Lecture 13 - Neural Control of Respiration

Question 1

why is it important to study neural control of respiration?

Answer 1

• breathing is an autonomic physiological function essential for life
• several respiratory disorders are caused by defects in the neuronal networks that control breathing
• simple experimental model to study structure-function behaviour mechanisms that can be applied to other neuronal networks

Question 2

list the six major parts of the respiratory system

Answer 2

• upper warways (nasal and oral cavities, pharynx, larynx)
• trachea
• lungs (bronchi –> bronchioles –> alveoli, and smooth muscles & connective tissue, pulmonary)
• muscles of respiration
• rib cage and pleura
• parts of CNS that regulate respiration

Question 3

peripheral pulmonary stretch receptors and peripheral chemoreceptors that monitor arterial oxygen and carbon dioxide provide afferents that terminate centrally in the:

Answer 3

nucleus of the solitary tract

Question 4

central chemoreceptors in this nucleus monitor CO levels

Answer 4

nucleus of the solitary tract

Question 5

brainstem rhythm generators in the ventrolateral medulla integrate information from central chemoreceptors with feedback from:

Answer 5

pulmonary stretch receptors

Question 6

respiratory premotor neurons in the medulla give rise to:

Answer 6

descending axons that innervate inspiratory motorneurons in the cervical spinal cord and thoracic spinal cord (that innervate inspiratory pump muscles)

Question 7

what are the inspiratory pump muscles?

Answer 7

the diaphragm and external intercostal muscles

Question 8

go review slide 297

Answer 8

i just cannot write all that down

Question 9

in 1936, Gesell and colleagues recorded the extracellular action potentials of individual neurons in the brainstem. this was the first clue that breathing must be generated by:

Answer 9

neuron-neuron communication in the medulla

Question 10

what are the five major components of the respiratory control network?

Answer 10

1) a rhythm generating network of neurons that produces the basic oscillation
2) a pattern generator that produces a coordinated pattern of activity in the respiratory muscles
3) respiratory muscles
4) mechanosensory and chemosensory regulatory elements
5) integrative components to coordinate breathing with behaviours

Question 11

what is the formula for ventilation?

Answer 11

Ve = (f)(Vt)

Ve - ventilation
f - frequency
Vt - tidal volume

Question 12

breathing is initiated in the medulla by specialized neurons called the:

Answer 12

• pontine respiratory group (PRG)
• dorsal respiratory group (DRG)
• ventral respiratory column (VRC)

Question 13

the pontine respiratory group and the dorsal respiratory group (DRG) play an important role in:

Answer 13

providing feedback on breathing

Question 14

part of the brainstem important for forced expiration

Answer 14

the parafacial respiratory group (pFRG)/ lateral parafacial (pFL)

Question 15

receives input from carotid bodies about O2 in the head

Answer 15

dorsal respiratory group (DRG)

Question 16

phrenic motor neurons innervate the:

Answer 16

diaphragm

Question 17

in virto preparations are used to examine how:

Answer 17

the nervous system controls breathing in newborn animals

Question 18

what are the seven main advantages of brainstem spinal cord preparations with respect to the respiratory system?

Answer 18

1) central respiratory network in the pons and medulla is intact
2) monosynaptic descending bulbospinal connections can be electrically activated
3) the brainstem and spinal cord can be bathed separately
4) phrenic, intercostal, and abdominal motor physiology can be compared
5) interaction with other motor behaviours (ie: locomotion) can be studied
6) fictive spinal respiratory motor output is correlated with ventilation
7) respiratory spinal plasticity can be studied in vitro

Question 19

is it possible to have spontaneously active respiratory neurons across the respiratory cycle (particularly in vitro)?

Answer 19

yes

Question 20

the preBotC is _____ and _____ to generate respiratory thythmic activity in mammals

Answer 20

necessary, sufficient

Question 21

a technique that isolates the area of the brainstem that is responsible for respiratory rhythmogenesis by making a series of lesions and then recording phrenic nerve activity

Answer 21

serial sectioning

Question 22

phrenic nerve activity and hypoglossal nerve activity are lost when a transection is performed to separate the ____ from the ____

Answer 22

preBotC, caudal portions of the respiratory network

Question 23

are respiratory structures unilateral or bilateral?

Answer 23

bilateral

Question 24

innervates the genioglossus muscle

Answer 24

CN XII (hypoglossal nerve)

Question 25

- rhythmically active - glutamatergic - express substance P receptors (NK1R) - (some) express somatostatin - depends on the transcription factor Dbx1 for proper development these are all characteristics of:

Answer 25

preBotC neurons

Question 26

what types of studies were used to determine the necessary role of the preBotC in respiratory control?

Answer 26

- lesion studies - inactivation studies - genetic knockout studies

Question 27

list two lesion studies used to determine the role of the preBotC

Answer 27

- substance P conjugated with saporin - preBotC laser ablation

Question 28

list an inactivation study used to determine the role of the preBotC

Answer 28

viral expression of allatostatin receptor in somatostatin (SST) receptors

Question 29

list a genetic knockout study determine the role of the preBotC

Answer 29

Dbx1 knockout mice

Question 30

a type I ribosome-inactivating protein that causes cell death

Answer 30

saporin

Question 31

the conjugate between substance P and saporin interacts with the _____ and the complex will be brought into the cell

Answer 31

neurokinin 1 receptors (NK1R)

Question 32

what percent of the NK1R need to be destroyed before respiratory breathing is disrupted?

Answer 32

80%

Question 33

in a medullary slice preparation, calcium activity is recorded with a:

Answer 33

two photon microscope to detect rhythm neurons

Question 34

the medullary slice preparation is designed to identify respiratory neurons and then:

Answer 34

individually laser ablate the target while monitoring network function in real time

Question 35

inactivation studies where the allatostatin receptor was expressed in drosophila, it was found that the allatostatin receptor is coupled to _____ and its activation causes _____

Answer 35

GIRK channels (inward-rectifying K+ channels), hyperpolarization in neurons

Question 36

Dbx1 is expressed in ____ cells in the preBotC

Answer 36

SST/NK1

Question 37

are SST/NK1 cells detected in knockout mice for Dbx1?

Answer 37

no

Question 38

do Dbx1 knockout mice exhibit breathing movements at birth?

Answer 38

no

Question 39

does substance P (a drug that usually activates preBotC neurons) restore rhythm activity in Dbx1 knockout mice?

Answer 39

no

Question 40

how was the reciprocal inhibition theory of the preBotC tested?

Answer 40

by blocking inhibition, but the study found that eliminating inhibition does not block respiratory activity

Question 41

how was the pacemaker neuron theory of the preBotC tested?

Answer 41

blocking current responsible for pacemaker properties, but the study found that elimination of pacemaker protperties does not eliminate respiratory rhythms

Question 42

idea that periodic inspiratory bursts of neural activity in the preBotC are due to intrinsic currents, which are ordinarily latent or unavailable, except when evoked synaptically in the context of network function

Answer 42

the group pacemaker hypothesis

Question 43

what is the most recent hypothesis for how respiratory rhythm is generate in the preBotC?

Answer 43

the Burstlet theory

Question 44

according to the Burstlet theory, if excitability of the preBotC neurons increases, then rhytmic bouts of synchronous low-level population activity (called burstlets) will:

Answer 44

develop into a burst of inspiratory activity (see slide 328)

Question 45

what muscle groups are activated during quiet inspiration?

Answer 45

the diaphragm and external intercostals

Question 46

what muscle groups are activated during forced inspiration?

Answer 46

the diaphragm, external intercostals, scalenes, sternoclaidomastoid, and pectoralis minor

Question 47

what muscle groups are activated during quiet exhalation?

Answer 47

none, quiet breathing is a passive process

Question 48

what muscle groups are activated during forced exhalation?

Answer 48

interior intercostals and abdominal wall muscles

Question 49

true or false: a group of rhythmogenic neurons is found in the parafacial respiratory group (pFRG/PFL)

Answer 49

true

Question 50

does the lateral parafacial region (pFRG/pFL) activate before or after the preBotC?

Answer 50

before

Question 51

it is thought that the the lateral parafacial region (pFRG/pFL) is involved in:

Answer 51

forced exhalation

Question 52

fentanyl supresses activity of _____ but _____ remains intact

Answer 52

the preBotC and inspiratory events, expiratory rhythmic activity

Question 53

separating the pFRG/pFL from the rest of the respiratory network abolishes:

Answer 53

active expiration (but leaves inspiratory activity intact)

Question 54

are pFRG/pFL neurons excited or inhibited at rest?

Answer 54

inhibited (remember: quiet exhalation is a passive process)

Question 55

blocking GABA and glycine neurons in the pFRG/pFL will increase forced expiration, therefore they are important for:

Answer 55

inhibiting forced expiration

Question 56

- silent at rest - glutamatergic - express NK1R - hypercapnia (increased CO2 in the blood) is an important stimulus these are all characteristics of:

Answer 56

pFRG/pFL neurons

Question 57

breathing is initiated in the medulla by specialized neurons, but modified by:

Answer 57

higher structures of the CNS, inputs from central and peripheral chemoreceptors, and mechanoreceptors in the lung/chest wall

Question 58

responses to hypercapnia are mediated by:

Answer 58

central and peripheral chemoreceptors

Question 59

responsible for 70% of the response to hypercapnia

Answer 59

central chemoreceptors

Question 60

what is the role of dorsal root ganglia (DRG) and ventral respiratory (VRC) neurons in the response to hypercapnia?

Answer 60

increase respiratory rate and tidal volume to restore appropriate PCO2 and pH levels

Question 61

list two types of respiratory network and sleep disordered breathing

Answer 61

- apneas (can be central, obstructive, or mixed --> see slide 343) - hypoventilation syndromes

Question 62

pauses in breathing that cause hypoxia/hypercapnia

Answer 62

apneas

Question 63

conditions where you still have the drive to breathe, but tidal volume is significantly reduced

Answer 63

hypoventilation syndromes

Question 64

what type of apnea is premature apnea?

Answer 64

a central sleep apnea

Question 65

at what point are premature babies at risk of respiratory instability?

Answer 65

<32 weeks

Question 66

in premature apneas, a dangerous positive feedback loop results from:

Answer 66

a biphasic hypoxic ventilatory response (HVR) and the fact that the hypoxic respiratory depression is very powerful in premature infants

Question 67

what is a risk of providing supplemental oxygen to premature infants?

Answer 67

high oxygen levels are toxic to lung development and can lead to bronchopulmonary dysplasia (BPD)

Question 68

how are apneas in premature infants treated if not with supplemental oxygen?

Answer 68

caffeine/theophylline (aka brain stimulants)

Question 69

what are the clinical issues of treating premature apneas with stimulants?

Answer 69

- not all infants respond to caffeine/theophylline - concerns about exposing developing brains to adenosine receptor antagonists

Question 70

what are other pathological conditions present with central sleep apneas?

Answer 70

heart failure, neurodegenerative disorders (Parkinson's, Alzheimer's, ALS), genetic disorders (Rett syndrome, Prader-Willis syndrome), and drug induced disorders (opiates, anesthetics, alcohol barbituates)

Question 71

how many adults have obstructive sleep apnea (OSA)?

Answer 71

~20%

Question 72

what is the dominant factor in 50% of obstructive sleep apnea (OSA)?

Answer 72

obesity

Question 73

a reduction in upper airway patency during sleep that can be caused by anatomical defects or a reduction in muscle tones of the upper airways

Answer 73

obstructive sleep apnea (OSA)

Question 74

how is obstructive sleep apnea (OSA) treated?

Answer 74

surgery (rear portion of soft palate and uvula are removed), or continuous positive airway pressure (CPAP) therapy

Question 75

a key determinant of upper airway patency

Answer 75

the genioglossus muscle

Question 76

which neurotransmitters increase genioglossus activity?

Answer 76

noradrenaline and serotonin

Question 77

which neurotransmitter decreases genioglossus activity?

Answer 77

acetylcholine

Question 78

which drugs are used to treat obstructive sleep apnea (OSA)?

Answer 78

haha trick question there are none, but there is hope that combination therapy (muscarinic antagonists, serotonergic agonists, and noradrenergic agonists) could work

Question 79

specialized neurons located close to the ventral surface of the medulla (in the retrotrapezoid nucleus) that come in close contact with blood vessels and cerebrospinal fluid

Answer 79

central chemoreceptors

Question 80

- glutamatergic - project to various regions of the respiratory network - tonically active (firing rate depends on pH) - express NK1R, neuromedin B, galanin - express Phox2b transcription factor these are all characteristics of:

Answer 80

neurons of the retrotrapezoid nucleus

Question 81

lesions with substance P - saporin conjugates shor that elimination of NK1R/Phox2b expressing neurons in the retrotrapezoid nucleus impairs the ability of:

Answer 81

mice and rats to respond to CO2

Question 82

the presence of which molecule activates chemoreceptors?

Answer 82

H+ (CO2 + H2O <--> H2CO3 <--> H+ HCO3-)

Question 83

retrotrapezoid nucleus activation by CO2 relies on its intrinsic pH sensitivity via the:

Answer 83

two-pore domain potassium channel TASK-2 and GPR4 (a GPCR)