15-­‐10-­‐15

Last  Class:  the  genesis  of  breathing…    

Rhythmogenic microcircuits or Central

Pattern Generators (CPGs) provide neural
computations by circuits controlling
rhythmic movements that are limited to:
1. Rhythm generation –transformation of tonic drive
(rhythmic afferent input not needed) into repetitive
signals that determine the period of the cycle

2. Pattern generation –distribution and modulation of

this signal to activate participating muscles with
appropriate force and timing
Feldman & Kam: The Journal of Physiology593: 3-23, 2014

Last  Class:  pa#ern  of  phrenic  motoroneuron  discharge  

ì  
Single motorneurons

ç  Integrated nerve Ryan Chow: looks like tidal volume tracing

recording

Whole nerve recording

ì  
Integrated  nerve  recording=  RecAfy  &  Integrate  
• flip  all  acAon  potenAal  deflecAons  posiAve  &    
• sum  the  area  under  the  curves    
Milano  et  al.,  J.Appl.Physiol.  1992    

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Last  Class:  recall  Mming  of  pump  vs  resistance  nerves  

VOLUME  
VT  

FLOW  
INSP.  
• Resp.  
0  
EXP.   Muscles  
INTEGRATED  
NERVE  ACTIVITY  
• “Pump”  
PHRENIC  N.   DIAPHRAGM  
vs  
RECURRENT   LARYNGEAL  
LARYNGEAL  N.   ABDUCTION  

ROLLING   • “Resistance”  
HYPOGLOSSAL  N.   STONES  

• note  Aming  
TIME

Brainstem  structures  with  respiratory  neurons  

Transverse Sections
Dorsal View Caudal VRG:  long  column  resp  
brainstem of medulla
neurons  containing:  
-­‐ nucleus  ambiguus,  NA   Ryan Chow: for upper airways
-­‐ nucl.  retroambiguus  RA  
-­‐ Botzinger  complex  &  
-­‐ pre-­‐Botzinger  complex  
-­‐ Mix  of  Inspiratory  &  
expiratory  cells  
-­‐ Segregated  column  of  
neurons    
PRG  =  ponAne  respiratory  group   -­‐ NA  cell  bodies  project  to  
larynx  via  ipsilat  vagus  
Nucleus  RA  I/E  neurons  cross  midline  to  project    to  spinal  cord    
e.g.  phrenic,  intercostal  &  others  

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Brainstem  structures  with  respiratory  neurons  

Transverse Sections
Dorsal View Caudal
brainstem of medulla

Pre-­‐Botzinger  Complex  
…….
-­‐ Site  of  rhythmogenesis    

-­‐ “Complex  mechanisms”    

-­‐ network  of  neurons  

resulAng  in  respiratory  
rhythm    

Google:  Jack  Feldman  UCLA  

 

Brainstem  structures  with  respiratory  neurons  

Transverse Sections
Dorsal View Caudal
brainstem of medulla
DRG:  dorsomedial  medulla  -­‐  
subnucleus  of  solitary  tract  
-­‐ Afferents  for  
glossopharyngeal  &  vagus  
nerves  

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Last  class:  Rhythmogenesis,  the  origins  of  mammalian    

respiraMon  in  neural  microcircuits  

PMN=premotor neurons
MN=motor neurons

Feldman & Kam: The Journal of Physiology593: 3-23, 2014

Modelling  mammalian    respiraMon  in  

neural  microcircuits  

An “early” model

Ryan Chow: Post-inspiratory: still some neurons firing

after peak tidal volume

Lindsay Rybak & Smith : Compr Physiology 2013

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Spinal  cord  &  control  of  breathing  

Location of Phrenic,
intercostal & abdominal
motoneurons Phrenic  mn:  longitudinal  
oriented  column    
Intercostal  mn:  External/
Internal  motor  columns  
through  thoracic  spinal  cord  
Abdominal  mn:  lower  
thoracic  &  upper  lumbar  
cord  

Spinal  cord  &  control  of  breathing  

Descending tracts for spinal
respiratory motoneurons

Dorsal
AutomaAc  respiratory  drive  
to  breathe:  ventrolateral   Ryan Chow: a tube is required when sleeping!
columns  
Voluntary  respiratory   Ryan Chow: allow breathing when sleeping
control:  corAcospinal  tract  
in  dorsolateral  spinal  cord  
 
Ventral Can  they  be  separated  in  
disease?  

Medial Lateral

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Control  of  breathing:  ObjecAves  

• Describe  ObstrucAve  Sleep  
Apnea  (OSA)  from  a  control  of   • Brain  stem  regions:  
breathing  perspecAve   • Impact  of  neural  

þ þ
• List  the  3  general  features  of  a   secAons  in  the  brain  
respiratory  controller  &  the   • Role  of  medulla,  pons  
primary  components   and  cortex  in  breathing  
• Outline  the  organizaAon  of   • Name  brain  stem  
brain  stem  respiratory  regions   structures  with  
respiratory  neurons  

Control  of  breathing:  ObjecAves  

• Spinal  cord  mechanisms  

• IdenAfy  the  brain  region   of  respiraAon  :  
responsible  for  generaAon  of   • Name  the  locaAons  of  

þ
rhythmic  breathing    
• Describe  the  role  of  a  
spinal  phrenic   þ
motorneurons  and  the  
mammalian  rhythm  generator   muscle  they  innervate  
• Contrast  automaAc  and  
voluntary  respiratory  
spinal  pathways  

Mr.  A.L.  integrated  control  of  breathing  &  disease…  

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Control  of  breathing:  chemorecepAon  

• Name  3  sAmuli  to  breathe   • Discuss  the  shape  of  the   Ryan Chow: O2, co2, H+
caroAd  body  response  
• IdenAfy  the  locaAon  of  peripheral   to  hypoxia  and  its  
chemoreceptors,  cell  body   evoluAonary  raAonale  
locaAon  &  sensory  pathways  to  
• Describe  the  central  
the  CNS  
chemoreceptor  areas  
• Compare  and  contrast  the   and  their  role  in  the  
chemoreceptor  mechanisms  for   venAlatory  response  to  
oxygen  and  carbon  dioxide   CO2  
•  Describe  the  caroAd  body  
response  to  hypoxia,  CO2  and  H+  

“Chemical”  Control  of  breathing:  

ChemorecepAon  
• Neural  pathways  from  
peripheral  arterial  
chemosensors      plus  
• CNS  pathways  that  
drive  breathing   CaroAd  sinus  nerve  
External  CaroAd  
  artery  
Hypoxia  -­‐  Low  oxygen   Ryan Chow: sense hypoxia
-­‐ CaroAd  bodies  
Ryan Chow: also sense hypoxia
-­‐ Hi  blood  flow   rco
 
stal ons  
r
Inte orneu
t
mo
-­‐  The  “California”  experience…   Ryan Chow: WAYYY higher than other regions of the body
Ryan Chow: therefore, ideal for sensing what's in the
blood

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CaroAd  body:  cellular  anatomy  

To  what  brain  area?  

• Type  I  cells  or  glomus  

Ryan Chow: responsible for sensation
cells  
• Type  II  cells   Ryan Chow: provide afferent signal
sustentacular  cells  that  
surround  Tyoe  I  cells     Type  II    
Cell    
 
Sensory  endings  synapAc  
link  with  Type  I  cells;    
Type  I  responsible  for  
sensaAon   Type  II  Cell    

CaroAd  body:  cellular  anatomy  

• Senses  PO2  of  arterial  

blood  
• Not  saturaAon  
• Carbon  monoxide  has   Type  I    
no  effect.   Cell     Ryan Chow: since the blood flow is so great, this is
indicative of whole body O2 levels

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CaroAd  body:  Afferent  response  

Nonlinear  response.  
• Large  é  discharge  at  
PO2  <  60  mmHg  
PaCO2=57  mmHg  
Ryan Chow: higher CO2... more sensitive?
pH=7.22  

External  CaroAd  
  artery   Ryan Chow: at around 60 mmHg, they become more
PaCO2=35  mmHg  
Hypoxia  -­‐  Low  oxygen   pH=7.33   sensitive
-­‐ CaroAd  bodies  
Ryan Chow: even at extremely high pO2 levels, there is
-­‐ Hi  blood  flow   SOME activity
-­‐  The  California  experience   Ryan Chow: therefore, the carotid body is NOT sensitive at
high levels of oxygen

Ryan Chow: Carotid bodies were taken out for severe

asthma.

CaroAd  body:  Afferent  response  

A Polymodol AFferent Receptor
Impact  of  hydrogen  ion  on  caroAd  body  discharge  
Arterial  [H+]=70  nM  

Ryan Chow: as hydrogen concentration increases,

PaCO2  =  26  mmHg  
sensitivity to CO2 increases.

Ryan Chow: constant CO2 with varying Hydrogen

concentration

Ryan Chow: keeping Hydrogen ion concentration constant

as PaCO2 changes for three values

Change  CO2  at  diff  [H+]  or  change  [H+]  @  constant  PCO2  

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CaroAd  body:  VenAlaAon  vs  Afferent  

 
acAvity  

VenAlaAon    
VenAlaAon  
Experiments    

(L/min)  
that  made    
the  connecAon  
AcAon  potenAals   CaroAd  chemoreceptor  
(spikes/s)   AcAvity  

Why  is  this  an  evoluAonary  advantage?  

Oxyhemoglobin  dissociaAon  curve  

• Sigmoid  shape  
• Flat  Plateau  region  
protects  arterial  
content.  
• Steep  slope<  60mmHg  
• promotes  unloading  
small  !PO2  cause  
large  !  Hb  saturaAon  

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 15-­‐10-­‐15  

The sensor for hypoxia mirrors the O2 dissociation curve of Hemoglobin! ie. we sense hypoxia
so we can stimulate hemoglobin saturation

Matching the O2 dissociation curve to

chemoreceptors activity
0

Rotate 90
degrees left 20

counter

Saturation (%)
clockwise 40

(also depicts
The lung) 60

80

100
0 20 40 60 80 100
PO2 (mmHg)
(JB  Downs  Respir  Care  48:  611-­‐20,  2003)  
 
Ryan Chow: so in Carbon monoxide poisoning, CO will
bind with greater affinity to Hg. But since there is still pO2,
no response in carotid body
CaroAd  body:  PaO2  vs  SaturaAon  
VenAlaAon   Hemoglobin    
SaturaAon  
VenAlaAon  (L/min)  

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VenAlatory  response  is  sensiAve    

to  drug-­‐induced  reducAons  
Ryan Chow: makes the carotid body less sensitive

The  Human  Response  to  hypoxia  

Hypercapnic   Ryan Chow: hypercapnic... ie. higher than normal
PCO2=48  mmHg   ventilation
VenAlaAon  (L/min)  

Recall  the  California    

experience  
Ryan Chow: an isocapnic response... ventilation is
drastically increased

Ryan Chow: remember: metabolism doesn't change

ß  PCO2  

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Central  chemoreceptors  
The  search  for  central  
chemoreceptors  
-­‐ 1950’s  perfuse  brain  with  
acidic  CSF    
-­‐ 1960’s  Mitchell  &  
Loeschcke  IdenAfied  
regions  on  the  ventral  
surface  of  the  medulla  
that  increased  breathing  
R  =  rostral  area  
C  =  caudal  area  
 

Central  chemoreceptors  
Central  chemoreceptor  
contribuAon  to  
venAlatory  responses:  
-­‐ approx  2/3  of  the  
venAlatory  response  
to  CO2  
-­‐ Since  H+  does  not  
cross  the  blood  brain  
barrier  the  hydraAon  
of  CO2  is  criAcal    

CO2  +  H2O  à  H2  CO3  à  H+  +  HCO3    

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The  Human  Response  to  CO2  

VenAlaAon  (L/min)  

• VenAlatory  responses  are  powerfully  modulated  by  sleep    

and  drugs.  

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Control  of  breathing:  chemorecepAon  

• Name  3  sAmuli  to  breathe   • Discuss  the  shape  of  the  
caroAd  body  response  
• IdenAfy  the  locaAon  of  peripheral   to  hypoxia  and  its  
chemoreceptors,  cell  body   evoluAonary  raAonale  
the  CNS  þ
locaAon  &  sensory  pathways  to  

• Compare  and  contrast  the  

•
þ
Describe  the  central  
chemoreceptor  areas  
and  their  role  in  the  
chemoreceptor  mechanisms  for   venAlatory  response  to  
oxygen  and  carbon  dioxide   CO2  
•  Describe  the  caroAd  body  
response  to  hypoxia,  CO2  and  H+  

15