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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