Lecture 13 - Neural Control of Respiration Flashcards
why is it more important to study neural control of respiration?
- breathing is an autonomic physiological function effestial 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
list the six major parts of the respiratory system
- 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
peripheral pulmonary stretch receptors and peripheral chemoreceptors that monitor arterial oxygen and carbon dioxide provide afferents that terminate centrally in the:
nucleus of the solitary tract
central chemoreceptors in this nucleus monitor CO levels
nucleus of the solitary tract
brainstem rhythm generators in the ventrolateral medulla integrate information from central chemoreceptors with feedback from:
pulmonary stretch receptors
respiratory premotor neurons in the medulla give rise to:
descending axons that innervate inspiratory motorneurons in the cervical spinal cord and thoracic spinal cord (that innervate inspiratory pump muscles)
what are the inspiratory pump muscles?
the diaphragm and external intercostal muscles
go review slide 297
i just cannot write all that down
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:
neuron-neuron communication in the medulla
what are the five major components of the respiratory control network?
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
what is the formula for ventilation?
Ve = (f)(Vt)
Ve - ventilation
f - frequency
Vt - tidal volume
breathing is initiated in the medulla by specialized neurons called the:
- pontine respiratory group (PRG)
- dorsal respiratory group (DRG)
- ventral respiratory column (VRC)
the pontine respiratory group and the dorsal respiratory group (DRG) play an important role in:
providing feedback on breathing
part of the brainstem important for forced expiration
the parafacial respiratory group (pFRG)/ lateral parafacial (pFL)
receives input from carotid bodies about O2 in the head
dorsal respiratory group (DRG)
phrenic motor neurons innervate the:
diaphragm
in virto preparations are used to examine how:
the nervous system controls breathing in newborn animals
what are the seven main advantages of brainstem spinal cord preparations with respect to the respiratory system?
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
is it possible to have spontaneously active respiratory neurons across the respiratory cycle (particularly in vitro)?
yes
the preBotC is _____ and _____ to generate respiratory thythmic activity in mammals
necessary, sufficient
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
serial sectioning
phrenic nerve activity and hypoglossal nerve activity are lost when a transection is performed to separate the ____ from the ____
preBotC, caudal portions of the respiratory network
are respiratory structures unilateral or bilateral?
bilateral
innervates the genioglossus muscle
CN XII (hypoglossal nerve)
- 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:
preBotC neurons
what types of studies were used to determine the necessary role of the preBotC in respiratory control?
- lesion studies
- inactivation studies
- genetic knockout studies
list two lesion studies used to determine the role of the preBotC
- substance P conjugated with saporin
- preBotC laser ablation
list an inactivation study used to determine the role of the preBotC
viral expression of allatostatin receptor in somatostatin (SST) receptors
list a genetic knockout study determine the role of the preBotC
Dbx1 knockout mice
a type I ribosome-inactivating protein that causes cell death
saporin
the conjugate between substance P and saporin interacts with the _____ and the complex will be brought into the cell
neurokinin 1 receptors (NK1R)
what percent of the NK1R need to be destroyed before respiratory breathing is disrupted?
80%
in a medullary slice preparation, calcium activity is recorded with a:
two photon microscope to detect rhythm neurons
the medullary slice preparation is designed to identify respiratory neurons and then:
individually laser ablate the target while monitoring network function in real time
inactivation studies where the allatostatin receptor was expressed in drosophila, it was found that the allatostatin receptor is coupled to _____ and its activation causes _____
GIRK channels (inward-rectifying K+ channels), hyperpolarization in neurons
Dbx1 is expressed in ____ cells in the preBotC
SST/NK1
are SST/NK1 cells detected in knockout mice for Dbx1?
no
do Dbx1 knockout mice exhibit breathing movements at birth?
no
does substance P (a drug that usually activates preBotC neurons) restore rhythm activity in Dbx1 knockout mice?
no
how was the reciprocal inhibition theory of the preBotC tested?
by blocking inhibition, but the study found that eliminating inhibition does not block respiratory activity
how was the pacemaker neuron theory of the preBotC tested?
blocking current responsible for pacemaker properties, but the study found that elimination of pacemaker protperties does not eliminate respiratory rhythms
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
the group pacemaker hypothesis
what is the most recent hypothesis for how respiratory rhythm is generate in the preBotC?
the Burstlet theory
according to the Burstlet theory, if excitability of the preBotC neurons increases, then rhytmic bouts of synchronous low-level population activity (called burstlets) will:
develop into a burst of inspiratory activity (see slide 328)
what muscle groups are activated during quiet inspiration?
the diaphragm and external intercostals
what muscle groups are activated during quiet inspiration?
the diaphragm, external intercostals, scalenes, sternoclaidomastoid, and pectoralis minor
what muscle groups are activated during quiet exhalation?
none, quiet breathing is a passive process
what muscle groups are activated during forced exhalation?
interior intercostals and abdominal wall muscles
true or false: a group of rhythmogenic neurons is found in the parafacial respiratory group (pFRG/PFL)
true
does the lateral parafacial region (pFRG/pFL) activate before or after the preBotC?
before
it is thought that the the lateral parafacial region (pFRG/pFL) is involved in:
forced exhalation
fentanyl supresses activity of _____ but _____ remains intact
the preBotC and inspiratory events, expiratory rhythmic activity
separating the pFRG/pFL from the rest of the respiratory network abolishes:
active expiration (but leaves inspiratory activity intact)
are pFRG/pFL neurons excited or inhibited at rest?
inhibited (remember: quiet exhalation is a passive process)
blocking GABA and glycine neurons in the pFRG/pFL will increase forced expiration, therefore they are important for:
inhibiting forced expiration
- silent at rest
- glutamatergic
- express NK1R
- hypercapnia (increased CO2 in the blood) is an important stimulus
these are all characteristics of:
pFRG/pFL neurons
breathing is initiated in the medulla by specialized neurons, but modified by:
higher structures of the CNS, inputs from central and peripheral chemoreceptors, and mechanoreceptors in the lung/chest wall
responses to hypercapnia are mediated by:
central and peripheral chemoreceptors
responsible for 70% of the response to hypercapnia
central chemoreceptors
what is the role of dorsal root ganglia (DRG) and ventral respiratory (VRC) neurons in the response to hypercapnia?
increase respiratory rate and tidal volume to restore appropriate PCO2 and pH levels
list two types of respiratory network and sleep disordered breathing
- apneas (can be central, obstructive, or mixed –> see slide 343)
- hypoventilation syndromes
pauses in breathing that cause hypoxia/hypercapnia
apneas
conditions where you still have the drive to breathe, but tidal volume is significantly reduced
hypoventilation syndromes
what type of apnea is premature apnea?
a central sleep apnea
at what point are premature babies at risk of respiratory instability?
<32 weeks
in premature apneas, a dangerous positive feedback loop results from:
a biphasic hypoxic ventilatory response (HVR) and the fact that the hypoxic respiratory depression is very powerful in premature infants
what is a risk of providing supplemental oxygen to premature infants?
high oxygen levels are toxic to lung development and can lead to bronchopulmonary dysplasia (BPD)
how are apneas in premature infants treated if not with supplemental oxygen?
caffeine/theophylline (aka brain stimulants)
what are the clinical issues of treating premature apneas with stimulants?
- not all infants respond to caffeine/theophylline
- concerns about exposing developing brains to adenosine receptor antagonists
what are other pathological conditions present with central sleep apneas?
heart failure, neurodegenerative disorders (Parkinson’s, Alzheimer’s, ALS), genetic disorders (Rett syndrome, Prader-Willis syndrome), and drug induced disorders (opiates, anesthetics, alcohol barbituates)
how many adults have obstructive sleep apnea (OSA)?
~20%
what is the dominant factor in 50% of obstructive sleep apnea (OSA)?
obesity
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
obstructive sleep apnea (OSA)
how is obstructive sleep apnea (OSA) treated?
surgery (rear portion of soft palate and uvula are removed), or continuous positive airway pressure (CPAP) therapy
a key determinant of upper airway patency
the genioglossus muscle
which neurotransmitters increase genioglossus activity?
noradrenaline and serotonin
which neurotransmitter decreases genioglossus activity?
acetylcholine
which drugs are used to treat obstructive sleep apnea (OSA)?
haha trick question there are none, but there is hope that combination therapy (muscarinic antagonists, serotonergic agonists, and noradrenergic agonists) could work
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
central chemoreceptors
- 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:
neurons of the retrotrapezoid nucleus
lesions with substance P - saporin conjugates shor that elimination of NK1R/Phox2b expressing neurons in the retrotrapezoid nucleus impairs the ability of:
mice and rats to respond to CO2
the presence of which molecule activates chemoreceptors?
H+
(CO2 + H2O <–> H2CO3 <–> H+ HCO3-)
retrotrapezoid nucleus activation by CO2 relies on its intrinsic pH sensitivity via the:
two-pore domain potassium channel TASK-2 and GPR4 (a GPCR)
