Cells of the CNS, their injury and repair
HUS2-24: Injury & Repair of the Nervous System
Introduction
Course Title: MEDU3300 Human Structure II
Institution: Faculty of Medicine, The Chinese University of Hong Kong (香港中文大學醫學院)
Instructor: Dr. Christopher See
Learning Objectives
Appreciate differences between Peripheral Nervous System (PNS) and Central Nervous System (CNS) responses to injury, focusing on neuronal and glial responses.
Describe regenerative processes of damaged neurons and axons in the PNS, known for better regeneration ability compared to CNS.
Understand varying mechanisms that hinder neural regeneration, specifically those exhibited by reactive CNS glial cells.
Neuronal Organization and Injury Impact
Neurons and their connections organized in a polarized arrangement.
Common injury consequence: Damage to long axons, leading to neuronal death and loss of connections, resulting in neural dysfunction.
Neuronal injury affects both afferent (incoming) and efferent (outgoing) connections.
Axonal Injury (Axotomy): A neuron can suffer damage, affecting both incoming and outgoing axons, leading to severe consequences for neural communication.
Kandel et al. discussed principles of neural science highlighting that neuronal injury leads to chromatolysis, where both afferent & efferent connections are affected.
Functional Outcomes Following PNS vs CNS Damage
PNS Injury: Generally results in good regeneration and functional recovery.
CNS Injury: Characterized by limited regeneration and poor recovery, largely due to different responses from glial cells.
Comparison:
Optic nerve (CNS fiber tract): Limited regeneration.
Peripheral nerve (PNS): Potential for good regeneration.
Regenerative Processes in PNS
Post-Injury Cellular Processes:
Axon degeneration occurs distal to the injury site, but the cell body and proximal axon remain intact.
Macrophages: Involved in clearing away degenerating axonal and myelin debris.
Growth Cone Formation: Tip of the proximal axon forms a growth cone that elongates the axon actively, facilitated by Schwann cells.
Schwann Cells: Form channels and secrete neurotrophic factors that guide regenerating axons.
Eventually, reconnection with the target cell leads to functional recovery.
Cellular Changes and Response to CNS Injury
The clearance of degenerated axonal and myelin debris post-injury is often slow and incomplete.
Activated Astrocytes: Increase in number and size to form a scar (gliosis), which can inhibit axonal growth.
Oligodendrocyte myelin and astrocytes produce inhibitory factors suppressing axon growth.
Microglia: Secrete factors that may induce neuronal death, resulting in failure of axonal regeneration, leading to permanent loss of function.
Influential Cell Types in PNS and CNS
PNS:
Schwann Cells: Secrete neurotrophic factors (e.g., Nerve Growth Factor).
CNS:
Oligodendrocytes: Produce inhibitory factors such as Nogo and myelin-associated glycoproteins.
Astrocytes: Produce inhibitory molecules associated with glial scar formation (e.g., chondroitin sulfate proteoglycans).
Microglia: Engaged in phagocytosis of dying neurons and secretion of neurotoxic factors.
Glial environments critically influence the success or failure of regeneration.
Mechanisms of Inhibition in CNS
Gliosis and hypertrophy of astrocytes lead to the production of growth-inhibitory factors after CNS injury.
Myelin Inhibitors: Such as Nogo and astrocyte-associated inhibitors act on axon-surface receptors to trigger signaling pathways affecting cytoskeleton assembly and dynamics.
Failure of Axonal Regeneration: Involves signaling pathway activation when growth inhibitors bind to axonal membrane receptors.
Strategies for Promoting CNS Regeneration
Transplantation Techniques:
Use of peripheral nerve segments.
Immature CNS tissue transplantation for conditions like Parkinson’s and Huntington’s diseases.
Olfactory nerve ensheathing cell transplantation.
Stem cell transplantation for replacing dead neurons or rescuing injured neurons.
Modifications to CNS Environment:
Neutralizing activity of oligodendrocyte inhibitors.
Enzymatic digestion of proteoglycans.
Suppressing microglial activity.
Clinical Examples of CNS Repair Strategies
Grafting of Peripheral Nerve Segments: Used to connect different CNS regions to stimulate regeneration (illustration of a PNS graft apposed to an optic nerve).
Fetal Tissue Transplantation: Aimed at treating Parkinson’s Disease.
Transplantation of Olfactory Nerve Ensheathing Cells: Implemented for spinal cord damage repair.
Stroke as a CNS Injury
Causes of Stroke:
Ischemic Stroke:
Thrombus: Local obstruction of a blood vessel.
Embolism: Distal source of occlusion.
Systemic Hypoperfusion: Shock-related.
Hemorrhagic Stroke: Involves intracranial bleeding (e.g., from ruptured aneurysms, hypertension).
Ischemic Effects on CNS Injury
Oxygen Deprivation: Leads to cellular injury and death via an ischemic cascade.
Areas of Stroke Impact:
Core: Includes irreversible damage resulting in neuronal death.
Penumbra: Tissue area that can be saved if reperfused.
Cellular Changes Over Time Post-Stroke:
Immediate (6 hours): No observable gross or histological changes.
Acute (2 days): Characterized by edema and inflammation (neutrophil infiltration), termed 'red neurons'.
Intermediate (2 weeks): Presents with cyst formation and macrophage infiltration.
Late (4 weeks+): Marked by gliosis, proliferation of glial cells, and loss of normal architecture.
Practical Applications in Stroke Diagnosis
Identifying Stroke Symptoms:
Correlate symptoms to functional loss and localize deficits to anatomical structures.
Example: Medial medullary stroke.
Classification of Peripheral Nerve Injury
Macroscopic Perspective:
Types and classifications of injury through examination of nerve bundles.
Injury Mechanisms:
Endoneurium: Structure containing fascicles surrounded by endoneurial fluid.
Perineurium: Surrounds fascicles (myofibroblast type) and forms connective tissue.
Epineurium: Outer layer of dense connective tissue housing vasculature.
Types of Injuries Include:
Physical trauma of peripheral nerves (tidy, untidy, traction injuries).
Mechanical injury (e.g., spinal cord, traumatic brain injuries).
Ischemic injury such as strokes.
Neurodegenerative diseases (e.g., Alzheimer’s, ALS).
Toxin-induced degenerations and retinal diseases (e.g., glaucoma).
Nerve Injury Classification Models
Seddon Classification:
Neurapraxia (Type I): Transient conduction block.
Axonotmesis (Type II): Lesion in continuity.
Neurotmesis (Types III, IV, V): Nerve division or disconnection.
Sunderland Classification offers a deeper tiered approach with a focus on specificity of injury and recovery potential.
Stages of Peripheral Nerve Regeneration**
Initial Stage:
Segmental demyelination and axon fragmentation.
Macrophage Infiltration:
Facilitates removal of myelin debris.
Schwann Cell Activity:
Neurotrophic factor secretion and formation of Bands of Bungner from Schwann cells to guide regenerating axon.
Axonal Growth:
Formation of a single enlarging axon filament and new myelin sheath reconstruction.
Conclusion: Historical Context of CNS Injuries
Historical documentation indicates poor prognoses for CNS injuries, as shown in notes from ancient Egypt found in the Edwin Smith Surgical Papyrus, highlighting the understanding of spinal injuries and their implications for recovery.
Noteworthy Figures:
Ramon y Cajal: Pioneer in studying CNS regeneration.
Rita Levi-Montalcini: Co-discoverer of Nerve Growth Factor (NGF), noted for its significance in neurite outgrowth.
These notes encapsulate a comprehensive overview of the principles surrounding injury and repair in the human nervous system, with detailed insights into cellular responses, mechanistic challenges to regeneration, and historical understanding, providing a robust resource for study in the field of human medical sciences.