Week 3: Spinal Cord Network of Lamprey = CHECKED

Question 1

Hierarchy of computation models going from very simplified to very detailed

Answer 1

Standard artifical neurons with no dynamics to multi-comaprtment condutance based models HH

Question 2

we may predisposed to pick the “most realistic” model (close to biology)

Answer 2

that would be the most complicated model

Question 3

All models are approximations (e.g., It does not model everything that is going on in the cell) , even..

Answer 3

even the most complex model; the multi-compartment conductance based models (HH)

Question 4

All models are approximation so aim is not to imitate

Answer 4

close to biology but pick right model for question you are answering

Question 5

Research has found that the spinal cord is not just a relay station (Cabelugen et al., 2003; Delvolve et al., 1997)

Methods (3)

Answer 5

They did a decerebrated preparation on a salamander so its only left with brain stem and spinal cord

Fixed their body in a solution which keeps their tissue in a viable state

Injected two electrodes to the MLR (just above the brain stem) that has a constant signal of current (no oscillation)

Question 6

What is MLR stand for?

Answer 6

Mesencephalic Locomotor Region

Question 7

Research has found that the spinal cord is not just a relay station (Cabelugen et al., 2003; Delvolve et al., 1997)

Results (2)

Answer 7

At low MLR stimulation, rest of the body attached to spinal cord will perform a walking gait

At high MLR stimulation, it will turn into a swimming gait

Question 8

Research has found that the spinal cord is not just a relay station (Cabelugen et al., 2003; Delvolve et al., 1997)

Conclusion (2)

Answer 8

They found depending on strength of input to brainstem we get different movements

This shows that we don’t need higher brain areas to produce locomotion patterns and that spinal cord is not a mere relay

Question 9

Two ways to record locomotor modes of salamanders (2)

Answer 9

Fictive locomotion

In vivo EMG data

Question 10

EMG records the

Answer 10

electrical activity in muscles via electrodes

Question 11

EMG data of salamander shows that muscle activation is different for the salamander’s

Answer 11

different locomotor modes

Question 12

From EMG data, the swimming gait of the salamander shows (2)

Answer 12

Wave of muscle activity that travels down the body (travelling wave)

There is a constant lag between one muscle and the next

Question 13

From EMG data, the walking gait of the salamander shows (2)

Answer 13

All muscles on one side of the trunk being active at first in unison with two legs

next cycle these muscles are silent and other side of the trunk is active (standing wave)

Question 14

Fictive locomotion metholodgy (2)

Answer 14

Extract the whole spinal cord and put it into a solution (which has NMDA) that keeps tissues in a viable state

Electrodes are placed directly on the ganglia

Question 15

What is ganglia?

Answer 15

Nerves that come out of the spinal cord

Question 16

Ficitive Locomotion what do you measure?

Answer 16

Measure the electrical activation of the spinal cord nerves which will summed to be the collective output of many spinal cord neurons sending action potential along the nerves

Question 17

Ficitive Locomotion what do you measure?

Answer 17

Measure the electrical activation of the spinal cord nerves which will summed to be the collective output of many spinal cord neurons sending action potential along the nerves

Question 18

NMDA is…

Answer 18

Excitatory NT which makes neuron fire

Question 19

Ficitive locomotion measured from

Answer 19

Ventral root recordings (VRs) - nerve ending that goes the muscles

Question 20

Fictive locomotion collective input graph (2)

Answer 20

Neighbouring spinal segments peak at slightly offset times

–> there is a phase lag

Question 21

Diagram of fictive locomotion collective input graph:

Answer 21

Question 22

From fictive locomotion collective input example from graphs, this reflects the properties we have seen in spinal networks like in …. as … (2)

Answer 22

muscle activation in the salamander’s swimming pattern

there is a wave of muscle active that travels down their body (traveling wave) and there is a constant lag between one muscle and the next one.

Question 23

In fictive locomotion, the neighbouring spinal segments peak at slightly different them and have a phase lag

suggests the neural organisation of the spinal cord that… (2)

Answer 23

Suggests that spinal segments (as neural networks) must be coupled to each other to influence each other locally

(e.g.,, one side of muscle is active the other side of muscle is relaxed)

Question 24

In terms of understanding how neurons work in salamanders on how they generate muscle activation for swimming, we have to use lampreys to ask this as (2)

Answer 24

more single neuron data on lampreys

swims like a salamander (i.e., muscle contract in alteration, left-right, left-right and slightly delayed along the body)

Question 25

**Extra Reading Actual swimming behaviour of lampreys from EMG data (4)**

Answer 25

- The lamprey swims by producing an alternating activation of motor neurons on left and ride of each segment - 100 different segments are activated successively with a phase delay - This allows the animal to push through water - The higher the frequency of alternation, the faster it will swim

Question 26

**Extra Reading Fictive methodology in lampreys show that**

Answer 26

Activation of NMDA receptors can give rise to alternating burst activity in low-frequency (0.1-3Hz)

Question 27

Various studies recorded individual neurons of lampreys, measured their ion channels and measured synaptic connectivity to produce

Answer 27

spinal network of lampreys

Question 28

Diagram of lamprey locomotor network

Answer 28

Question 29

In the diagram of lamprey locomotor network it represents

Answer 29

one segment of the spinal cord

Question 30

Lamprey locomotor network What does CCIN mean?

Answer 30

cross inhibitory neurons

Question 31

Lamprey locomotor network What does EIN mean?

Answer 31

excitatory inter neuron

Question 32

Lamprey locomotor network MN is

Answer 32

motor neurons

Question 33

**Extra Reading The spinal cord network of lampreys how does it work to produce locomotion? (5) **

Answer 33

1. The alternating rhythmic activity is initiated when the interneurons and motor neurons (MN) receives the descending excitation from reticulospinal (RS) neurons in the brainstem (McCllellan & Grillner, 1984) 2. Recurrent connection between the EIN within half-segment of spinal cord 3. These EINs have an excitatory connection to MNs which will make muscle contract 4. At same time, EINs excite the CCINS which have inhibitory connections to all the neurons of the other side of the spinal cord (contra-lateral half segment) 5. This means inhibition of contra-lateral half segment means one side of the spinal cord is active while other side is silenced (prevent from firing APs) so both sides not active simultaneously

Question 34

What does it mean when there is tonic input from the brain stem?

Answer 34

constant flow of action potentials is impacting the spinal cord neurons

Question 35

Diagram of recurrent connection

Answer 35

Question 36

**Extra Reading**What makes one-half of the spinal cord segment stop firing action potentials if tonic input is from the brain stem? (2)

Answer 36

1. Spike-frequency adapation 2. Lateral Interneurons (LINs) being active mid-cycle and inhbiting CCINs

Question 37

Extra Reading: LINs terminate ongoing activity so alternating activity occurs by

Answer 37

Later during ipsilateral bursting activity of EINs and MNs, the LIN becomes active, inhibiting the CCIN and allowing network neurons on the contralateral side to disinhibit (Wallén et al., 1992).

Question 38

Spike frequency adaptation means..

Answer 38

the reduction of a neuron's firing rate to a stimulus of constant intensity.

Question 39

Spike frequency adaption research, Yasunhiko and Tadashi (1999) found that

Answer 39

As you increase the input of current that is injected, number of action potentials increased and takes longer to reach to a steady state

Question 40

How does spike-frequency adaptation help to terminate activity on one side of a spinal cord segment? (4)

Answer 40

One side of spinal cord segment becomes active first in which EINs fire loads of APs which inhibits the other side of spinal cord After a while of firing APs, spike-frequency adaptation takes place so firing rate of EINs reduces The intervals of EINs without spikes becomes larger with time which makes other side of spinal cord not as strongly inhibited (i.e., fewer inhibitory APs arrive at the contra-lateral side) This means the other side time to become active and starts firing multiple action potentials quickly in succession and inhibits the previously active side (called escape from inhibition)

Question 41

Spike-frequency adapation is due to a phenomenon called

Answer 41

sAPH

Question 42

sAPH is

Answer 42

spike after hyer-polarisation

Question 43

Hyperpolarisation means that (2)

Answer 43

Membrane potential becomes more negative than resting membrane potential It makes it more difficult for next spikes (i.e., fire action potentials ) to be emitted in that neuron

Question 44

sAPH is because of (4)

Answer 44

Ca+ flows into the cell (due to Ca+ ion channel opening) with each action potentials (alongside Na+) and slowly accumulates in neuron Ca+ has a hyperpolarization current through different ion channel (Kaca channel) that brings down the MP down slowly The accumulation of Ca+ is sensed by a channel called Calcium-dependent Potassium Kca channel The Ca+ accumulates slowly until it reaches a steady-state where the amount of Ca+ transported away (decay of Ca+ concentration) equals to the amount of Ca+ that flows in.

Question 45

How is neural properties of spinal cord determining this network function of locomotion?

Answer 45

A single cell model using HH neuron model

Question 46

In HH we have an equation for each

Answer 46

individual ion channel

Question 47

In multi-compart HH model, it is different from HH model as it has (2)

Answer 47

they have multiple compartments that constitute different parts of the neuron Each compartment has different channels (Na, K, Ca, Kca)

Question 48

Diagram of Ekeberg's single cell compartment model

Answer 48

Question 49

Single-cell model of multi-compartment HH has a

Answer 49

soma compartment and three other compartment for the dendrites of the neuron. compartment is made up of sodium , potassium , calcium [Ca] and calcium-dependent potassium ion channels [KCa]

Question 50

Single-cell multi-compartment model of HH was proposed by

Answer 50

Ekeberg et al., (1991)

Question 51

In the multi-compartment HH model, equation of rate of change of MP over time, if Eleak (resting MP) is equal to E (current MP) and there aren't any inputs then (2)

Answer 51

change of MP over time (dE/dt) is 0 neuron stays at rest

Question 52

Pros of multi-compartment HH model (2)

Answer 52

It is more realistic and closer to biology stimulate effects of ion channels (i.e., ion channels given by separate equations)

Question 53

Cons of multi-compartment HH model (3)

Answer 53

- Need more data to fix the composition of ion channels as need to measure elements of equation in real neurons for model to map loosely to biology (very labour intensive task) - Very expensive computationally to stimulate in computer (perform equation for every compartment for every different ion channel) - Hard to tune parameters (because haven't measured all parameters then come up with plausible values but there is whole range of values to utilise and have to make a decision of which ones)

Question 54

In the multi-compartment HH model, the equation of rate of chanve of MP over time tells how (2) and Ekeberg at each timestep get

Answer 54

MP changes over time At each timestep, get value of MP and plot it

Question 55

Evidence of sAPH in multi-compartment HH model (3) using DE/dt (change of MP over time)

Answer 55

Ca+ flows in, activates a hyperpolarising current bringing MP down as Ca+ decays, MP goes up This is what gives increase in spike distance (spike frequency adaptation)

Question 56

The change in calcium concentration is modelled in Ekeberg's single cell model by a

Answer 56

differential equation:

Question 57

From experiments, they found there are two types of calcium pools (2)

Answer 57

First calcium pool is one where Ca+ flows in and entering through Ca+ channels due to each AP in soma Second Ca+ pool is Ca+ flows in at NMDA synapse (when NMDA receptors are activated)

Question 58

The calcium-dependent potassium current strength equation in Ekeberg's paper is

Answer 58

driven by the two calcium pools

Question 59

Two pools of Ca+ in whcih we have fast and slow Inflow and decay of Ca+ ions happen Fast for Slow for (4)

Answer 59

Ca+ dynamics Inflow and decay of Ca+ ions happen at different time scales for these two pools It is fast for membrane Ca+ It is slow for NMDA-synapse Ca+

Question 60

For Ca+ membrane, Ca+ goes in

Answer 60

with each AP

Question 61

For NMDA-synapse Ca+ goes in due to.... (2)

Answer 61

Ca+ goes in due to receptor-docked on NMDA synapse After enough Ca+ accumulates (accumulation of Ca+ sensed by Calcium-dependent Potassium channel), triggers a strong hyper-polarising current to bring MP down.

Question 62

What is plateau potentials generally?

Answer 62

When action potentials are blocked with Tetrodotoxin

Question 63

In NMDA plateau potentials, It is when you block the generation of action potentials with TTX (tetrodotoxin) which - (3)

Answer 63

suppresses Na+ channel from opening and closing as well as no Ca+ flowing in soma so does not affect MP Still can affect MP with other ion channels There is strong and constant NMDA input (Ca+ flowing in NMDA synapse) which brings MP up, MP plateaus and then decays (When enough Ca+ accumulates, one of Calcium-dependent Potassium channels brings MP down)

Question 64

FL is slower than

Answer 64

in vivo locomotion

Question 65

Plateau potentials related to fictive locomotion since (4) in FL what happens.... NMDA docks Thus hypothesised NMDA Ca+ dynamics produce In other words... (4)

Answer 65

In FL, isolated spinal cord is placed in a solution that contains large NMDA concentration NMDA docks to all the receptors in the spinal cord neurons Thus it is hypothesised that NMDA Ca+ dynamics produce these slow fictive locomotion signals that are slower than actual in-vivo locomotion In other words, FL is slower than actual in vivo locomotion due to product of un-naturally large NMDA concentration

Question 66

Wallen et al., (1992) paper where

Answer 66

connect multi-compartment HH model neurons in network looks similar for lamprey's spinal cord network

Question 67

In a paper by Wallen et al., (1992), they stimulated the network of neurons with Kainate that activates non-NMDA receptors which gives

Answer 67

There is left and right side alternative of APs (e.g., left side firing APs, other side disinhibited until left side is fatigued then other side active and fires APs; vice-versa)

Question 68

**Extra Reading**In paper by Wallen et al., (1992), with increased stimulation of Kainate,

Answer 68

faster oscillations, increased spikes per cycle, translates to faster swimming

Question 69

In paper by Wallen et al., (1992), if you add serontin (5-HT) to HH model of spinal cord (4)

Answer 69

It will reduce the influence of Ca-dependent Potassium channel It will reduce the amplitude of AHP which will be weaker so takes longer for Spike adaptation frequency to occur Oscillations will last longer Swimming frequency will be slower

Question 70

In a paper by Wallen et al., (1992), Higher NMDA added to model, (2)

Answer 70

the slower and longer NMDA osciliations it has This is because more Ca+ flows in and once have oscillations terminated it takes a long time for Ca+ to decays before neuron becomes active again

Question 71

Evidence of LIN as burst terminating factor (terminates activity of one side) in Wallen et al., paper (3)

Answer 71

* Compared bursting activity of network with LINs connected and disconnected from the network model * The rhythm becomes more slower and irregular when LINs as disconnected * Thus synaptic inhibitory connections from the LINS onto CCINs constitute this burst terminating factor at the level of activation.

Question 72

In a paper by Wallen et al., (1992), As we can block action potential generation by blocking Na+ with TTX in the model by (2)

Answer 72

Setting sodium conductance to 0 Produces NMDA-plateau potentials

Question 73

The lamprey locomotor network is an example of a

Answer 73

central pattern generator (CPG)

Question 74

CPG is

Answer 74

networks that take simple inputs (e.g., tonic [i.e., constant] signal from brain stem) and produce a more complex pattern of neural activity (e.g., oscillations for rhythmic muscle activation)

Question 75

Examples of CPG (3)

Answer 75

Locomotor networks for different gaits (swimming, stepping trotting etc...) Heartbeat Digestion