Lecture 18; Rhythm Generation 2

Question 1

Describe the updated model;

Answer 1

RTN (exh.)
preBOTc (insp)

• these two areas interact
• Lung inflation is +ve feedback to RTN and -ve to preBOTc
• Lung deflation is +ve feedback to preBOTc and -ve to RTN

Question 2

Is rhythm generation static or dynamic?

Answer 2

Dynamic

• preBOTC are sensitive to noradrenalin and seratonin

Question 3

What is subthreshold activity? - in regards to DAMGO activity?

Answer 3

There is synaptic current and changes in RMP but not AP are elicited. No burst activity therefore no mechanical consequence

Question 4

What are the types of noradernergic receptors?

Answer 4

Two receptor sub types a1and a2

a1 is excitatory and a2is inhibitory

Question 5

What are a1 and a2 coupled to?

Answer 5

a1 is coupled to G protein q/11 using the PLC and IP3 system

a2is coupled to G protein i/0 using the cAMPand PKA system

Question 6

What causes the noradernergic excitatory and inhibitory effects?

Answer 6

Excitatory effect due to increase in Ca2+and activation of Ca2+activated cation conductance.

Blocking resting K+conductance also postulated.

Inhibitory effect due to blocking of Ihcurrent

Question 7

What are the seratonin receptors?

Answer 7

Three receptor subtypes suggested 5-HT2A, 5-HT2C and 5-HT1A

Question 8

What are the functions of the different seratonin receptors?

Answer 8

5-HT2A and 5-HT2C have excitatory effects and increase frequency 5-HT1A has inhibitory effect and decreases frequency

Question 9

What are the seratonin receptor pathways?

Answer 9

Converging second messenger pathways, share pathways with noradrenergic receptor mechanisms.

Question 10

What are the pre-natal respiratory movements in humans?

Answer 10

Fetal breathing movements (FBM) rare before 20 weeks

FBM episodic with long apnea in 21-25 weeks

FBM more stable in frequency in 28-39 weeks

At late development has sleep rhythm and inhibited by hypoxia

Question 11

Describe the state of the neural respiratory networks prior to birth;

Answer 11

• All neural networks must be developed prior to birth
• fetal breathing movements allow for the lungs to be exercised, for these circuits to develop more and to exercise the muscles.

Question 12

What happens at birth?

Answer 12

There is a huge flux of opioids to prevent the baby from feeling pain. This also inhibits preBOTc function.

However this is functional.

Question 13

What happens post natally?

Answer 13

Circuits continue to develop, increased inputs.

As does modulation, functionality i.e muscle groups, increased lung capacity, decreased resistance

Therefore there must be enough development to allow breathing at birth.

Question 14

What do ST and NE act on?

Answer 14

Rhythm generation

Pattern formation

Question 15

What are the predominant neuromodulators?

Answer 15

ST and NE are the predominant neuromodulators.

Question 16

Describe the development of breathing rhythm in the fetus;

Answer 16

1 every five hours FBM. (E-16)ish

Becomes more episodic until rhythm is generated. (E18ish)

Networks, feedback i.e chemo,mechano receptors develop late on

Circadian rhythms develop therefore rhythm variation

Question 17

How does hypoxia influence FBM?

Answer 17

Inhibited by hypoxia as no circuitry yet to initiate the increased resp. rate. therefore preterm must have controlled environment i.e temperature, oxygen, PaO2

Question 18

Describe the plethysmography in pre and post natal mice;

Answer 18

E16 - periodic FBM (infrequent)
E18- episodic FBM (frequent but not stable (no rhythm)
P4 - Stable breathing rhythm (circuits in place)

Question 19

Describe the phrenic nerve preparations firing in pre natal mice;

Answer 19

Medullary preparations; (network)

E16 - Have resp. bursts that correlate with insp.

E18 - Increased, more periodic and stable

brainstem slices; (Rhythm cells)

E15 - More stable, reproducible and continuous than p measurements

Question 20

What is the mechanism that leads to the recordings in the brainstem and medullary samples?

Answer 20

• The PBC rhythm develops in line with FBM in Rats and Mice
• Early gestation (E 15-E17.5) first sign of rhythmical activity (prebotC hence E15 trace)
• Initial PBC activity not sensitive to hypoxia or NE
• But very sensitive to 5-HT
• By E20 in rats the RTN responds like in neonates

Question 21

Why are the pre-natal mice not sensitive to hypoxia or NE?

Answer 21

Not sensitive = Networks yet to develop

• Hypoxia may utilise NE for response
• Hypoxia may not utilise 5HT

Therefore all systems must develop in parallel but delayed

Question 22

At what stage are preBOTC active?

Answer 22

E15.5 = Rhythmic activity
E14.5-15.5 = preBOTc spontaneously start firing.

Question 23

When does respiratory rhythm activity start?

Answer 23

Two distinct areas.

• Some activity ~14.5 (rostral) then Caudal (preBOTc) later.

Question 24

What are the nerves involved in respiration?

Answer 24

Hypoglassal = Upper airway

Phrenic nerve = Diaphragm, thoracic.

Question 25

Describe the changes in firing of the phrenic nerve over time and why;

Answer 25

Decrementing -> Continuous -> augmented Decrementing; Base Rhythm only Continuous; Networks / Medullary inputs form, firing pattern changes Augmented; External sources added (chemo, mechanoreceptors)