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CONTROL OF PH HOMEOSTASIS, MOTOR CONTROL AND NEURAL TISSUE HOMEOSTASIS ARE NOT ACTUALLY RELATED, BUT ARE DISTINCT AND INDEPENDENT ROLES THAT ARE SHARED BY THE 5HT SYSTEM
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SEROTONINERGIC NEURONS AS
CARBON DIOXIDE SENSORS
THAT MANTAIN PH
HOMEOSTASIS
MSCs: Angelo Bruschi, MD
[G.B.Richerson. Nature Reviews Neuroscience 5, 449-461, Jun. 2004]
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One of the essential tasks for maintaining life is breathing,
not only for oxygen, but also to maintains carbon dioxide levels
within a narrow range.
The most important thing our brain does is to keep us alive.
INTRODUCTION (I)
Central chemoreceptors in the brainstem ( VLMS) monitor
carbon dioxide levels (PCO2) and control lung ventilation.
A variations of pH in blood as
little as 0.1μM is fatal.
Central
Chemoreceptors
Respiratory Control
NetworkDiaphragm
(e.g. Hypercapnic Acidosis) (Tonic drive in respiratory centre) (Contraction of muscles)
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There is a high concentration of serotonin (5-HT)-immunoreactive nerveterminals within the main respiratory nuclei, and these nuclei also containnerve terminals that are immunoreactive for substance P and thyrotropin-releasing hormone (TRH).
The nerve terminals arise from serotonergic neurons in the medullary raphéand ventrolateral medulla.
SEROTONINERGIC NEURONS (II)
Serotonergic neurons in
the medullary raphé
project to all of the main
respiratory nuclei,
including the nucleus
tractus solitarius, nucleus
ambiguus, preBötzinger
complex, Bötzinger
complex, hypoglossal
motor nucleus (XII) and
phrenic motor nucleus.
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Serotonergic neuronsseem primarily to have anEXCITATORY effect onbreathing, and they arethought to provide tonicdrive to maintainrespiratory output duringwakefulness. (see fig.)
However, there is evidencethat 5-HT can have anINHIBITORY effect onsome elements of thenetwork that controlsrespiratory output, and asubset of 5-HT neuronsmight inhibit respiratoryoutput.
SEROTONINERGIC NEURONS (III)
Respiratory airflow in a rat in vivo
Fentanyl induces respiratory depression, and
is reversed 5-HT4a agonist BIMU8.
+ CARBON DIOXIDE SENSORS (IV)
MEDULLARY 5-HT NEURONS ARE CO2/PH
CHEMORECEPTORS
A subset is highly sensitive to changes
in CO2 (see figure)
A different subset of neurons (15%) is
equally sensitive to changes in CO2 but
with an opposite response
All CO2 stimulated neurons from the
medullary raphé, but none of the CO2
inhibited neurons, are serotonergic.
SEROTONERGIC NEURONS MIGHT MODULATE SOME NON-RESPIRATORY
BRAINSTEM AND SPINAL CORD FUNCTIONS IN RESPONSE TO CHANGES
IN CARBON DIOXIDE.
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Changes in arterial carbon dioxide
probably influence breathing indirectly
through changes in brain pH. Medullary
serotonergic neurons are highly sensitive
to intracellular pH, and their relationship
with blood vessels is consistent with a
specialized role as arterial carbon
dioxide sensors. Lesions of these
neurons lead to blunting of the ventilatory
response to increased carbon dioxide.
CARBON DIOXIDE SENSORS (V)
Confocal imaging after
immunohistochemistry for
tryptophan hydroxylase shows
SEROTONINERGIC NEURONS
closely associated with the
BASILARY ARTERY (B) and its
main MIDLINE BRANCHES
+ CARBON DIOXIDE SENSORS (VI)
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5-HT, TRH and substance P enhance excitability of the respiratory
network through numerous mechanisms and at multiple sites within the
respiratory network, including rhythm-generating neurons, respiratory
premotor neurons and respiratory motor neurons.
SEROTONERGIC RAPHE HAS A ROBUST ABILITY TO CONTROL
VENTILATION
RESPIRATORY NETWORK
STIMULI(VII)
+ RESPIRATORY NETWORK
STIMULI(VIII)
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Serotonergic neurons in the midbrain also sense carbon
dioxide.
MIDBRAIN 5-HT NEURONS (IX)
Confocal images of arteries
and 5ht neurons in the
midbrain. SEROTONINERGIC
NEURONS closely associated
with ARTERIES
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5HT-neurons in the midbrain might have a role in inducing various
non-respiratory effects, such as AROUSAL from sleep, ANXIETY
and changes in cerebrovascular TONE (migraine)
(A single breath of 35% of CO2 induces anxiety in normal people)
MIDBRAIN 5-HT NEURONS (X)
Exercise has profound effect on acid/base balance, serotoninergic
system could couple motor control with Ph control
(Co2 level drop during exercise in many species)
CONTROL OF PH HOMEOSTASIS, MOTOR CONTROL AND NEURAL
TISSUE HOMEOSTASIS ARE NOT ACTUALLY RELATED, BUT ARE
DISTINCT AND INDEPENDENT ROLES THAT ARE SHARED BY THE 5HT
SYSTEM
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A role for serotonergic neurons in pH control might help to explain how three
seemingly unrelated human disorders — sudden infant death syndrome
(SIDS), panic disorder and migraine — could all be linked to this single,
relatively homogeneous, small group of neurons.
CONCLUSION (XI)
+FUTURE STUDIES SHOULD CONSIDER THE RELEVANCE OF THE LARGE
RESPONSE OF THE RAPHE NEURONS TO ACIDOSIS, AND THE DIRECT
INVOLVEMENT OF A SUBSET OF THESE NEURONS IN CENTRAL
RESPIRATORY CHEMORECEPTION.
MIDBRAIN 5-HT NEURONS (X)
Parable of the Blind Man
(drawing from K. Hokusai)
“Focusing too
closely on
individual
parts blurs a
bigger picture”
+THANKS FOR THE
ATTENTION