, 2006; Dobkin et al, 2006; Garcia-Alias et al, 2009 Practice Makes Pigeonholed?

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The Dilemma: How to broaden the benefits of task-specific training? Practice variety of tasks within same broad category eg writing in print vs cursive letters, etc - Winstein and Wolf 2009 Random practice order rather than ordered blocks

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Learning Objectives 1.Recognize differences between axonal injury and repair in the PNS versus CNS. 2.Understand levels of neural plasticity from subcellular to network plasticity. 3.Recognize approaches and targets for improving neural repair. 4.Understand principles of neurorehabilitation essential in conjunction with any other drug, cellular, or engineering-based treatments.

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BAPTISTE, D. C. & FEHLINGS, M. G. (2006) Pharmacological approaches to repair the injured spinal cord. J Neurotrauma, 23, 318-34. BRADKE, F., FAWCETT, J. W. & SPIRA, M. E. (2012) Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci, 13, 183-93. CAFFERTY, W. B., MCGEE, A. W. & STRITTMATTER, S. M. (2008) Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci, 31, 215-20. HAREL, N. Y. & STRITTMATTER, S. M. (2006) Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat Rev Neurosci, 7, 603-16. KERSCHENSTEINER, M., SCHWAB, M. E., LICHTMAN, J. W. & MISGELD, T. (2005) In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat Med, 11, 572- 7. KRAKAUER, J. W. (2006) Motor learning: its relevance to stroke recovery and neurorehabilitation. Curr Opin Neurol 1:84-90. PASCUAL-LEONE, A., AMEDI, A., FREGNI, F. & MERABET, L. B. (2005) The plastic human brain cortex. Annu Rev Neurosci, 28, 377-401. RAMON Y CAJAL, S., DEFELIPE, J. & JONES, E. G. (1991) Cajal's degeneration and regeneration of the nervous system, New York, Oxford University Press. Further Reading