The Spinal Cord
In the spinal cord, MNs are organized into columns (Table 1) based on the location of their target muscle [reviewed in Matise and Sharma (2013) and Stifani (2014)]. Within each column, the MNs innervating each muscle are clustered into motor pools, each containing of 20–300 cells depending on the muscle (Bryan et al., 1972; McHanwell and Biscoe, 1981). α-MNs located in the spinal cord are archetypal MNs that innervate extrafusal muscle fibers, thus creating force to move the skeleton (Table 2). In contrast, γ-MNs innervate intrafusal fibers, which modulate the sensitivity of muscle spindles to stretch (Table 2) (Hunt and Kuffler, 1951; Kuffler et al., 1951; Kanning et al., 2010). β-MNs are not as well characterized as α-MNs but they innervate both intrafusal and extrafusal muscle fibers (Bessou et al., 1965). Both α and γ-MNs have large dendritic trees but γ-MNs have fewer large dendrites than α-MNs (7–11) and they also branch less (Westbury, 1982). The somas of γ-MNs are smaller than those of α-MNs and they also possess thinner axons, which reflects their slower conduction velocity (<55 m/s in γ-MN vs. ∼70–90 m/s in α-MNs in cats) (Table 2) (Westbury, 1982). γ-MNs receive only indirect sensory inputs. Therefore, γ-MNs do not directly participate in spinal reflexes (Eccles et al., 1960; Stifani, 2014), but they contribute to the modulation of muscle contraction instead.
Table 1  Segmental organization of spinal cord columns.
Pools of MNs that innervate muscles of similar embryonic origin are stereotypically localized within the ventral spinal cord, known as motor columns. The medial motor column (brown) is present in the whole spinal cord and it comprises MNs that innervate the long muscles of the back and the body wall musculature. The spinal accessory column (purple) and the phrenic column (red) are found along the five first cervical segments (C1 to C5) and between C3 and C5, respectively. The preganglionic column (yellow) extends from the first thoracic segment (T1) to the second lumbar segment (L2), and between sacral segments 2 and 4 (S2 to S4) where the Onuf’s nuclei (∗) are found. MNs in the preganglionic column innervate neurons of the sympathetic ganglia. The hypaxial motor column (blue) is restricted to the thoracic spinal cord (T1 to T12). The lateral motor column (green), connected to the limbs, comprises the cervical and thoracic spinal cord (from C5 to T1) and the lumbar spinal cord (L1 to L5).
Table 2  Comparison of α- and γ-spinal motor neurons.
Spinal α-MN  Spinal γ-MN
Target muscle fiber  Extrafusal1  Intrafusal1
Soma size  Larger2,3,4,5  Smaller2,3,4,5
Axon diameter  Larger2  Thinner2
Dendrite branching  More2  Less2
Motor unit size (innervation ratio)  Larger6  Smaller6
Membrane input resistance  Larger7  Smaller7
Firing  Subtype-dependent8  Subtype-dependent8
Axon conduction velocity  Faster2,7,9  Slower2,7,9
Afterhyperpolarization duration  Subtype-dependent7,9  Variable7,9
Spinal reflex  Yes10  No10
Affected in ALS  Yes11,12  Less11,12
Affected in aging  Yes13,14  No13,14
Markers  Osteopontin15RBFOX3/NeuN16Hb9::GFP5NKAα117 (adult)  Err316Weak NeuN5,16NKAα317 (adult)ESRRG16GFRα15HTR1D18 (early marker)WNT7A19 (late embryonic stage)
ESRRG, estrogen-related receptor gamma; GFRα1, GDNF family receptor alpha 1; HTR1D, serotonin receptor 1D; NAKα1/3, Na+/K+-ATPases 1/3; RBFOX3, RNA binding protein fox-1 homolog 3. 1(Kuffler et al., 1951), 2(Burke et al., 1977), 3(Westbury, 1982), 4(Friese et al., 2009), 5(Shneider et al., 2009), 6(Adal and Barker, 1965), 7(Kemm and Westbury, 1978), 8(Murphy and Martin, 1993), 9(Gustafsson and Lipski, 1979), 10(Eccles et al., 1960), 11(Mohajeri et al., 1998), 12(Lalancette-Hebert et al., 2016), 13(Swash and Fox, 1972), 14(Hashizume et al., 1988), 15(Misawa et al., 2012), 16(Friese et al., 2009), 17(Edwards et al., 2013), 18(Enjin et al., 2012), 19(Ashrafi et al., 2012). A distinct group of MNs in the sacral spinal cord termed ‘Onuf’s’ neurons, innervate the striated muscles of the external urethra, external anal sphincter via the pudental nerve, and the ischiocavernosus and bulbocavernosus muscles in males (Sato et al., 1978; Nagashima et al., 1979; Kuzuhara et al., 1980; Roppolo et al., 1985). These MNs are histologically similar to limb α-MNs (Mannen et al., 1977) and they are located anteromedial to the anterolateral nucleus and extend between the distal part of the S1 segment and the proximal part of S3.
α-motor units can be subdivided according to their contractile properties, into fast-twitch (F) and slow-twitch (S) fatigue-resistant types (Table 3) (Burke et al., 1973). In addition, fast-twitch α-motor units can be further categorized into fast-twitch fatigable [FF] and fast-twitch fatigue-resistant [FR] types, based on the length of time they sustain contraction. The basis of this classification is the duration of the twitch contraction time (Burke et al., 1973). F- and S-MNs also exhibit different afterhyperpolarization duration (AHP) properties. AHP is the phenomenon by which the membrane potential undershoots the resting potential following an action potential. S-MNs have a longer AHP than F-MNs, indicating that S-MNs have a longer “waiting period” before they can be stimulated by an action potential. Thus, they cannot fire at the same frequency as F-MNs (Eccles et al., 1957), so the larger FF-MNs take longer to reach an activation threshold. Similarly, other electrical properties differ between S- and F-MNs (Table 3), including their input resistance (a measure of resistance over the plasma membrane) and rheobase (a measure of the current needed to generate an action potential). S-MNs have a higher input resistance than F-MNs, underlying Hennenman’s size principle which postulates that S-motor units are the first to be recruited during movement, followed by FR and then FF units (Henneman, 1957; Mendell, 2005). Hence, a slow movement generating a small force will only recruit S-MNs, whereas a quick and strong movement will also recruit F-MNs, as well as S-MNs.
Table 3  Comparison of fast (FF, fast-fatigable; FR, fast-resistant) and slow (S) spinal α-motor neurons.
Spinal α-MN
F  S
Target muscle fiber  IIb (FF), IIa (FR)1  I1
Soma size  Similar2,3,4,5,6  Similar2,3,4,5,6
Axon diameter  Larger7,8  Thinner7,8
Dendrite branching  More4,9  Less4,9
Motor unit size (innervation ratio)  Larger1,10  Smaller1,10
Membrane input resistance  Smaller11,12,13  Larger11,12,13
Firing  Phasic14,15  Tonic14,15
Axon conduction velocity  Faster1,13  Slower1,13
Afterhyperpolarization duration  Shorter14  Longer14
Recruitment  Late15  Early15
Affected in ALS  Early16,17,18  Late16,17,18
Affected in aging  Early19,20,21  Late19,20,21
Markers  CHODL22 CALCA22  SV2a23 SK324 ESRRB22 (adult)
CALCA, calcitonin-related polypeptide alpha; CHODL, chondrolectin; SV2A, synaptic vesicle glycoprotein 2a; SK3, postsynaptic Ca2+-activated K+ 3; ESRRB, estrogen-related receptor beta. 1(Burke et al., 1973), 2(Kernell and Zwaagstra, 1981), 3(Burke et al., 1982), 4(Cullheim et al., 1987), 5(Vinsant et al., 2013), 6(Hadzipasic et al., 2014), 7(Burke et al., 1977), 8(Dukkipati et al., 2018), 9(Ulfhake and Kellerth, 1981), 10(Burke and Tsairis, 1973), 11(Bakels and Kernell, 1993), 12(Gardiner, 1993), 13(Zengel et al., 1985), 14(Eccles et al., 1957), 15(Zajac and Faden, 1985), 16(Frey et al., 2000), 17(Hegedus et al., 2007), 18(Pun et al., 2006), 19(Hashizume et al., 1988), 20(Kadhiresan et al., 1996), 21(Kanda and Hashizume, 1989), 22(Enjin et al., 2010), 23(Chakkalakal et al., 2010), 24(Deardorff et al., 2013). In addition, at least eleven types of interneurons are involved in the control of movement, as part of central pattern generators in the spinal cord. Interneurons arise from five progenitor cells and, according to the expression of distinct transcription factors, they mature into different lineages. This includes excitatory V2a, V3, MN and Hb9 neurons and inhibitory V0C/G,V0D, V0V, V1, V2b, Ia and Renshaw cells (belonging to the V1 interneuron subclass), which display specific locations and projections within the spinal cord (Ramírez-Jarquín et al., 2014).