1. Regulation of Respiration
Generating a rhythmic pattern
for the skeletal muscles of
respiration
1

2. 2

3. Respiratory CPG’s
3

4. Respiratory CPG’s
• Neurons of the RF of the medulla
establish the basic rhythmic activity.
(CPG for resp)
3

5. Respiratory CPG’s
• Neurons of the RF of the medulla
establish the basic rhythmic activity.
(CPG for resp)
These partially overlap RF neurons that
regulate CV function.
3

6. Respiratory CPG’s
• Neurons of the RF of the medulla
establish the basic rhythmic activity.
(CPG for resp)
These partially overlap RF neurons that
regulate CV function.
• Other areas of the RF assist, including
neurons in the RF of the pons.
3

7. Simple model oscillator
Positive feedback
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

8. Simple model oscillator
1. 2 populations of neurons:
Positive feedback
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

9. Simple model oscillator
1. 2 populations of neurons:
– inspiratory
Positive feedback
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

10. Simple model oscillator
1. 2 populations of neurons:
– inspiratory
– expiratory Positive feedback
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

11. Simple model oscillator
1. 2 populations of neurons:
– inspiratory
– expiratory Positive feedback
2. Members of a given population are:
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

12. Simple model oscillator
1. 2 populations of neurons:
– inspiratory
– expiratory Positive feedback
2. Members of a given population are:
– mutually excitatory (epsp’s)
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

13. Simple model oscillator
1. 2 populations of neurons:
– inspiratory
– expiratory Positive feedback
2. Members of a given population are:
– mutually excitatory (epsp’s)
– inhibitory to other population (ipsp’s)
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

14. Simple model oscillator
1. 2 populations of neurons:
– inspiratory
– expiratory Positive feedback
2. Members of a given population are:
– mutually excitatory (epsp’s)
– inhibitory to other population (ipsp’s)
3. Depolarize spontaneously following
inhibition (or “pacemakers”?)
There are two types of neurons that behave
exactly like our model and are phase
spanning models 4

15. Oscillator function
5

16. Oscillator function
• Early active inspiratory neuron excites
others 
5

17. Oscillator function
• Early active inspiratory neuron excites
others 
– positive feedback burst of AP’s (I phase)
5

18. Oscillator function
• Early active inspiratory neuron excites
others 
– positive feedback burst of AP’s (I phase)
– inhibition of expiratory neurons
5

19. Oscillator function
• Early active inspiratory neuron excites
others 
– positive feedback burst of AP’s (I phase)
– inhibition of expiratory neurons
• Membrane properties limit duration
and frequency of inspiratory AP’s (PI
phase)
5

20. Oscillator function
• Early active inspiratory neuron excites
others 
– positive feedback burst of AP’s (I phase)
– inhibition of expiratory neurons
• Membrane properties limit duration
and frequency of inspiratory AP’s (PI
phase)
• Expiratory neurons “escape” inhibition
and fire their own burst. (E-2 phase)
5

21. Actual respiratory CPG
6

22. Actual respiratory CPG
6 distinct types of neurons identified:
6

23. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
6

24. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
2. Inspiratory (active throughout I phase)
6

25. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
2. Inspiratory (active throughout I phase)
3. late-I span phase of I-to-E
6

26. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
2. Inspiratory (active throughout I phase)
3. late-I span phase of I-to-E
4. post-I (behave like “expiratory” neurons
of simple oscillator)
6

27. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
2. Inspiratory (active throughout I phase)
3. late-I span phase of I-to-E
4. post-I (behave like “expiratory” neurons
of simple oscillator)
5. E-2 (active only during expiration)
6

28. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
2. Inspiratory (active throughout I phase)
3. late-I span phase of I-to-E
4. post-I (behave like “expiratory” neurons
of simple oscillator)
5. E-2 (active only during expiration)
6. pre-I span phase of E-to-I
6

29. Cellular mechanisms
7

30. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
7

31. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
7

32. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
7

33. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
• “burst” discharge by epsp’s
7

34. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
• “burst” discharge by epsp’s
(glutamate epsp’s  positive feedback)
7

35. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
• “burst” discharge by epsp’s
(glutamate epsp’s  positive feedback)
• “modulation” as K+ channels open
7

36. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
• “burst” discharge by epsp’s
(glutamate epsp’s  positive feedback)
• “modulation” as K+ channels open
• “termination” as Ca2+ channels close
7

37. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
• “burst” discharge by epsp’s
(glutamate epsp’s  positive feedback)
• “modulation” as K+ channels open
• “termination” as Ca2+ channels close
• “reciprocal inhibition” by ipsp’s (glycine, GABA)
7

38. Cellular mechanisms
• ↓ ipsp’s  depolarization (“disinhibition”)
• “trigger” depolarization:
rapid ↑ permeability for Ca2+ & Na+
• “burst” discharge by epsp’s
(glutamate epsp’s  positive feedback)
• “modulation” as K+ channels open
• “termination” as Ca2+ channels close
• “reciprocal inhibition” by ipsp’s (glycine, GABA)
• Cl- / HCO3- permeability modulates
frequency
7

39. 8

40. Overall respiration
9

41. Overall respiration
• The activities of the 6 types  smooth
rhythm of respiration over many rates
and conditions.
9

42. Overall respiration
• The activities of the 6 types  smooth
rhythm of respiration over many rates
and conditions.
• Resulting output spinal cord
9

43. Overall respiration
• The activities of the 6 types  smooth
rhythm of respiration over many rates
and conditions.
• Resulting output spinal cord
 α motor neurons of phrenic nerve
9

44. Overall respiration
• The activities of the 6 types  smooth
rhythm of respiration over many rates
and conditions.
• Resulting output spinal cord
 α motor neurons of phrenic nerve
(and other) nerves
9

45. Overall respiration
• The activities of the 6 types  smooth
rhythm of respiration over many rates
and conditions.
• Resulting output spinal cord
 α motor neurons of phrenic nerve
(and other) nerves
9

46. Overall respiration
• The activities of the 6 types  smooth
rhythm of respiration over many rates
and conditions.
• Resulting output spinal cord
 α motor neurons of phrenic nerve
(and other) nerves
• Earliest “oscillator” in fetus is simpler,
and becomes modified with
maturation. 9

47. Role of the pons
10

48. Role of the pons
• “Phase spanning” neurons of the
medulla and pons “smooth” the
change-over from the inspiratory to
the expiratory phase (and back again)
10

49. Role of the pons
• “Phase spanning” neurons of the
medulla and pons “smooth” the
change-over from the inspiratory to
the expiratory phase (and back again)
• These are also part of the reticular
formation.
10

50. Actual respiratory CPG
6 distinct types of neurons identified:
1. early-I neurons (similar to “inspiratory”
population of simple oscillator)
2. Inspiratory (active throughout I phase)
3. late-I span phase of I-to-E
4. post-I (behave like “expiratory” neurons
of simple oscillator)
5. E-2 (active only during expiration)
6. pre-I span phase of E-to-I
11

51. Other brain areas
12

52. Other brain areas
• The hypothalamus modifies the
pattern of the respiratory CPG in
association with general internal
regulation:
12

53. Other brain areas
• The hypothalamus modifies the
pattern of the respiratory CPG in
association with general internal
regulation:
– temperature regulation
12

54. Other brain areas
• The hypothalamus modifies the
pattern of the respiratory CPG in
association with general internal
regulation:
– temperature regulation
– emotional states
12

55. Other brain areas
• The hypothalamus modifies the
pattern of the respiratory CPG in
association with general internal
regulation:
– temperature regulation
– emotional states
• The cerebral cortex (various areas) 
other patterns, including those based
on learning. (singing, playing a wind
instrument) 12

56. “Fine tuning”
of the
respiratory pattern
13

57. Reflex modifications
14

58. Reflex modifications
• Stretch receptors in the thorax signal
inflation (inhalation).
14

59. Reflex modifications
• Stretch receptors in the thorax signal
inflation (inhalation).
– These afferents  inhibitory synaptic
connections in the medullary CPG.
14

60. Reflex modifications
• Stretch receptors in the thorax signal
inflation (inhalation).
– These afferents  inhibitory synaptic
connections in the medullary CPG.
– NOT influential in normal conditions!
14

61. Reflex modifications
• Stretch receptors in the thorax signal
inflation (inhalation).
– These afferents  inhibitory synaptic
connections in the medullary CPG.
– NOT influential in normal conditions!
• Chemoreceptor effects by PO2, PCO2,
and pH:
14

62. Reflex modifications
• Stretch receptors in the thorax signal
inflation (inhalation).
– These afferents  inhibitory synaptic
connections in the medullary CPG.
– NOT influential in normal conditions!
• Chemoreceptor effects by PO2, PCO2,
and pH:
– peripheral (carotid bodies)
14

63. Reflex modifications
• Stretch receptors in the thorax signal
inflation (inhalation).
– These afferents  inhibitory synaptic
connections in the medullary CPG.
– NOT influential in normal conditions!
• Chemoreceptor effects by PO2, PCO2,
and pH:
– peripheral (carotid bodies)
– CNS (medullary RF)
14

64. Peripheral
Chemoreceptors
Detection of changes in
PO2, pH and/or PCO2
in arterial blood
15

65. Carotid body O2 sensors
16

66. Carotid body O2 sensors
• ↓ PO2  ↑ activity in the sensory
afferents
16

67. Carotid body O2 sensors
• ↓ PO2  ↑ activity in the sensory
afferents
• In turn, the afferents  ↑ ventilation.
16

68. Carotid body O2 sensors
• ↓ PO2  ↑ activity in the sensory
afferents
• In turn, the afferents  ↑ ventilation.
• The mechanism is unusual:
16

69. Carotid body O2 sensors
• ↓ PO2  ↑ activity in the sensory
afferents
• In turn, the afferents  ↑ ventilation.
• The mechanism is unusual:
– In the presence of O2, a special K+
channel is open  hyperpolarization of
the cells.
16

70. Carotid body O2 sensors
• ↓ PO2  ↑ activity in the sensory
afferents
• In turn, the afferents  ↑ ventilation.
• The mechanism is unusual:
– In the presence of O2, a special K+
channel is open  hyperpolarization of
the cells.
– As O2 falls, the K+ channels close,
permitting the sensory cells to depolarize.
16

71. Carotid body O2 sensors
• ↓ PO2  ↑ activity in the sensory
afferents
• In turn, the afferents  ↑ ventilation.
• The mechanism is unusual:
– In the presence of O2, a special K+
channel is open  hyperpolarization of
the cells.
– As O2 falls, the K+ channels close,
permitting the sensory cells to depolarize.
– In turn, this  ↑ AP frequency in the 16

72. 17

73. pH and PCO2 sensors
18

74. pH and PCO2 sensors
• The carotid and aortic bodies also
respond to:
18

75. pH and PCO2 sensors
• The carotid and aortic bodies also
respond to:
– ↓ pH
18

76. pH and PCO2 sensors
• The carotid and aortic bodies also
respond to:
– ↓ pH
– ↑ PCO2
18

77. pH and PCO2 sensors
• The carotid and aortic bodies also
respond to:
– ↓ pH
– ↑ PCO2
• Both changes  ↑ stimulation of
ventilation in the medullary RF CPG.
18

78. pH and PCO2 sensors
• The carotid and aortic bodies also
respond to:
– ↓ pH
– ↑ PCO2
• Both changes  ↑ stimulation of
ventilation in the medullary RF CPG.
• Chronic acid-base changes re-set the
sensitivity of the CPG for these effects.
18

79. Central
Chemoreceptors
Acid-base changes in CSF
or brain ECF adjust ventilation
19

80. 20

81. Pappenheimer’s goats
21

82. Pappenheimer’s goats
• Respiratory mask for varying PCO2
21

83. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
21

84. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
– carotid artery “loop”
21

85. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
– carotid artery “loop”
– jugular vein
21

86. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
– carotid artery “loop”
– jugular vein
• Brain cannulae for:
21

87. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
– carotid artery “loop”
– jugular vein
• Brain cannulae for:
– lateral ventricle (inflow)
21

88. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
– carotid artery “loop”
– jugular vein
• Brain cannulae for:
– lateral ventricle (inflow)
– recovery of CSF outside the brain
(outflow)
21

89. Pappenheimer’s goats
• Respiratory mask for varying PCO2
• Blood measurements:
– carotid artery “loop”
– jugular vein
• Brain cannulae for:
– lateral ventricle (inflow)
– recovery of CSF outside the brain
(outflow)
– allow perfusion past the medulla
21

90. Respiratory regulation
breath-to-breath regulation:
feedback by CO2
22

91. Chronic acid-base changes
23

92. Chronic acid-base changes
• Feeding for 72 hours:
23

93. Chronic acid-base changes
• Feeding for 72 hours:
– weak acid  metabolic acidosis
23

94. Chronic acid-base changes
• Feeding for 72 hours:
– weak acid  metabolic acidosis
– bicarbonate  metabolic alkalosis
23

95. Chronic acid-base changes
• Feeding for 72 hours:
– weak acid  metabolic acidosis
– bicarbonate  metabolic alkalosis
• But blood-brain barrier transport
minimizes the changes in CSF & brain
ECF.
23

96. Chronic acid-base changes
• Feeding for 72 hours:
– weak acid  metabolic acidosis
– bicarbonate  metabolic alkalosis
• But blood-brain barrier transport
minimizes the changes in CSF & brain
ECF.
• However, these changes  resetting of
ventilation due to ↑ PCO2
23

97. Chronic acid-base changes
• Feeding for 72 hours:
– weak acid  metabolic acidosis
– bicarbonate  metabolic alkalosis
• But blood-brain barrier transport
minimizes the changes in CSF & brain
ECF.
• However, these changes  resetting of
ventilation due to ↑ PCO2
– acidosis  shift “left” (more sensitive)
23

98. Chronic acid-base changes
• Feeding for 72 hours:
– weak acid  metabolic acidosis
– bicarbonate  metabolic alkalosis
• But blood-brain barrier transport
minimizes the changes in CSF & brain
ECF.
• However, these changes  resetting of
ventilation due to ↑ PCO2
– acidosis  shift “left” (more sensitive)
– alkalosis  shift “right” (less sensitive)
23

99. CSF HCO3- predicts ventilation
24

100. CSF HCO3- predicts ventilation
• No matter what the acid-base
condition of peripheral blood,
knowing the HCO3- of CSF accurately
predicts ventilation.
24

101. CSF HCO3- predicts ventilation
• No matter what the acid-base
condition of peripheral blood,
knowing the HCO3- of CSF accurately
predicts ventilation.
• Since CSF is in equilibrium with brain
ECF, the same HCO3- bathes medullary
neurons of the respiratory CPG.
24

102. CSF HCO3- predicts ventilation
• No matter what the acid-base
condition of peripheral blood,
knowing the HCO3- of CSF accurately
predicts ventilation.
• Since CSF is in equilibrium with brain
ECF, the same HCO3- bathes medullary
neurons of the respiratory CPG.
• CO2 diffuses rapidly  local acid-base
changes around the medullary
24

103. 25

104. Central chemoreceptors
26

105. Central chemoreceptors
• An inhibitory (ipsp) mechanism of the
cells of the medullary CPG is known to
depend on a special permeability
channel:
26

106. Central chemoreceptors
• An inhibitory (ipsp) mechanism of the
cells of the medullary CPG is known to
depend on a special permeability
channel:
↑ CO2  ↑ H+
26

107. Central chemoreceptors
• An inhibitory (ipsp) mechanism of the
cells of the medullary CPG is known to
depend on a special permeability
channel:
↑ CO2  ↑ H+
 ↓ inhibition of the CPG,
26

108. Central chemoreceptors
• An inhibitory (ipsp) mechanism of the
cells of the medullary CPG is known to
depend on a special permeability
channel:
↑ CO2  ↑ H+
 ↓ inhibition of the CPG,
and therefore ↑ ventilation.
26

109. Central chemoreceptors
• An inhibitory (ipsp) mechanism of the
cells of the medullary CPG is known to
depend on a special permeability
channel:
↑ CO2  ↑ H+
 ↓ inhibition of the CPG,
and therefore ↑ ventilation.
• Chronic acid-base changes interact
with this mechanism. 26

110. Central chemoreceptors (2)
27

111. Central chemoreceptors (2)
• Because CO2 diffuses rapidly, this
mechanism accounts for the sensitive
adjustment of ventilation from breath
to breath.
27

112. Central chemoreceptors (2)
• Because CO2 diffuses rapidly, this
mechanism accounts for the sensitive
adjustment of ventilation from breath
to breath.
• These effects can be more easily seen
in a hibernating mammal breathing ~
once every 2 minutes.
27

113. Central chemoreceptors (2)
• Because CO2 diffuses rapidly, this
mechanism accounts for the sensitive
adjustment of ventilation from breath
to breath.
• These effects can be more easily seen
in a hibernating mammal breathing ~
once every 2 minutes.
• Overall, this central mechanism is
more sensitive than the peripheral
sensors.
27