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PERIPHERAL AXONS: CHARACTERISTICS

Axons   Caliber   Conduction velocity   Motor unit action potentials   Myelin   Nerve injury     Proximal stump     Neuroma   Transport   Unmyelinated Cutaneous afferents Dorsal root ganglia Mechanotransduction Motor Muscle spindle Muscle & tendon afferents Sensory   Types   Nociceptors   Thermoreceptors     Temperature-sensitive channels External link   Nerve impulse

Mills

Sensory Axon types

Myelinated Sizes: ≥ 3 μM to 8 μM Saltatory Conduction velocities (CV) Normal: 35 M/s to 75 M/s Related to Axon diameter: Proportional Myelin thickness Internode length/Axon diameter Lower with Height: Increased Adult age: Increased Immaturity Temperature: Low Axon size: Small Myelin Types: Molecular Large Myelin contains: P0 + MBP Smaller Myelin contains: P0 Smaller, Regenerated axon Myelin contains: P0 + MBP ± NCAM Schwann cell relation One axon per Schwann cell   Structural patterns along axon Myelin Internodes Nodes of Ranvier Axon structure components Neurofilaments + Microtubules Unmyelinated Size: 0.2 μM to 3 μM Conduction velocity: 0.1 M/s to 5 M/s Types Thermoreceptors Nociceptors Schwann cell relation Several axons per Schwann cell   Asssociated Schwann cells: Components Normal, mature nerve: NCAM Immature or Damaged nerve: MBP Axon structure components Microtubules > Neurofilaments

Myelinated Intermediate-sized Axon with associated Schwann Cell

Sensory Axons

CUTANEOUS SENSORY AFFERENT AXONS
Mechanoreceptors: Low Threshold 13
Light touch   Mechanosensitive channel: PIEZO2   Indentation forces for activation: As low as 0.5 mN
Name	Stimulus Type	Skin End Organ	Axon Class	Sensation	Molecular Factor
					Survival	Functional
Glabrous (Hairless) Skin
Rapid   adapting	Displacement   velocity	Meissner Corpuscle   Dermal papillae apex	Aαβ   TrkB+: Rapid adapt   Ret+: Slower adapt   26–91 m/s   Receptive field     Intermediate	Vibration   40 to 60 Hz Tapping Allodynia	?	USH2A S100   Lamellar cells
Pacinian   corpuscle Rapid adapt	Displacement   transient	Pacinian Corpuscle   Dermis, Deep   Glabrous & Hairy     Skin	Aαβ   Ret+   26–91 m/s	Vibration   100 to 400 Hz Buzz; Flutter	?	S100   Lamellar cells
Slow   adapting     (SA) 1	Displacement	Merkel cell-Neurite   Rete ridge   Glabrous & Hairy     Skin	Aαβ   TrkC   16–96 m/s   Receptive field     Small	Sustained   pressure     (Indentation) Vibration Shape; Texture Light touch Itch	NT3	BDNF PIEZO2 Marker: Atoh1
Slow   adapting     (SA) 2	Displacement	Ruffini   Dermis	Aαβ   20–100 m/s	Stretch >   Indentation	?	?
Hairy Skin
Field	Displacement   velocity	Hair follicles   Awl/auchene   zigzag   Guard Nerve Ending   Circumferential	Aαβ   TrkC+/Ret+   15-25 m/s   Receptive field     Large	Skin stroke	?	?
D hair	Displacement   velocity Lowest   mechanothreshold	Hair follicles   Awl/auchene   zigzag Nerve Ending   Longitudinal     Lanceolate	Aδ   TrkB   5-30 m/s   Receptive field     Intermediate	Hair deflection   Direction-     selective Skin stroke Indentation	NT4; NT3 via TrkB	± p75; ?NT4 T-Ca++ channel   (Cav3.2) 2
C tactile   (C-LTMR)	Light touch   Low threshold	Lanceolate	C   TH+   0.2-2 m/s   Receptive field     Intermediate	Hair deflection Skin stroke Indentation	?	VGLUT3 Tyrosine   hydroxylase PDIA2
Rapidly   Adapting	Displacement   transient	Hair follicle   Guard   awl/auchene Nerve ending   Longitudinal     Lanceolate	Aαβ   26-91 m/s	Hair deflection Skin stroke Indentation	?	ASIC-2 Na+   channel
Mechanoreceptors: Other
High   Threshold	Displacement	Hair follicles   Epidermis   Guard   awl/auchene   zigzag Nerve ending   Free   Circumferential	Aαβ, Aδ, C   0.5-100 m/s	High force   Indentation   Hair pull	?	?
Thermoreceptors 10
Name	Stimulus Type	End Organ	Class	Sensation	Trophic Factor
					Survival	Functional
Cold	Cooling Menthol	Unmyelinated   neurite complex	Aδ C	Cool   Innocuous	?	?
Cold   Allodynia	Cooling	?	Large   Neurons	Pain	?	?
Warm	Warming   Slow adapting   Fast adapting	?	C	Warm   Innocuous	?	?
Also see   Temperature-sensitive channels   Noxious temperature
Nociceptors
Name	Stimulus Type	End Organ	Class	Sensation	Trophic Factor
					Survival	Functional
Myelinated	Pain	Unmyelinated   Neurite-Schwann   cell complex Basal epidermis Myelinated axons	Aαβ Aδ	Pain   Sharp   Stinging	NGF	p75; NGF
C	Inflammation →   Hyperalgesia Not responsive to   mechanical &     heat pain	Unmyelinated   axons Project to spinal   Lamina I &   Lamina IIouter	CMi	Pain   Dull   Sharp Burn   Cold	NGF trkA	p75; NGF; trkA; CGRP; Substance P &   NK1 receptor
	Nerve injury →   Hyperalgesia Responsive to   mechanical &     heat pain	Unmyelinated   axons Project to spinal   Lamina IIinner Noxious heat: TRP-V1	CM	Pain   Dull or   Sharp Burn	NGF trkA	GDNF; Ret GFRα; FRAP & TMP; P2X3 ATP   Receptor
	Heat Cold	Unmyelinated   axons	C	Temperature   hypersensitive	?	mTORC1
	Itch Histamine	Unmyelinated   axons Project to spinal   Lamina I	C	Itch	trkA	?

Muscle Axons

MUSCLE & TENDON AFFERENT AXONS: Proprioception
Name	Stimulus Type	Afferent End Organ	Efferent Termination	Effect	Axon Class	Trophic Factor	Marker
1° sensory	Muscle stretch   Phasic/Dynamic Vibration	Spindle Intrafusil fibers   Nuclear region   DB1; 1 branch   SB2 & Chain;     2nd branch	Motor Neuron   Mono-synaptic	Excite   Homonymous muscle	Ia Largest	NT3	Calb2 ? Lmcd1
2° sensory	Muscle stretch   Tonic/Static   Length	Spindle Nuclear chain fibers   ± SB2	Intermediate   Spinal cord Poly- > Mono-   synaptic	Excite   Homonymous muscle	II Smallest		? Fxyd7
Golgi tendon	Muscle contraction   Tendon stretch     Sustained Force	Myotendinous     Junction Golgi tendon organ   Few in:   Thoracic axial	Intermediate   Spinal cord Poly-synaptic	Inhibit   Homonymous muscle	Ib		? Pou4f3
Proprioception 8   Peripheral features     Axon Current stimulus: Mechanical activation (MA); Muscle stretch     Axon Current type: Rapidly adapting     Neuron currents       Ion: Na+ > > Ca++       Axon Channel: Piezo2         Location: Muscle spindle & Golgi tendon organ sensory endings         Function: Mechanotransduction       DRG cell body: Scn1a; Scn8a     Molecular markers       Afferent neuron: Parvalbumin; Whirlin; Runx3; Ntrk3; Etv1       Limb-specific proprioceptors: Efna5   Central     Afferent axon termination: External Cuneate nucleus

MUSCLE SPINDLES

Disorders General Histology Innervation   Afferent   Efferent Structure   Capsule   Axons   Muscle fibers	MUSCLE SPINDLE INNERVATION (simplified) From: University of Glasgow

• General
  • Total: 50,000 spindles in body
  • Spindles are few or absent: Face muscles
  • Spindles common: Trunk muscle; Deep masseter; Hands
  • EOM: Different spindle structure
• Functions
  • Proprioceptive component of skeletal muscles
  • Sensitive to stretch
• Development
  • Initiation: Sensory axons contact immature muscle fibers → Induce differentiation
  • May require: LRP4; Ig-NRG1
• Structure
  • Muscle fibers
    • Nosology: Intrafusil
    • Anatomy
      • Fiber Numbers: 3 to 20
      • Length: Up to 8 mm in humans
      • Diameter: 8 to 25 μM
      • Contractile filaments
        • Mostly at polar regions
        • Central region: Subsarcolemmal distribution
    • Marker molecules
      • Myosin heavy chain: MYH3; MYH6; MYH7; MYH7B
      • Myosin light chain: MYL2; MYL3; MYL4; MYL6b; MYL10
      • Other: Myoz2; Tnni1; Tnnt1; Padi2
    • Types
      • Bag fibers
        • Central bag-like region with aggregate of nuclei
        • Can extend beyond capsule
        • Attached to intramuscular connective tissue
        • Express: MYH7 & MYH6
        • Bag1 fibers: Dynamic stretch response
        • Bag2 fibers: Static stretch response
      • Nuclear chain fibers
        • Uniform width
        • Chain-like array of nuclei
        • Attached to polar regions of nuclear bag fibers
        • Express: MYH3 & MYH8
        • Static stretch response
    • Differentiation factor: Egr3
    • Multiple innervation
  • Enclosure
    • Fusiform connective tissue capsule
    • Markers: Collagen IV; Collagen VI: Vcan; Sbspon; Efemp1; Postn
    • Vcan: Extracellular space between inner & outer capsule
    • Capsule cells
      • May secrete connective tissue
      • Markers: SLC2A1/GLUT1; Anpep; Gli1
      • SLC2A1: Present at outer regions of spindle capsule
      • Inner capsule cells: Similarities to endoneurial fibroblasts
      • Outer capsule cells: Express perineurial markers
  • Axons: Innervation
    • Motor
      • Innervation locations: Polar ends of intrafusil fibers
      • γ > β motor neurons (Small axon caliber)
      • Endings: Plate & Trail at polar regions of muscle fibers
      • Transmitter: Cholinergic
      • Induce contractions at polar ends of spindle fibers
    • Sensory: Muscle Spindle Afferents
      • Axon size:
      • Express α3 isoform of Na⁺/K⁺-ATPase
      • Innervation locations: Central region of intrafusil fibers
      • Markers
        • Piezo2; SLC17A7; ATP1A3
        • Subsets of afferents: Lmcd1 ; Runx1 ; Fxyd7 ; Calb2
      • Anatomic
        • IA afferents
          • One IA afferent fiber per spindle
          • Wrap around central region of intrafusil muscle fiber
          • Every intrafusal muscle fiber in spindle innervated by same IA neuron
          • Sensory terminals: Form irregular coils with branches & varicose swellings
        • 2 afferents
          • Flank 1A afferents: 1 or Both sides
      • Responses to stretch: 2 types
        • Dynamic (Phasic)
          • Afferents from: bag1 fibers
          • Respond to: Velocity of changes in muscle fiber length
        • Static (Tonic)
          • Afferents from: bag2 fibers; Chain fibers
          • Respond to: Amount of stretch
          • Encode length by: Frequency of firing
      • Terminals
        • Adhere to surface of intrafusal muscle fibres
        • Dystrophin: Absent in muscle membrane near regions of adherence
        • Stretch receptor potential components: Na⁺ (80%) & Ca⁺⁺ (20%)
        • Stretch receptor channels: Mechanotransduction
          • Piezo2
          • Possibly DEG/ENaC/ASIC
        • Contain vesicles
          • Activity regulated glutamate secretory system
          • Phospholipase D-coupled metabotropic glutamate (PLD-mGluR) receptor
      • Central Collaterals
        • Innervate motor circuits: In spinal cord & brainstem
        • Reflex pathways: Control alternation & coactivation of agonist & antagonist muscles
        • IA: Central connectivity to homonymous motor neurons that control activity of same muscle target

Gomori trichrome stain

Silver stain

VvG stain

Esterase stain

NADH stain

Babinski 1889

• Spindle loss
  • EGR3 deficiency
  • HSAN III
  • Cytoplasmic dynein heavy chain 1 (DYNC1H1) deletion
  • BAX mutation
  • NT-3 knockout
• Spindle excess
  • Congenital Myopathy with Muscle Spindle Excess
    • Noonan phenotype: Increased number of spindles ¹¹
  • NT-3 Over-expresion (Mice): Increased number of spindles
  • Myostatin null
• Spindles abnormal
  • Myotonic dystrophy: Increased number of intrafusil muscle fibers per spindle:
    • Up to 140 fibers reported
    • More in: Distal muscles; Polar regions
    • Fibers may all be type 1
  • Focal myositis
    • Increased connective tissue in, and around, spindles
• Spindle innervation: Overactivity during development
  • DA5E
• Stretch-evoked responsiveness in muscle spindles
  • Whirlin mutations: Reduced responsiveness

Axon: Caliber

• Axon diameter: Related to Neurofilament content
  • Amount: More neurofilaments in larger axons
  • Degree of phosphorylation
    • Decreased phosphorylation: Neurofilaments more densely packed
    • Increased phosphorylation: Side arms spread; Neurofilaments more widely spaced
  • Myelination: Effects on neurofilaments
    • Axons narrower in regions without myelin: Initial segment; Node of Ranvier
    • Unmyelinated axons have more densely packed neurofilaments
• Size principles
  • Large motor neuron
    • Large axon
    • Myelin: Thick; Long internodes
    • Fast conduction velocity
    • High threshhold to depolarization
    • Type II muscle fibers innervated
    • Voluntary contraction: Activated with large effort
  • Small motor neuron
    • Small axon
    • Myelin: Thin; Short internodes
    • Slow conduction velocity
    • Low threshhold to depolarization
    • Type I muscle fibers innervated
    • Voluntary contraction: Activated first
  • Sensory axons
• Unmyelinated axons
  • Properties
    • Diameters
      • Range: 0.1 to 3 μM
      • Normal adults: 0.5 to 1.5 μM
      • Older adults: More smaller diameter unmyelinated axons
    • No myelin
    • Fewer neurofilaments than larger axons
    • Numbers
      • Unmyelinated to Myelinated = 4 to 1 in sural nerve
      • Range: 17,000 to 49,000/mm²
      • Age relation: More in children than adults
    • CNS: No unmyelinated axons
  • Non-Myelinating Schwann cells (NM-SC)

    Length: 200 to 500 μM Age associations: Axons/Schwann cell Neonates: Numerous 6 months: 2 to 6 Adults: 1 or 2 Axon sprouts: > 3 Axon length associations Nuclei separated by < 90 μM Junctional complexes between neighboring cells Cutaneous nerves: Fewer NM-SC near terminals C-fibers: Lose NM-SC in epidermis Single axons may exchange among Remak bundles Single NM-SC may ensheath sensory & sympathetic axons NM-SC Components NM-SC locations in PNS Unmyelinated axons Neuromuscular junction: Terminal Schwann cells (Teloglia) Sensory transducers: Pacinian & Meissner’s corpuscles Satellite cells of sensory & autonomic ganglia NM-SC pathology Anatomy NM-SC may proliferate Response to neighboring pathology Demyelination Wallerian degeneration

  • Remak fibers (History): Unmyelinated axons + Non-myelinating Schwann cells
    • Identified by Robert Remak in 1838 ⁹ (fibrae organicae)
      • External link
    • Anatomy
      

      J Physiol 1896; 19:267–311

Axon: Conduction & Velocity (CV) ¹⁵

• CV: Normal Ranges
  • Myelinated axons, Large: 35 to 75 M/s
  • Myelinated axons, Small: 20 to 35 M/s
  • Unmyelinated axons: 0.1 to 5 M/s
• Saltatory CV: Mechanisms
  • Action current
    • Inward
    • Ionic: Na⁺ channels
    • Location: Node of Ranvier
  • Driving current
    • Capacitative
    • No ion flow
    • Generated when
      • Voltage-gated Nav 1.6 channels at previous active node open
      • Generates inward Na⁺ ion current
      • + Charge then flows along axon → Depolarizes next node
    • Result: Opening of Nav 1.6 channels at the next node
    • Terminated by: Delayed K⁺ efflux from axon
  • Action potential direction
    • From: Node with Action curent (Generates action potential)
    • To: Node with Driving current
  • Conduction time between successive nodes of Ranvier
    • Mainly due to: Time for node to reach threshold to generate action potential
      • Normal = ~ 25 μs
      • Demyelination
    • Internodal conduction: Virtually instantaneous
  • Parameters
    • Safety factor: Driving current/Threshold = 5 to 10
    • Conduction failure: Driving current/Threshold < 1
• Saltatory CV speed (Myelinated axons): Related to
  • Axon diameter: Proportional
    • 5.7 x Diameter = Conduction Velocity
    • Larger diameter axons: Conduct at faster velocities
    • Axon atrophy: Reduces rate of axonal conduction
  • Myelin thickness
    • Myelin layers "insulate" axon: Depolarization occurs only at nodes of Ranvier
    • Produces rapid saltatory conduction: Current jumps from node to node
    • Large diameter myelinated axons: Longer internodal segments; Faster conduction velocity
    • Thickly-myelinated fibers conduct more rapidly
    • Maximal velocity: g-ratio = 0.6 to 0.7
    • Failed impulse propagation
      • g-ratio > 0.95
      • Myelin thickness < 3% to 4% of normal
  • Internode length/Axon diameter
    • Optimal ratio: 100
  • Warming: Increases conduction velocity
    • Facilitates activation & inactivation of sodium conductance
    • Lowers amplitude of action potential
    • Increases rate of transmission
    • NCV: Increases by 1.5 to 2.5 m/s per 1°C
    • Distal motor latencies: Decrease by 0.2 m/s per 1°C
  • Development & Age
    • Birth: Conduction velocities 50% of adult values
    • 1 year of age: Conduction velocities 75% of adult values
    • 3 to 5 years of age: Conduction velocities 100% of adult values
    • Adults: Decrease slightly with age
      • Especially > 60 years
      • 0.5 to 4 m/s per decade
      • Age effect more for sensory than motor axons
  • Other factors
    • Height: Slower with increased height
    • Proximal nerve segments: Faster
• Demyelination/Myelin pathology: Reduces rate of impulse conduction along axon
  • Driving current leaks: Diluted over a larger area in nodal region
  • Membrane transverse resistance: Decreased
  • Exposure & activation of juxtaparanodal K⁺ voltage gated channels
  • Membrane potential shifts toward more negative values
  • Increased time for node to reach threshold for generating an action potential: Outcomes
    • Conduction velocity slowing: Time up to 600 μs
    • Conduction failure: Safety factor < 1
  • Electrophysiologic features of peripheral myelinopathies
    • Conduction velocity: Slow
    • Distal motor latencies: Prolonged
    • CMAPs: Temporal dispersion
    • Conduction block
• Hereditary Myelinopathies

Axon: Transport ⁴

• General substrates
  • Axons & Dendrites
    • Microtubules
      • Formed from association of dimers of α-tubulin and β-tubulin into protofilaments
      • Protofilaments: Associate laterally to form a tubule
      • Growth of polymer: Addition of tubulin subunits to plus end of filament
      • Shortening of polymer: Subunit loss
      • Dampening of microtubule dynamics in neurons: Microtubule-associated proteins (e.g., tau)
      • Polarity of plus (Fast growing) end
        • Axon & Distal dendrites: Distal
        • Proximal dendrites: Mixed
      • Microtubule orientation in proximal axon
        • Determined by TRIM46
      • Role in: Axon elongation & growth
      • Disorders
    • Motor molecules
    • Neurofilaments: Disorders
  • Synaptic regions (Pre- & Post-)
    • Actin filaments: Barbed (Growing) end points to plasma membrane
• Outward (Anterograde) direction ¹²
  • Cargos
    • General
      • Transport speed may be related to proportion of time that cargo-structures spend moving
    • Rapid transport (20 to 400 mm/day)
      • mRNA: 20–200 mm per day
      • Golgi-derived vesicles (containing neurotransmitters): 200–400 mm/day
      • Neurosecretory granules (contain hormones or neurotrophic factors): 50–400 mm/day
    • Intermediate transport (2 to 8 mm/day; SCb): Cytosolic proteins
      • Membrane proteins
      • Enzymes
      • Proteins: Independent mechanisms
        • Actin: Transport mechanism involves local assembly & biased polymerization; No relation to microtubules
        • Synapsin: Anterogradely biased flow
        • Clathrin: Particles move intermittently & frequently, with overall anterograde bias
    • Slow transport (0.2 to 1.0 mm/day; via Hsc70 binding protein; SCa): Cytoskeletal proteins
      • Neurofilaments
      • Tau
      • Tubulin
    • Bidirectional (< 50 mm per day)
      • Mitochondria
      • Lysosomes
  • Motor molecules: Kinesins
    • Kinesin domains
      • Motor domains
        • Bind to microtubule
        • Kinesin heavy chain
        • Move on microtubules by hydrolyzing ATP
      • Tail regions
        • Recognize & bind to cargo
        • Kinesin light chain
    • Kinesin molecules
      • KIF1A
        • Binding proteins: DENN/MADD; Liprin-α
        • Cargo functions: Synaptic vesicle precursor
      • KIF1Bα
        • Binding protein: KBP
        • Cargo: Mitochondria
      • KIF1Bβ
        • Binding proteins: DENN/MADD; Liprin-α
        • Cargo functions: Synaptic vesicle precursor
      • KIF1C
        • Functions
          • Migration of neurons & other cells during development
          • Anterograde movement of secretory vesicles in young neurons
          • Binding protein: KBP
        • Disease: SPAX2
      • KIF2A
        • Cargo: Vesicles
        • Cargo functions: Microtubule depolymerizer
      • KIF3A
        • Binding protein: Fodrin
        • Cargo: Plasma membrane precursor; N-cadherin; K_v channel
      • KIF4A
        • Binding protein: PARP-1
        • Cargo: Menbranous organelles
        • Cargo function: Neuronal survival
      • KIF5A (Neuron specific)
        • Plus-end–directed microtubule motor
        • Involved in anterograde transport of membranous organelles in axons
        • Expression: Only in neurons
        • Binding proteins: JIP-1; JIP-2; JIP-3; APP; Syntabulin; Milton-Miro complex; TRAK1
            GRIP; Slp-Rab27B; HAP1; Huntingtin; LIS1-NUDEL complex; mNUDC; Myosin Va; HSC70
        • Cargos: Vesicles; Mitochondria; Dynactin complex; Slow transport molecules (Neurofilaments; Tubulin)
        • Slow axonal transport
          • Cargo: Tubules; Neurofilaments; Other soluble proteins
          • Mechanisms
            • KLC (In KIF5 motor complex): Contains DnaJ-like domain tetratricopeptide repeat that interacts with Hsc70
            • Hsc70: Forms scaffolding between cytoplasmic proteins & KIF5 motor complex
            • Complex may function as switch between slow & fast transport
        • Axonal protein synthesis
          • KIF5 recognizes mRNA-containing protein complexes (mRNPs)
        • Axons vs Dendrites
          • KIF5 motor domain specifically recognizes axonal microtubules
          • Paclitaxel: Eliminates specificity of axonal recognition
        • Disorder: SPG10
      • KIF13B (GAKIN)
        • Binding protein: PIP3BP
        • Cargo: PIP3 vesicles
        • Involved in neuronal polarization to axons
      • KIF17
        • Binding protein: Mint
        • Cargo: NR2B vesicles
        • Dendrite specific
      • KIF20A
        • Disease: Restrictive Cardiomyopathy 6 (RCM6)
      • KIF26A
        • Binding protein: Grb2
        • Cargo function: Inhibition of GDNF-Ret signaling
      • KIFC2
        • C-terminal motor domain KIF
        • Location: Neuronal dendrites
        • Moves on microtubules toward their minus ends (Similar to cytoplasmic dynein)
        • Cargo: Multivesicular-body-like organelle
    • Kinesin disorders
• Inward (Retrograde) direction
  • Disorders
  • Cargos
    • Organelles
      • Degradative
        • Lysosomes: Bidirectional; < 50 mm/day
        • Autophagosomes: 40 mm/day
      • Endosomes: 200 mm/day
        • Recycling vesicles
        • Contain signaling platforms from nerve terminals, hormones or trophic factors
    • Exogenous molecules
      • Viruses: 200 mm/day
      • Tetanus toxin: 100 to 400 mm/day
      • Horseradish peroxidase: 200 mm/day
  • Molecule classes involved in retrograde transport: Dynein/Dynactin
    • Dynein
      • Primary motor
      • Microtubule-activated ATPases
      • Move along microtubules by hydrolyzing ATP
      • Cytoplasmic subtype
      • Large complex
        • 2 heavy chains
          • ATPase activity
          • Generate movement along the microtubules
        • 2 intermediate chains
        • 4 intermediate light chains
        • Several light chains
      • Associated with: Endosomes
      • Regulates: Protein degradation; Signal transduction
    • Dynein Cytoplasmic 1, Heavy chain 1 (DHC1) associated molecules
      • Dynactin: Protein complex
        • DCTN1 (p150^Glued)
        • Sequestosome 1 (SQSTM1; p62)
        • Dynactin 2 (DCTN2; Dynamitin) : Binds to Cargos (Vesicles & Mitochondria)
        • Actin-related protein 1 (ACTR1A; Arp1)
        • CAPZa
        • CAPZb
        • Cyclin-dependent kinase inhibitor 1B (CDKN1B; p27)
        • Tubulin polymerization-promoting protein (TPPP; p24)
      • Lis1 (PAFAH1B1)
        • Facilitates anterograde transport of cytoplasmic dynein
        • Associated with: Neuronal migration
      • Ndel1
      • Huntingtin-Associated Protein (HAP1)
        • DHC1 binding protein
        • Cargo: BDNF vesicles
      • Gephyrin (GPHN)
        • DHC1 binding protein
        • Cargo: Glycine receptor
      • Rab-interacting lysosomal protein (RILP)
        • Interacts with: RAB7
        • Cargo: NGF-TrkA signaling endosome; p75; TrkB
        • Controls: Late endocytic transport
      • Bassoon
        • Binding protein
        • Cargo: Active-zone-protein vesicles
        • Function: Vesicle reloading at active zones
      • Neurotrophin receptors
      • Cdk5
  • Retrogradely transported injury signals
    • Activate cell-intrinsic regeneration program via transcription factors
    • Molecules
      • Phosphorylated cJun N-terminal kinase (JNK)
        • Activates AP-1 transcription factor c-Jun
      • Dual leucine zipper kinase (DLK; MAP3K12) ⁶
        • Required for retrograde transport of injury signal
        • Activates intrinsic axon regeneration program
        • Cellular mechanisms
          • Supports growth cone performance, not formation
          • Role in stimulus to axon growth of preconditioning injury
          • Regulates retrograde transport of: STAT3 ; JIP3 (MAPK8IP3) ; p-JNK
• Synaptic regions: Transport
  • Substrate: Actin filaments under plasma membrane
  • Primary motors: Myosins
    • Myosin Va (MYO5A)
      • Localization: Postsynaptic density & vesicle fractions in brain
      • Binding proteins: FIP-Rab11; NF-L
      • Cargo: AMPA receptor (GluRI) vesicles; Neurofilaments; Secretory granules; mRNA-protein (mRNP) complex
    • Myosin Vb (MYO5B)
      • Binding proteins: FIP-Rab11
      • Cargo: AMPA receptor (GluRI) vesicles
    • Myosin VI (MYO6)
      • Retrograde motor
      • Binding proteins: GIPC1; AP2-SAP97
      • Cargo: BDNF-TrkB signaling endosome; AMPA receptor vesicles (Internalization)
    • Myosin X (MYO10)
      • Intrafilopodial transport
      • Binding proteins: Neogenin, DCC
      • Cargo: Netrin receptors; Intrafilopodial vesicles
• Disorders: Axon transport-related
  • Tubulin
    • Hereditary disorders:
      • TUBA1A (α1A- Tubulin) : Lissencephaly 3 ; Spastic-Ataxia; CFEOM
      • TUBA4A: ALS 22
      • TUBA8 (α8- Tubulin): Complex cortical dysplasia with other brain malformations 8 (CDCBM8)
      • TUBB (β-Tubulin) : Complex cortical dysplasia with other brain malformations 6 (CDCBM6)
      • TUBB1 : Macrothrombocytopenia
      • TUBB2A : Complex cortical dysplasia with other brain malformations 5 (CDCBM5)
      • TUBB2B : Polymicrogyria (CDCBM7)
      • TUBB3 : CFEOM 3A ; Cortical dysplasia (CDCBM1)
      • TUBB4A : Leukoencephalopathy (H-ABC; HLD6); DYT4
      • TUBB4B : Sensorineural deafness; Leber congenital amaurosis with early-onset deafness (LCAEOD)
      • TUBB6: Facial palsy, congenital, with Ptosis & Velopharyngeal dysfunction (FPVEPD)
      • TUBBG1 (γ1-Tubulin) : Complex cortical dysplasia with other brain malformations 4 (CDCBM4)
    • Immune neuropathy: IgM vs β-tubulin (Demyelinating neuropathy)
    • Toxic neuropathy: Podophyllotoxin; Paclitaxel; Vincristine
  • Microtubule modulators
    • HSPB1: CMT 2F
      • Affected process: Microtubule acetylation
    • HSPB3: HMN 2C
    • HSPB8: CMT 2L
    • Spastin: Spastic paraplegia 4 (SPG4)
    • Atlastin 1: SPG3A
      • Functions altered: Endoplasmic reticulum to Golgi transfer; Spastin binding
    • VAPB: ALS8
      • Functions altered: Endoplasmic reticulum to Golgi transfer
    • Androgen receptor (AR): BSMA
      • Affected process: Kinesin binding to microtubules
    • Tubulin-specific chaperone E (TBCE) : Hypoparathyroidism-retardation-dysmorphism syndrome
    • Tau tubulin kinase 2 (TTBK2) : Spinocerebellar ataxia 11 (SCA11)
    • LMNA: AR-CMT2A
    • TRPV4: CMT 2C; HMN8; SPSMA
    • LRRK2 : Parkinson disease 8
    • Presenilin 1 (PSEN1)
      • Disease: Alzheimer disease 3 ± Spastic paraparesis
      • Affected processes
        • Microtubule stabilization: Through GSK3β activation
        • Cargo binding to motor proteins
    • Microtubule-associated protein tau (MAPT)
      • Diseases
        • Dementia, frontotemporal (FTD)
        • Pick disease
        • Supranuclear palsy, progressive or atypical
        • Tauopathy & Respiratory failure
        • Parkinson disease, susceptibility
      • Affected processes
        • Microtubule stabilization
        • Motor protein binding to microtubules
        • Cargo binding to motor proteins
  • Dynein/Dynactin complex: Retrograde transport machinery
    • BICD2: SMALED2A
    • DCTN1: Hereditary motor neuropathy 7B; Perry syndrome
    • DCTN2 : Over-expression causes mouse motor neuron disease
    • DYNC1H1: CMT 2O; SMA-LED
    • DYNC2H1 : Short-rib polydactyly 3 ; Asphyxiating thoracic dystrophy 3
    • GPHN : Molybdenum cofactor deficiency, type C (MOCODC)
    • Lis1 (PAFAH1B1) : Lissencephaly1; Subcortical laminar heterotopia
    • NudE neurodevelopment protein 1 (NDE1) : Microhydranencephaly (MHAC) : Neurodevelopmental Lissencephaly 4 (LIS4) with microcephaly
    • SQSTM1: ALS predisposition
  • Kinesins
  • Transport cargos
    • Neurofilaments
      • Toxins
        • Reduced anterograde transport (Proximal NF accumulation): ββ'-IDPN; Aluminum salts
        • Increased anterograde transport (Distal NF accumulation): 2,5-Hexanedione, Carbon disulfide (CS₂)
      • Hereditary
        • NEFL: CMT 1F; CMT 2E; AR-CMT (CMT 2B5)
        • NEFH: ALS
        • HSPB1: CMT 2F
          • Affected process: Neurofilament transport
        • SOD1: ALS1
          • Affected process: Neurofilament phosphorylation & binding to motor proteins
    • WNK1: Hereditary Sensory Neuropathy II (HSAN II)
    • Mitochondria
      • MFN2: CMT 2A2
      • E3 ubiquitin-protein ligase parkin (PRKN) : Parkinson, juvenile, recessive (PARK2)
      • Serine/threonine-protein kinase (PINK1) : Parkinson, early onset, recessive (PARK6)
      • Oncogene DJ1 (PARK7) : Parkinson, early onset, recessive (PARK7)
      • ARS
        • AARS: CMT2N
        • GARS: CMT2D
        • HARS: CMT2W
        • KARS: CMTRIB
        • MARS: CMT2U
        • YARS: CMTDIC
      • Polyneuropathies, Other
    • Endosomal & Vesicle trafficking
      • Alsin: ALS2; Infantile onset spastic paraparesis (IAHSP)
      • DNM2: CMTDIB; CMT 2M; CNM; LCCS5
      • GAN: Giant Axonal Neuropathy 1
      • Maspardin (ACP33): SPG21
      • NIPA1: SPG6
      • Protrudin (ZFYVE27): SPG33
      • RAB7: CMT 2B
      • Receptor expression-enhancing protein (REEP1): SPG31
      • Spastizin (ZFYVE26): SPG15
      • SPG11: CMT 2X; SPG11; ALS 5
      • VAPB: SMAFK; ALS8
    • APP
      • Disorders: : Alzheimer ; Amyloid angiopathy
      • Undergoes axonal transport
      • Related to retrograde transport of NGF
    • α-synuclein (SNCA) : Parkinson disease (PARK1)
  • Actin interactions
    • PFN1: ALS 18
  • Cargo modulators & adaptors
    • Androgen receptor: X-linked Bulbospinal Muscular Atrophy (Mutant blocks axonal transport)
    • Huntingtin : Huntington disease (Mutant blocks transport of BDNF)
    • Jip1 (MAPK8IP1) : ?? Diabetes mellitus, noninsulin-dependent
  • Myosins
  • Also see: Disorders with axonal swellings

Motor Unit Action Potentials (MUAP)

• Duration
  • Normal: 5 to 15 ms
  • Proximal & Bulbofacial muscles: Shorter
  • Lower temperature: Longer
  • Increasing age: Larger
    • Children vs Adults: Due to increased size of muscle fibers
    • Young vs Old Adults: Due to loss of motor units (~1%/yr) with aging
• Amplitude
  • Normal: 100 μV to 2 mV
• Stable: From potential to potential
• Firing pattern
  • Normal: 7 to 15 Hz; All faster than 4 to 5 Hz
  • Firing frequency/#MUAPs firing = 5:1

Dorsal Root Ganglion

• DRG: Neural crest
  • Time: During early embryogenesis
  • Other neural crest cells: Schwann; Cranial sensory ganglion; Sympathetic & Enteric autonomic
  • DRG cells
    • Initially bipolar
    • Central process grows into root
    • Peripheral process enters segmental nerve
    • Proximal regions of axons eventually coalesce: Forms pseudounipolar configuration
• Perineurial sheath cells: Mesenchymal fibroblasts

• Location: In intervertebral formation; Region where dorsal & ventral roots merge
• DRG ganglion cells
  • Size
    • 10 μM to 100 μM
    • 2 classes: Large clear cells; Small dark cells
  • Location: Clustered around sensory fiber fascicles
  • Proximal axon configuration: Often coiled in glomerulus-like configuration
  • Single ganglion cells may give rise to several peripheral axons
  • Associated with 4 to 6 satellite cells surrounding DRG cell body
  • DRG cells & satellite cells surrounded by basal lamina
• Perineurium & epineurium continuous with dura
  • Region where roots enter spinal canal
  • Traction injuries produce avulsion of roots from cord
• Blood supply
  • From segmental arteries
  • Capillaries in ganglion are fenestrated: Lower barrier to diffusion than blood nerve barrier

• Primary afferents synapse in dorsal gray of spinal cord: Secrete excitatory neurotransmitteers
• Possible neurotransmitters: Numerous
  Glutamate; Aspartate; Substance P; Somatostatin; VIP; Cholecystokinin;
  Angiotensin II; Bombesin; CGRP; Nerve growth factor; Other neurotrophins

• Cutaneous Mechanoreceptors
  • Axons: Large Aβ
  • Termination: Laminae III, IV, V, VI (dorsal)
  • Channels
• Cutaneous Nociceptors
  • Axons: Aδ; C
  • Termination: Laminae I & II
• Temperature: Ranges & Correlations

  Skin Temperature	< 15°C Noxious Cold		15°C to 30°C Innocuous Cold		30°C to 43°C Innocuous Warm		> 43°C Noxious Heat
  Skin Sensation	Cold Pain	Burning	Cold	Cool	Warm	Hot	Burning	Heat Pain
  				Thermal Comfort
  Afferent Neurons	Cold Nociceptive Other stimuli   Heat   Mechano, Nociceptive		Cool   Other stimuli   Menthol   Heat, Noxious		Warm		Heat Nociceptive FGF13/Nav1.7 complex TRPV1
  CNS Motor	Protective						Protective

• Temperature: Cold
  
  • Axons
    • Types: Aδ; C
    • Small-diameter myelinated (Aδ) in primates
  • Neurons
    • Dorsal Root Ganglion: Small; Average cell body diameter 15 μm
    • Lamina I: Pyramidal cells
    • Activity: Ongoing at temperatures between 10°C & 42°C
  • Stimuli
    • Cooling
      • Activation: Innocuous cold (5°C to 10°C)
      • Inhibition: Warm
    • Menthol
      • Enhances cool sensation of mild low temperatures
      • Receptor: TRPM8
        • Voltage-dependent gating cold-sensitive channel
        • Transient receptor potential (TRP) family
        • TRPM8 Channel counterbalance
          • Shaker-like Kv1.1-1.2 channels of excitability brake I_KD
    • Capsaicin: Stimulates cold-sensitive polymodal nociceptors
    • Also see: Cold allodynia
    • Other
      • Noxious heat
      • Mechano-insensitive
  • Molecular mechanisms ¹
    • Channels
      • Cooling-gated ion channels: TRPM8
      • K⁺ channels on unmyelinated axons
      • Na⁺ channels on A fibers
    • Cooling closes a background K⁺ channel
      • Causes depolarization & axonal firing
      • Firing secondarily increases [Ca⁺⁺]_i
      • Identity of specific inhibited K⁺ channel not defined
    • Axon firing: Limited by slower reduction of cationic inward current (I_h)
    • Cold-insensitive neurons
      • Firing is prevented by a slow, transient, 4-AP-sensitive K⁺ current (IK_D)
      • Acion: Excitability brake
      • Pharmacological blockade of IK_D
        • Induces thermosensitivity in cold-insensitive neurons
    • Cold allodynia
  • Physiology
    • Highly excitable
    • Time-dependent inward rectification during hyperpolarizing current pulses
    • Rebound firing at the end of hyperpolarizing pulses
• Temperature: Heat
  • Axons
    • C
    • Unmyelinated
    • Density of innervation: Lower than cold-sensitive
  • Ongoing
    • Steady state: Between 30°C & 40°C
    • Maximal activity: 44°C to 48°C
  • Stimuli
    • Warm
    • Capsaicin
    • Mechanoinsensitive
  • Receptors
    • Capsaicin/Heat receptor: VR1/TRPV1
    • Warm: TRPV3/TRPV4 (VRL-2)
  • Noxious Heat: Related channels
    • TRPM3
    • TRPV1
    • TRPA
• Deep somatic & viscera afferents
  • Axons
    • Unmyelinated
    • Terminate in laminae I & V of spinal cord
  • Stimuli: Warm; Mechanosensitive
• Muscle afferents
  • Axons: Aα; Aβ
  • Distal Termination
    • Spindles, primary endings (Aα): Laminae VI; VII
    • Spindles, secondary endings (Aβ): Laminae Iv; V; VI; VII; IX
    • Golgi tendon organs (Aα): Laminae V; VI; VII
• Central terminations
  • Myelinated afferents (Aβ/δ) conveying innocuous mechanoreceptive information: Laminae IIi–V
  • Myelinated afferents (Aβ/δ) conveying noxious mechanoreceptive information: Laminae I & V
  • Unmyelinated afferents, often noxious stimuli: Lamina I & IIo

Temperature Sensing Channels ³

Ion channel	Activating temperature	Activators
VRL-1 (TRPV2)	53 °C	Noxious heat
VR1 (TRPV1)	45 °C	Noxious heat Capsaicin pH < 5.9 Vanilloids Endocannabinoids
TRPV3/TRPV4 (VRL-2)	30 to 40 °C	Warm
TRPM3 TRPV1 TRPA1	> 41 °C	Noxious heat
CMR1/TRPM8	< 25 °C	Cold Menthol
TRPA1 (ANKTM1)	< 17 °C	Noxious cold Icilin
See Transient receptor potential (TRP) channels Pain

Mechanotransduction Channels ⁵

• Non-selective depolarizing (SAC)
  • Stretch-activated
  • Ions: Permeable to Na⁺, K⁺, Mg⁺⁺ & Ca⁺⁺
  • Channels
    • Piezos, General ¹⁴
      • Tetramers
      • Rapid kinetics of activation
    • Piezo1 (FAM38A)
      • Inhibition by: Ruthenium red, Gadolinium, Spider toxin GsMTx4
      • Conductance: 10-fold higher than Piezo2
      • Inactivation rate: Voltage-dependent; Slows with depolarization
      • Diseases
        • Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema : Dominant
        • Lymphedema, hereditary, III : Recessive
    • Piezo2 (FAM38B)
      • Function: Proprioception
      • Location: Muscle spindle & Golgi tendon organ afferents
      • Current: Rapid activation
      • Inhibition by: Ruthenium red, Gadolinium
      • Inactivation rate: Voltage-dependent; Slows with depolarization; Faster than Piezo1
      • Expressed by: Merkel cells; SA1 Aβ-axons
      • Modulates conversion of touch to itch via Merkel cells
      • Diseases
• Hyperpolarizing K⁺ channels (SAK)
  • Ions: K⁺ selective
  • Hyper/Repolarizing
  • Stretch-activated
  • Channels: KCNK class
    • KCNK2 (TREK-1)
    • KCNK10 (TREK-2)
    • KCNK4 (TRAAK)

Remak: 1st description of non-myelinated fibers (axons) ⁹