Breathing Flashcards
Describe swimming pattern
Inspiratory phase (Phrenic nerve) Post inspiratory phase Active inspiration (forcing air out of lungs i.e running)
What controls breathing pattern?
CPG in brain stem (medulla oblongata)
Isolating the brainstem-spinal chord of neonate = rhythmic respiratory related discharge (breathing like rhythm)
Weak evidence for importance of the preBotC
Evidence for the importance of the preBötC
Contains neurons that fire before the onset of inspiration
Axonal projections of preBötC neurons restricted to the medulla
Activation of GABA receptors (by injecting agonist into preBötC) causes long-lasting apnoea
Experiment to show key role of prebotC (stronger evidence)
11 cuts in direction of rostral to caudal
Looked at phrenic nerve discharge, eventually around nerve 9 no respiratory rhythm
In brain slice, 12th nerve showed respiratory related discharge, the 12th nerve innervate airways which dilate and constrict in a way that is in phase with inspiration and post inspiration
Evidence of presence of pacemakers in preBotC.
CNQX which is glutamate antagonist causes no 12th nerve activity but neurons continue to carries on firing, which suggests neurons that have pacemaker properties
Evidence for establishing importance of preBotC neurons in respiratory rhythm generation
Substance P is a powerful modulator of the respiratory rhythm
NK1 receptors on preBötC but not BötC neurons
preBötC neurons have NK1 receptors
Substance P (neuropeptide) is an NK1 ligand
Use Substance P to target a toxin to preBötC neurons and kill them
NK1R staining abolished
An alternative genetic approach to assessing the role of the preBötC
Express the insect allatostatin receptor in neurons of preBötC
Allatostatin receptor is inhibitory, and a ligand for this receptor is not present in mammalian brain
This gives a rapid way of inactivating neurons, by application of allatostatin
O2 and CO2 roles in breathing
Respiration is sensitive to the levels of O2 and CO2 arterial blood and brain
If PO2 falls breathing increases
If PCO2 increases breathing increases
Respiration serves to keep the levels of these gases constant
CO2 and H+ exert independent effects on respiration via central chemoreceptors
Where is PO2 sensed ?
Oxygen (PO2) is sensed in the periphery
In the Carotid Body -located in the bifurcation of the carotid artery which supplies the brain
What does hypoxia cause ?
Low PO2 = CO2/H= INTO type 1 cell = ATP into carotid sinus nerve
Ondine’s curse
Patients lack chemosensitive reflexes, but have otherwise normal respiratory machinery
They can regulate arterial PO2 and PCO2 while awake but not during sleep, and thus stop breathing while asleep (and die)
Mutations in Phox2b underlie at least some cases of CCHS
Mouse models of CCHS with human mutations of Phox2b lack CO2 chemosensitivity –this can be fatal for the mouse
How is CO2 detected
Three possible signals:
CO2
pH (intra- or extracellular)
HCO3-
Where is CO2/PH sensed ?
Sensed 30% in peripheral and 70% in central
Arterial CO2 is detected at the ventral surface of the medulla oblongata
ATP release during hypercapnia
ATP is released from chemosensory sites during hypercapnia
ATP release measured in vivo with a biosensor
Cx26
CO2 binds to K125 and R 104
CO2 binds directly to Connexin 26 onto a specific lysine residue via a labile covalent bond
CO2 binding creates a “carbamate bridge” between adjacent subunits that biases the hemichannel to the open state
Cx26DN –a genetic tool to remove CO2 sensitivity from Cx26
Cx26DN removes CO2 sensitivity from Cx26WT hemichannels
Cx26 in glial cells contributes nearly half of central chemosensitivity
