Module 3, lecture 6 Flashcards
Is recovery from damage faster if nerve is crashed or severed
crashed
Recovery from nerve damage is generally faster when a nerve is bruised or crushed (axonotmesis) compared to when it is completely severed (neurotmesis). In axonotmesis, the nerve sheath remains intact, allowing for potential regeneration of nerve fibers, while complete transection requires surgical intervention and may not always lead to full recovery.
Recovery from damage of nerve involves
injury in early vs late development
involves similar molecular pro-growth mechanisms/genetic programs than those involved in development
If injured during EARLY development, CNS axons can regenerate robustly (can regrow axon easily)
LATE: inhibition in regrowth, can’t regrow when mature
Differences in adult vs. embryonic environment
Distances between pre- and postsynaptic targets
Degree of differentiation and organization of synaptic target (early developmental time, early target)
Differences in environment in CNS vs. PNS
e.g. glial cells + immune response
➔ RESTRICTIVE to axonal regrowth (CNS) vs. PERMISSIVE to axonal regrowth (PNS)
Cellular Basis of Peripheral Nerve Regeneration:
Major cellular elements facilitate peripheral nerve recovery:
- Schwann cells – provide physical and trophic support
- Fibroblasts –secretion of ECM (facilitate regeneration)
- Macrophages – clear debris (myelin on injured axon, myelin is inhibitory to axonal regrowth. Facilitates regrowth.
- Endothelial cells – provide physical support and essential nutrients
Formation of a nerve bridge
requires the cooperation of all 4 of these cells (schwann, fibroblasts, macrophages, endothelial cells)
Endothelial and migrating cord of schwann cells are the main nerve bridge components
Cells in PNS can reactivate genetic and signalling programs that allow a cell to regrow an axon
Re-apposition
key for axonal recovery
Schwann cell plasticity and response to nerve injury steps
- neuron w/axon in PNS (injured)
- Trans-differentiation into regeneration-promoting cells creating permissive environment
-Proliferation + downregulation of pro-myelinating genes
-Secretion of cytokines and trophic factors
-Recruitment of macrophages - Formation of bands of Büngner (trophic and physical support)
- Re-differentiation into myelinating cells and remyelination of axons (some schwann cells direct reinnervation into axon terminal)
Differences between PNS and CNS recovery from injury
- Damage to the CNS tissue (neurons, axons) tend to extend cell death to nearby tissue (broader extension of cell death compared to PNS)
- Lack of re-activation of developmental genetic and signalling programs for axonal growth in adult CNS (no reactivation of growth)
- Up-regulation of growth-inhibiting genetic and signalling programs in CNS (inhibiting)
- Inhibitory activation of glia in CNS vs. trans-differentiation of Schwann cells in PNS that support re-growth
Neuronal maturation-associated processes and inhibition of axon regeneration
(During maturation, axons transition from a developmental state of rapid growth to a relatively static, hard- wired condition in which they are specialized for the transmission of information)
neuron matures and becomes specialised to its target
Synapse Formation and the onset of neurotransmission
- Entrapment of the injured axon tip by a synapse-like structure
- Activation of neurotransmission machinery, suppressing growth
Gene Expression Changes
-Failure to express or sustain expression of genes that are critical for axon outgrowth
- Upregulation of receptors for growth-inhibitory (mature neuron) molecules expressed in the extracellular environment
-Upregulation of genes involved in neurotransmission or homeostasis (communication with target) - specialises to communicate with its target
Changes in intracellular transport and/or trafficking
-Exclusion of growth-promoting molecules from the axon by polarised transport and/or trafficking
-Decline in endoplasmic reticulum and mitochondrial transport with maturation
Signalling
-Inactivation of signalling pathways driving axon outgrowth
- Shift in signalling pathways from axon outgrowth to synaptic plasticity
Cytoskeletal dynamics
Suppression of cytoskeletal processes that enable rapid axon growth during early neuronal development
Glial Scar Formation in the Injured Brain
-Brain injury elicits responses from astrocytes, oligodendrocytes, and microglia that actively opposes regrowth (oligodendrocytes are first, then microglia, then astrocytes)
→activated glia: form peripheral zone (outside) of the glial scar (target looking thing)
The overgrowth of the 3 activated glia + immune cells form the glial scar
Proliferation -> hypertrophy increase in size of cells
Glial-mediated Inhibition of Axonal Re-growth
Glial cells secrete or have on their cell surface, a variety of ligands (e.g., MAG, NOGO, FGF)
Anything with myelin = inhibitory when it comes to axonal regrowth.
MAG = myelin associated protein
Newly generated axons of damaged neurons have on their surface a variety of receptors (e.g., Lingo-1, PirB) for these ligands.
→ inhibitory signals against axonal growth
Immune Activation and Inflammation with Brain Injury
Glial activation is often accompanied by a massive influx of immune cells facilitated by disruption of blood-brain barrier (BBB) if BBB is compromised due to injury, immune cells can enter
- e.g. T-lymphocytes, neutrophils, and monocytes (macrophages). First: neutrophils will enter and then T-lymphocytes (2nd)
Also: secretion of pro- inflammatory mediators
- e.g., cytokines, interleukins
