Can the spinal cord generate locomotor or autonomic activity?

Question 1

What is the most sophisticated spinal cord motor reflex?

Answer 1

flexion reflex
- it involves activation of nociceptive cutaneous receptors driving local circuits and limb withdrawal - the extension of the contralateral limb provides compensatory postural support

Question 2

Why are spinal cord reflexes so important?

Answer 2

one of there important functions is to help maintain balance

Question 3

what does the spinal cord do to assist movements?

Answer 3

it can generate a complex rhythmic motor output that underpins walking, running or swimming

Question 4

How do you get rhythmic movement at the spinal level ?

Answer 4

through neuronal circuits called “central pattern generators” - it is defined as an oscillatory local circuit
- made up of spinal interneurones and motoneurones which working together give rise to rhythmic motor activity

Question 5

What are CPGs responsible for during limb movement?

Answer 5

they are responsible for alternating flexion and extension h limb in a rhythmic pattern - it is constantly activating this alternating pattern while walking

Question 6

What did experiments in cats demonstrate about the central pattern generators?

Answer 6

demonstrated that there are adapted patterns
for example acceleration from walking to gallop is subject to higher control
- by isolating the spinal cord they showed that the pattern needs to be able to adapt so movement occurs at the appropriate speed and in coordination as well as ensuring alternation occurs

Question 7

How did they prove that the central pattern generators are localised to the spinal cord?

Answer 7

cut the spinal cord and dorsal roots to remove any sensory input (central and afferent responses removed)
then they recorded the electrical activity of flexors and extensors and the alternation between left and right and this demonstrated that the basic rhythmic pattern of limb movement isn’t dependent on sensory input or on input from higher brain centres
it proved there is an oscillatory spinal cord local circuit e.g the CPG that is involved in alternating flexion and extension

Question 8

How does the spinal cord generate rhythmic patterns of activity?

Answer 8

neuronal rhythms arise due to

• neuronal intrinisc properties= pacemaker neurones
• an emergent property of the network that is dependent upon synaptic properties and patterns of connections between neurones

Question 9

What is one theory of gaining rhythmic activity?

Answer 9

by specialised pacemaker neurones

- neurones with intrinsic membrane properties that impart pacemaker or oscillatory activity

Question 10

What is the concept behind pacemaker neurones and follower neurones?

Answer 10

the follower will fire randomly when it is uncoupled from the pacemaker neurone
but
the follower neurones will follow the activity of the pacemaker neurones when they are coupled

Question 11

How are intrinsic oscillators activated or altered?

Answer 11

by activity of other brain structures and by afferent inputs

Question 12

What is a common model used for testing locomotion?

Answer 12

lamprey

- jawless parasitic fish, no fins and body is made up of segments

Question 13

How do lamprey move?

Answer 13

They move by contraction and relaxation of each muscle segment in sequence creating a sinusoidal motion

Question 14

What was shown when they isolated the lamprey spinal cord?

Answer 14

after isolating the spinal cord they maintained it and recorded its activity- as it was isolated it wasn’t receiving any supra spinal or afferent inputs
- the locomotor pattern generated from the isolated spinal cord was similar to that of an intact lamprey
this indicates the spinal cord is generating a fictive locomotor pattern= CPG - it is still present even without inputs to muscle or any sensory inputs

Question 15

What receptors are involved in the pacemaker properties of lamprey spinal interneurones and how does it work ?

Answer 15

NMDA receptors and calcium-activated potassium channels

1) NMDA and calcium activated potassium channels are closed
2) glutamte actiavtes NMDA receptors causing calcium influx which releases magnesium block so more calcium enters and cell depolarises
3) intracellular calcium concntration rises and this causes calcium-activated potassium channels to open leading to potassium efflux and cell hyper polarisation and the NMDA channels close causing the magnesium block to reform
4) calcium levels fall and this causes potassium channels to close- membrane potential is reset, ready for another oscillation

Question 16

How was the pacemaker properties of lamprey determined?

Answer 16

by using TTX to block sodium influx

Question 17

How can rhythms emerge from a network?

Answer 17

rhythms can arise from collective behaviour of a circuit

• it is an “emergent property” formed from synaptic coupling between non-bursting neurones
• a network can act as a pacemaker to impose their own rhythm on other neurones

Question 18

How can simple networks generate rhythmic activity?

Answer 18

they can only do this if they have a time-dependent process that can enhance and/or reduce activity within other neurones

Question 19

How does the neurona network in lamprey swimmining work?

Answer 19

the activity of each segment is initiated by glutamatergic axons from the reticular formation and this increases activity of neurones by NMDA receptors

Question 20

What are the neurones involved in lamprey swimming and how do they interact? (for rhythm generation (L+R ) and pattern generation (flexor-extensor))

Answer 20

excitatory interneurones act on motor neurones and inhibitory interneurones
there are inhibitory interneurones inch side of the spinal cord that can inhibit other interneurones on the opposite side to them , they cross the midline - this allows reciprocal inhibition allowing alternating activation of flexor and extensor muscles bilaterally
PROCESS REQUIRES MANY DIFFERENT NEURONES

Question 21

Why have transgenic mice models been helpful in determining the neurones involved in generating locomtion?

Answer 21

allows identification and/or ablation of specific groups of neurones to give an insight into their function
- knock out a group of interneurones or
- record from a specific group of interneurones that express a specific transcription factor
THEN YOU OBSERVE MOTOR ACTIVITY-SEE HOW ITS CHANGED

Question 22

What pacemaker neurones did they record from in rodents?

Answer 22

carried out recordings in the ventral roots
- recorded from EphA4 positive interneurones using a single electrode
- indication they were involved in pacemaker activity
1) interneurones demonstrated coordinated activity when NMDA/5HT is applied
2) have monosynaptic connections to motoneurones
these results indicate that they could be important in CPG

Question 23

What happens when EphA4 interneurones were deleted in mice?

Answer 23

it produces hopping in the mice

- although this is abnormal it doesn’t prove they are the main pacemaker cells

Question 24

What was discovered about Hb-9 positive interneurones?

Answer 24

Hb-9= transcription factor
recorded from these neurones and they had analogous activity to the motor neurones in the ventral roots
they were excitatory
this evidence indicates they could be involved in the CPG

Question 25

What evidence indicates that HB-9 positive interneurones are not the main pacemaker cells?

Answer 25

when all other inputs were removed and these interneurones were recorded from they didn’t demonstrate much activity
- then they continually activated them and oscillations occurs even when they were synaptically isolated

then another group determined that they actually fire just after motor neurones in the ventral root fire, therefore although they are likely important in the netwrok, they are not driving the activity

Question 26

What happened when VI interneuron population was knocked out?

Answer 26

this involved also knocking out renshaw cells that express En1
the rhythm is slowed but the flexor-extensor alternation is not changed
when the GIRK channels(linked to allostatin receptors) of these interneurones are activated it silences the VI interneurones and this also slows the rhythm

Question 27

What is the main candidate for the interneurones involved in L-R coordination?

Answer 27

VO commissural interneurones
-Dbx ko deletes VO interneurones and Left and right ventral root activity loses reciprocity but flexor (IL2) and extensor (IL5) alternation is maintained

Question 28

What other interneurones may also be involved in left and right coordination ?

Answer 28

V2A interneurones (may include some Eph4 neurones)

Question 29

How do babies indicate that humans demonstrate CPGs?

Answer 29

when you hold a baby up erect they show rhythmic stepping movement - this suggested basic locomotor circuits are established at birth

Question 30

When are basic circuits brought under control ?

Answer 30

they are brought under control of supra spinal systems in 1st year- from automatic stepping to walking

Question 31

What is the difference between spinal transaction in human adults compared to cats?

Answer 31

there is little rhythmic activity in adults compared to cats and this is likely due to the dependence on upper motor neuronal pathways in humans

Question 32

in humans why cant rhythmic activity be achieved?

Answer 32

because human locomotion is bipedal therefore we need to maintain posture (via brainstem) so it cant be achieved only at the spinal level

Question 33

In humans what is critical for locomotion?

Answer 33

supraspinal control is critical as we get older to make our walking better -central pathways are crucial

Question 34

What does motor complete spinal cord injury mean ?

Answer 34

it means the patient is incapable of any motor activity

Question 35

What did 10 motor complete patients receive?

Answer 35

continuous epidural stimulation

- all 4 muscle groups co-activated and “locomotor-like” patterns with alternating activations of antagonists

Question 36

What factors influence spinal pattern generators?

Answer 36

DESCENDING INPUTS (epidural stimulation)
- brainstem 
- cerebral cortex- visuolomotor coordination
- cerebellum 
DRUGS
- serotonin, dopamine, NMDA, bicculine, strychinine and NA
AFFERENT SIGNALS 
- sensory inputs - proprioceptors

Question 37

What can stimulation of the parapyramidal medulla do ?

Answer 37

it can induce locomotor activity

- serotonin is important in many different activities

Question 38

Why is serotonin important for locomotion?

Answer 38

it can produce rhythmic sympathetic activity in spinal cord
- in spinalised rats NMDA didn’t elicit rhythmic acitvity whereas in spinal cord slices recordings from the IML demonstrated that descending serotonin pathways elicited rhythmic activity that was synchronous to intact animals