Neuro Week 3: Brain Injury and Repair

Edwin Smith surgical papyrus

~2500 BC; earliest reference to CNS injury — cervical dislocation causing paralysis is "a disease one cannot treat"

Plasticity

Adaptive structural and functional change — ability of the nervous system to change activity in response to intrinsic or extrinsic stimuli by reorganising structure, function or connections (e.g. after TBI or stroke)

Functional reorganisation without repair

Undamaged regions reorganise to restore some function after damage (e.g. stroke) without replacing lost neurons

3 reasons adult motor cortex retains use-dependent plasticity

Horizontally spreading axonal connections; altered GABAergic inhibition via horizontal connections; local sprouting of axons/dendrites from intact neurons

3 types of neuronal repair

1) Regrowth of axons (peripheral) 2) Restoration of damaged central nerve cells 3) Genesis of new neurons

Most successful type of neuronal repair

Regrowth of axons after peripheral injury — cell bodies remain intact

Regrowth of axons requires

Reactivation of developmental growth/guidance and synapse formation, plus activity-dependent competition to match regrown afferents to denervated targets

Restoration of damaged central nerve cells — what's needed?

Surviving neurons must regrow dendrites, axons and synapses from the existing cell body, cooperating with glia

Why does restoration of central nerve cells generally fail?

Glial overgrowth, complex immune interplay, and production of signals that inhibit neuronal growth

3 criteria for adult neurogenesis

1) Retained multipotent neural stem cells 2) Located in a distinct niche 3) Recapitulation of migration, process outgrowth and synapse formation

3 mechanisms of peripheral nerve injury

Compression (carpal tunnel, tumour), stretch (dislocation), laceration/transection (stab wound)

Epineurium / perineurium / endoneurium

Surround the whole nerve / each fascicle / each individual axon

Neurapraxia

Mildest: temporary conduction block, no structural damage; all sheaths intact; full rapid recovery (days)

Axonotmesis

Axons and myelin damaged but endo-, peri- and epineurium intact; repair via Wallerian degeneration; recovery possible but slower

Neurotmesis

Most severe: complete transection of axon, myelin and connective tissue; requires surgical intervention

Wallerian degeneration

Sequence of events after nerve transection in which the axon separated from its cell body degenerates; described by Augustus Waller (1850, frogs)

Wallerian-like degeneration

Similar axon degeneration after blunt force or crush injury

Steps of Wallerian degeneration and regeneration

Injury → macrophages rapidly remove myelin debris → cell body expresses growth-related genes → Schwann cells proliferate and release growth signals, neurotrophins, ECM, adhesion molecules → growth cone regrows and reinnervates target

Role of Schwann cells in peripheral repair

Proliferate, promote and guide axon regeneration, and remyelinate the regrown axon

Sir Henry Head's experiment (1903)

Had his own radial and external cutaneous nerves cut near the elbow and sutured, then mapped sensory recovery as a trained observer

Henry Head's key findings

Sensitivity to strong stimuli (prick, 50 °C water, ice) returned before gentle stimuli (cotton wool, 25–38 °C water); full function by ~3 years

Cut vs crush nerve regeneration

Crush regenerates far more efficiently (sheaths intact); cut nerves regrow but never as well

Exercise and peripheral nerve repair experiment

Mouse fibular nerve graft; treadmill 10 m/min, 1 hr/day, 5 d/week for 2 weeks → much greater axon regrowth than unexercised controls

3 ways the CNS is damaged

1) Acute physical trauma 2) Hypoxia/ischaemia (stroke, drowning) 3) Neurodegenerative disease (Alzheimer's)

Key to recovery after CNS injury

Supporting survival of neurons not killed outright by the insult

Chronic Traumatic Encephalopathy (CTE)

Neurodegeneration from repeated head trauma, marked by tau deposits; e.g. NFL player John Grimsley (died at 45)

AFL and CTE

AFL acknowledged the head trauma–CTE link in a Senate concussion inquiry submission; strict concussion protocols now

3 reasons CNS regeneration is limited

1) Necrotic and apoptotic cell death 2) Injury site doesn't recapitulate developmental growth signalling 3) Upregulation of growth-inhibiting chemorepellent molecules

Extent of cell death — central vs peripheral

Much more neuronal death centrally; CNS axons and cell bodies are close, so cell bodies are often damaged, unlike distal peripheral axon injury

Necrosis vs apoptosis

Necrosis: uncontrolled death from direct damage. Apoptosis: programmed, controlled cell death

Manabat et al. 2003 experiment

7-day-old mouse, carotid transiently constricted → infarct on Nissl stain; NeuN (red) neurons co-labelled with activated caspase-3 (yellow) = apoptosis

Excitotoxicity

Neuronal damage/death from excess glutamate

Apoptosis cascade after brain injury

Glutamate/cytokines → Bcl2 blocked → cytochrome c released from mitochondria → caspase-9 → caspase-3 → apoptosis + phagocytosis

Bcl2

Anti-apoptotic gene that normally prevents cytochrome c release from mitochondria

Features of apoptosis

Chromosome condensation, DNA fragmentation, membrane blebbing, cytoskeletal changes

How do central glia differ from peripheral glia after injury?

Schwann cells support regrowth; CNS glia proliferate, form a glial scar and release inhibitory signals

Glial markers: astrocytes / oligodendrocytes / microglia

GFAP / NG2 / CD11b

Resting vs activated microglia

Resting: small cell body, thin highly branched processes. Activated: larger cell body, thicker shorter processes, phagocytose debris

Molecules secreted by astrocytes in glial scar that inhibit axons

Semaphorin 3A, ephrins, Slit

Extracellular inhibitory components of glial scar

Tenascin and chondroitin sulphate proteoglycans (CSPGs)

Peripheral vs CNS axon injury

PNS: Schwann cells, rapid debris clearance, growth signals, target reinnervated. CNS: oligodendrocytes, prolonged clearance, glial scar, inhibitory signals stall growth cone

Cajal's "harsh decree" (1928)

After development, axon/dendrite regeneration dries up; adult nerve paths are fixed — nothing may be regenerated

Altman & Das (1965)

Injected rats with tritiated thymidine + autoradiography → showed postnatal neurogenesis in hippocampus and lateral ventricle zone

Why tritiated thymidine labels new cells

Thymidine is a DNA precursor incorporated only by dividing cells; tritium is radioactive, detected by autoradiography

Two adult neurogenic niches

Subventricular zone (SVZ) of lateral ventricle and subgranular zone of the hippocampal dentate gyrus

SVZ lineage

B cell (radial glia-like) → C cell (transient amplifying) → A cell (neuroblast) → neuron

Dentate gyrus lineage

Type I (radial glia-like) → Type II (nonradial precursor) → IPC → neuroblast → granule neuron

Rostral migratory stream (RMS)

Glial tube through which SVZ-born neuroblasts migrate to the olfactory bulb

Proposed functions of new neurons in each niche

SVZ/olfactory bulb: smell (major in rodents). Dentate gyrus: memory

Nestin

Type VI intermediate filament; marks radial glia-like stem cells

Vimentin

Type III intermediate filament (mesenchymal cells); stem cell marker in SVZ

GFAP (in neurogenesis)

Glial fibrillary acidic protein; expressed by stem cells and astrocytes

Sox2

Developmental transcription factor; stem/progenitor marker in dentate gyrus

MCM2

Minichromosome maintenance complex component 2; marks proliferating progenitors and neuroblasts

DCX (doublecortin)

Microtubule-associated protein; marks neuroblasts / immature migrating neurons

NeuN

Neuronal nuclear antigen (Fox-3); marks mature neurons

Calretinin / Calbindin

Calcium-binding proteins marking mature neurons

Core marker sequence for neurogenesis

Nestin (stem cell) → DCX (immature neuron) → NeuN (mature neuron)

Mash1

Proneural protein (Neurogenin family) promoting cell fate commitment

GABA action on new neurons

Depolarising (excitatory) in immature neurons via tonic GABA; hyperpolarising (inhibitory) once mature

Open question about adult neurogenesis

Why is it restricted to 2 regions? Lecturer's research suggests slower niches may exist elsewhere

Summary: 3 types of adult repair ranked

1) Peripheral axon regrowth (most effective) 2) Local sprouting/extension of CNS axons and dendrites (limited) 3) Adult neurogenesis (limited evidence of wholesale replacement)