Neuroscience: Exploring the

Brain, 4e

Chapter 13: Spinal Control of Movement

Jun-­‐An  Chen,  IMB,  Academia  Sinca  

Introduc)on  

•  Motor Programs
–  Motor system: Muscles
and neurons that control
muscles
–  Role: Generation of
coordinated movements
–  Parts of motor control
•  Spinal cordà
coordinated muscle
contraction
•  Brainà activate motor
programs in spinal
cord
The  Soma)c  Motor  System    

•  Types  of  Muscles  

–  Smooth:  diges@ve  tract,  
arteries,  related  structures  
–  Striated:  Cardiac  (heart)  
and  skeletal  (bulk  of  body  
muscle  mass)  

•  Soma@c  Musculature  
–  Axial  muscles:  Trunk  
movement  
–  Proximal  muscles:  Shoulder,  
elbow,  pelvis,  knee  movement  
–  Distal  muscles:  Hands,  feet,  
digits  (fingers  and  toes)  
movement  
The  Soma)c  Motor  system    

Types  of  motor  neurons  

–  Lower  motor  neuron:  
Innervated  by  ventral  
horn  of  spinal  cord  
–  Upper  motor  neuron:  
Supplies  input  to  the  
spinal  cord  
Lower  Motor  Neurons      

Alpha  Motor  Neurons  –  

extrafusal  skeletal  muscle  and  drive  muscle  contrac@on  

–  Motor  unit:  Motor  neuron  and  

all  the  muscle  fibers  it  
innervates  
–  Motor  neuron  pool:  All  the  
motor  neurons  that  innervate  
a  single  muscle  
Lower  Motor  Neurons      

•  Topographical  distribu@on  of  

lower  motor  neurons  in  the  
ventral  horn  
–  Motor  neurons  controlling  
flexors  lie  dorsal  to  extensors  
–  Motor  neurons  controlling  
axial  muscles  lie  medial  to  
those  controlling  distal  
muscles  
 Diversified  motor  neuron  types      
The  human  body  has  more  than  300  bilateral  pairs  of  muscles    containing  more  than    
100  million  muscle  fibers,  which  are  innervated    by  more  than  120,000  motor  neurons    
in  the  spinal  cord  alone.    

Alpha  Motor  Neurons  –  

extrafusal  skeletal  muscle  and  drive  muscle  contrac@on  

Ia  VGlut1+  innerva@on  
Diversified  motor  neuron  types      
 Topographic  logic  distribu)on  of  motor  neuron  
pools  

Br

Th

Lu

Discussion  later:  
How  is  motor  pool  diversity  is  created    
By  transcrip@onal  factor?  
 Excita)on-­‐Contrac)on  Coupling  

•  Muscle  Contrac@on  
 
–  Alpha  motor  neurons  release  
ACh  
–  ACh  produces  large  EPSP  in  
muscle  fiber  via  nico@nic  Ach  
receptors  
–  EPSP  evokes  muscle  ac@on  
poten@al  
–  Ac@on  poten@al  triggers  Ca2+  
release  
–  Fiber  contracts  
–  Fiber  relaxes  
–  Ca2+  lowered  by  organelle  
reuptake  
 How  is  lower  motor  neuron  is  controlled  to  
generate  movement?    

•  Inputs  to  Alpha  Motor  Neurons  

 
 Sensory  input  to  control  reflex  movement    

•  Monosyna@c  reflex  (ie.knee  jerk  reflex)  –  only  take  50  milli  seconds  
 
 Propriocep)ve  input  to  control  movement  
   
•  The  sixth  sense  of  the  body  to  “feel”  the  posi@on  of  human  body  
 
Propriocep)ve  input  to  control  movement  
   
•  Viral  infec@on  kills  propriocep@ve  neurons  
 

✗  

(BBC,  The  Man  Who  Lost  His  Body)  

Interneurons  to  coordinate  the  moving  behaviour    
Spinal  Control  of  Motor  Units  
•  Inhibitory  Input  
–  Reciprocal  inhibi@on:  Contrac@on  of  one  muscle  set  accompanied  
by  relaxa@on  of  antagonist  muscle  
•  Example:  Myota@c  reflex  
Spinal  Control  of  Motor  Units  

•  Excitatory  Input  
–  Flexor  reflex:  Complex  
reflex  arc  used  to  withdraw  
limb  from  aversive  s@mulus  
–  Crossed-­‐extensor  reflex:  
Ac@va@on  of  extensor  
muscles  and  inhibi@on  of  
flexors  on  opposite  side    
   
How  does  interneurons  control  and  coordinate  the  
moving  behaviour  ?  

(Youtube)  
Spinal  Control  of  Motor  Units  

•  Spinal  Interneurons  
–  Synap@c  inputs  to  spinal  interneurons:  
•  Primary  sensory  axons  
•  Descending  axons  from  brain  
•  Collaterals  of  lower  motor  neuron  axons  
•  spinal  interneurons  impinge  on  motor  neurons  –  namely  
V0,  V1,  V2,  V3  
 
 
   
Molecular  programs  of  interneuron  diversity  in  the  
ventral  spinal  cord  
The  Genera)on  of  Spinal  Motor  Programs  for  Walking  
How  can  we  study  the  func)ons  of  individual    
Interneuron  contributed  to  motor  output?  
Kills  the  Specific  Individual  Neuron    

Find  the  V2a  interneuron  in  the  spinal  cord  

Get  the  toxin  to  kill  V2a  interneurons  specifically  

 
Iden@fy  the  motor  circuit  defects  
Gene)c  Manipula)ons  to  Kill  the  Specific  Individual  
Neuron    
Gene)c  Manipula)ons  to  Kill  the  Specific  Individual  
Neuron    

(J  Physiology)  
 In  mice  lacking  V2a  interneurons,  gait  depends  on  
speed  of  locomo)on  
Normal  Speed   Increase  Speed  

WT  

Chx10  
DTA  mice  

(Crone  SA,  et  al  2009)  

In  mice  lacking  V2a  interneurons,  gait  depends  on  
speed  of  locomo)on  

(Crone  SA,  et  al  2009)  

V3  Interneurons  are  Required  for  Asymmetrical  
PaWerns  of  LeX-­‐Right  Ac)vity  

(Zhang  Y,  et  al  2008)  

Interneurons  Control  the  leX-­‐
right    
Alterna)on  and  burst  
robustness    
of  motor  neurons  

(Silvia  Arber  2008)  

Movement  control  by  upper  motor  neurons    
The  Soma)c  Motor  system    

•  Soma@c  Musculature  and  

distribu@on  of  lower  motor  
neurons  in  spinal  cord  
–  Axial  muscles:  Trunk  
movement  
–  Proximal  muscles:  Shoulder,  
elbow,  pelvis,  knee  
movement  
–  Distal  muscles:  Hands,  feet,  
digits  (fingers  and  toes)  
movement  
Upper  –lower  Motor  Neuron  
To  control  daily  movement      
The  Soma)c  Motor  system    
Motor  neurons  per  se  
   
 The  loss  of  Motor  neurons  lead  to  paralysis  
   
Amyotrophic  lateral  Sclerosis   Spinal  cord  Injury  
Clinical utilization of ES cells
Differentiation of ES cells into spinal motor neurons

Motor neurons
 Multiple developmental steps to motor neurons

blastocyst Endoderm, mesoderm

Default pathway (Nieuwkoop, 1952; Hemmati-Brivanlou, 1997)

neural brain
?

spinal spinal interneurons

?

Motor
Spinal cord brain neurons

What are the relevant signals?

Sonic hedgehog with retinoic acid pattern ventral spinal cord

RALDH2
Retinoic acid Sonic hedgehog

Spinal
cord

S S
FP
somites
N

notochord

Retinoic acid is a vitamin A derivative

- produced and secreted from somites (S)
- caudalizes neural tissue (T. Edlund, 1999)

Sonic hedgehog is a small protein

- secreted from the notochord (N) and floor plate (FP)
- ventralizes neural tissue (T. Jessell, 1994)
 Multiple developmental steps to motor neurons

blastocyst

neural brain

RA
spinal spinal interneurons

RA
Motor
Shh neurons
 Multiple developmental steps to motor neurons

ES cells

neural Retinoic acid

RA
spinal

RA
Motor
Shh neurons

Hh agonist
Embryonic stem cells
 EMBRYOID BODIES
RA and SHH induce motor neurons

control RA + SHH
 Transplantation of ES cell-derived motor neurons
DNA sequence which controls motor neuron specific expression
connected to the gene of green fluorescent protein (GFP)

GFP

(I. Lieberam)
Transplantation of mouse motor neurons
into chick embryos
 Validation of ES-derived motor neurons
Neurofilament
HB9::GFP mouse GFP Transplant in chick

Ach transporter Ach receptors

Synoptobrevin Synoptobrevin
GFP GFP
Synchronous and progressive differentiation of ES cells

ES cells Neural plate pMN Postmitotic MNs

RA RA
Shh

Sox1 Olig2 Hb9

Mouse embryonic development
Day 4.5 Day 8 Day 9 Day 10-12

RA HhAg

Sox1 Olig2 Hb9

Mouse ES cell differentiation

Day 0 Day 3 Day 4 Day 5-7
Functions of non coding RNAs during motor neuron
generation and degeneration

Embryonic  stem  
(ES)  cells  

motor  neuron  

SMA  or  ALS  ES  cells  

Possible
Pathology
mechanism
 Use ESC and iPS to model ALS

ALS  

1.  How  to  differen@ate  ESc/iPSc  to  motor  neurons?   ✔  

2.  Does  ALS  iPSc  derived  MNs  recapitulate  ALS  pathology?  

Ruggiu M et al. Mol. Cell. Biol. 2012;32:126-138

 Induced  pluripotent  stem  cells  generated  from  82-­‐yr  old  
pa)ents  with  ALS  can  be  differen)ated  into  motor  neurons  

(Dimos JT Science 2008)

A  small  molecule  screen  in  stem-­‐cell-­‐derived  MNs  
iden)fies  a  kinase  inhibitor  as  a  candidate    
therapeu)c  for  ALS  

(Yang YM CSC 2013)

A  new  paradigm  for  neurodegenera)ve  disease  study  

(Eggan K Neuron 2013)

 Summary  of  spinal  control  movement  

knee  jerk  reflex   Myota@c  reflex   Flexor  reflex  

 Summary  of  spinal  control  movement  

Local  Mo@on  control-­‐  Walking,  Hopping,  and  Galloping  Gait  Control    

Unsolved  ques)ons  of  spinal  control  movement  

How  is  the  diversity  of  the  interneurons  and  motor  neurons  defined?  
We  are  s@ll  lacking  a  complete  census  map  of  the  spinal  neurons    

Can  we  decipher  the  circuitry  in  every  moving  behaviour  ?    

Can  we  model  the  motor  neuron  degenera@on  in  vitro  by  ESCs  or  iPSCs?    

Is  that  possible  to  recons@tute  motor  circuit  for  spinal  cord  injury  or    
In  spinal  neuron  degenera@on  ?    
 References  

Probing  the  Locomotor  Conundrum:  Descending  the  ‘V’  Interneuron  

Ladder.  Anna  E.  Stepien1,  2,  Silvia  Arber1,  2,    Neuron,  2008  

Measured  mo)on:  searching  for  simplicity  in  spinal  locomotor  networks  

Sten  Grillner1,  Thomas  M  Jessell2,    Current  Opinion  in  Neurobiology,  2009  
 
 Motor  Neuron  Diversity  in  Development  and  Disease.  Annual  Review  of  
Neuroscience  2010  Chris  Henderson  

Construc)ng  and  Deconstruc)ng  Stem  Cell  Models  of  Neurological  Disease  

 Steve  S.W.  Han1,  2,  Luis  A.  Williams2,  Kevin  C.  Eggan  Neuron  2013  
 
Assembly  and  Func)on  of  Spinal  Circuits  for  Motor  Control  
Catarina  Catela,  Maggie  M.  Shin,  and  Jeremy  S.  Dasen    
Annual  Review  of  Cell  and  Developmental  Biology  2015  

HHMI  Tom  Jessell  2009  Holiday  lecture