Central
control of breathing in mammals: neuronal
circuitry, membrane properties, and
neurotransmitters
A Bianchi, M Denavit-saubié, J
Champagnat
Laboratoire de Neurobiologie
et Neurophysiologie Fonctionnelles, Laboratoire
de Biologie Fonctionnelle du Neurone, Institut
Alfred Fessard, CNRS, France
I. INTRODUCTION In mammals, the
uptake of oxygen and release of carbon dioxide
in the lungs resault from rhytmic contractions
of the diaphragm, intercostal, and abdominal
muscles. The pressures generated by these "pump"
muscles, combined with the flow resistance of
the airways determined by the state of
contraction of both striated and smooth muscles
in them, cause changes in lung volume.
Motoneurons driving the respiratory pump
muscles are located at various levels of the
spinal cord: 1) phrenic motoneurons innervating
the diaphragin at C3-C6; 2) motoneurons
innervating the intercostal muscles at T1-T12
motoneurons innervating the abdominal muscles at
T4-L3.
The motoneurons innervating muscles
controlling airway dimensions are located in the
brain stem. Those for the alae nasi are in the
facial nucleus; those for pharyngeal muscles,
via the glossopharyngeal and pharyngeal branch
of the vagus nerves, are in the nucleus
ambiguus; and those for bronchial smooth muscle,
via the vagi and the larynx, via the recurrent
laryngeal nerves, are also in the nucleus
ambiguus. Other cranial motoneurons innervate
muscles exhibiting rhythmic respiratory
activity. These include 1) hypoglossal
motoneurons for genioglossus muscle that governs
tongue protrusion in inspiration; 2) naso-labial
motoneurons for the muscles surrounding the
nasal passages, via the facial nerve and 3)
tensor veli palatini motoneurons, via the
mandibular branch of the fith nerve, maintain
nasopharyngeal isthmus patency in
inspiration.
These motoneurons are also involved in such
nonrespiratory functions as postural control,
phonation, protective reflexes of the upper
airway (coughing, sneezing, and swallowing), and
such expulsive maneuvers as vomiting,
defecation, parturition, and micturition.
Breathing in mammals relies on a neuronal
network located within the bram stem. Central
control unplies that the central nervous system
(CNS) is intrinsically capable of providing the
proper timing of muscle activation, although
sensory inputs can modulate respiratory rhythm
and pattern and adapt breathing to changes in
state. This neuronal network develops a rhythm
essentially based on two stable phases,
inspiration and expiration. However, a new
concept has proposed that the respiratory rhythm
generates three phases instead of two,
expiration being divided in two phases, ie.,
stage 1 of expiration (or postinspiration) and
stage 2 of expiration.
Altough the basic elements making up this
network are located within the brain stem,
structures outside the brain stem can and do
affect respiration. However, these components
are not essential to the network because their
elimination does not impair rhythmogenesis.
These elements external to the network are
reminiscent of various structures previously
called "centers." The earlier belief that
specific respiratory functions resided within
circumscribed structures (e.g., the pneumotaxic
center) has been modified, by using the term
central pattern generator (CPG) or central
rhythm generator.
As part of the brain stem, neurons of the
respiratory CPG share common morphological and
electrophysiological characteristics with other
brain stem neurons. For example, the axons of
respiratory and nonrespiratory cranial
motoneurons project dorsomedially then
laterally, whereas those of bulbospinal
interneurons first project laterally or medially
then rostrocaudally. However, the respiratory
CPG elaborates a periodic pattern of discharge
that remains spontaneously active throughout
life. Other rhythmic outputs such as
swallowing, coughing, vomiting, or locomotion
are also generated by brainstem neuronal
networks, the neurons of which exhibit
similar augrnenting (ramp) or decrementing
discharge patterns and abrupt phase transitions.
However, these rhythmic nonrespiratory but vital
functions need to be triggered by specific
afferent inputs; moreover, they are
discontinuous (or irregular), whereas breathing
is continuous.
A special feature of the respiratory CPG is
that it functions automatically but can be
controlled voluntarily.
In this way, respiration, as a sensory-motor
act, can be modulated much like posture and
locomotion. The CNS processes afferent inputs to
provide an appropriate motor output. In the
respiratory system, chemosensitive, pulmonary,
and even proprioceptive afférents
determine the appropriate respiratory outputs to
maintain homeostasis. Voluntary control involves
the forebrain, with information being
distributed to premotoneurons and motoneurons
through pyramidal and extrapyramidal pathways.
In contrast, automatic control involves the
brain stem, the output of which is distributed
to interneurons and motoneurons through
proprio-brain stem pathways to cranial
motoneurons, and through pathways in the
ventrolateral spinal cord to interneurons and
motoneurons.
In this review, we describe the factors
contributing to respiratory rhythmogenesis, ie.,
the organization of the respiratory CPG in terms
of its neuronal elements, synaptic connections,
and possible interactions with the different
intrinsic membrane properties of different types
of neurons, interconnections, and
neurotransmitters. It would be an
oversimplification to believe that respiratory
activity is generated by a single pacemaker or a
specific neurotransmitter. Moreover, synaptic
interactions alone cannot adequately explain the
rhythmic character of respiration. Additional
mechanisms, based on intrinsic membrane
properties, are likely responsible for the
transitions between respiratory phases (also
referred to as on- and off-switch functions).
Several groups of neurons with différent
intrinsic properties, specific interconnections,
and neurotransmitters are probably
involved.
Specific neurotransmitters are now known to
be present in fast synaptic transmission and in
neuromodulation of the respiratory CPG.
Excitatory amino acids play an essential role in
the reexcitatory mechanisms, in bulbospinal
transmission of inspiratory drive, and in phase
termination involving cooperative action of
various receptor types. Glycine and
gamma-aminobutyric acid (GABA) acting via
chloride channels mediate inhibitory
postsynaptic effects. Voltage-dependent currents
(e.g., low-threshold calcium current) or
calcium-dependent potassium current are
presumably activated and appear as essential in
the determination of respiratory patterns.
Unfortunately, most of these ionic conductances
have been demonstrated in in vitro preparations,
and their existence in vivo remains to be
unambiguously demonstrated. Although it is
difficult to detennine whether intrinsie
membrane properties obtained in vitro by
membrane voltage manipulation are compatible
with the membrane voltages recorded in vivo, we
propose a network model generating oscillations
of membrane potentials of brain stem neurons as
part of respiratory rhythmogenesis, and based on
dynamic cooperation between synaptically induced
membrane potential changes and intrinsic
membrane properties of the neurons.
V. CONCLUSION
According to our model, respiratory rhythm is
not generated by a single conditional pacemaker
process. Instead, respiration is a sequential
motor behavior, extending over a time scale very
long compared with such fast
electrophysiological events as action potentials
but very slow with respect to long-term
neuromodulatory processes. Respiratory neurons
included in the model are subjected continuously
to excitatory or inhibitory synaptic inputs
which modulate their intrinsic membrane
properties throughout the respiratory cycle. As
already implicit in the three-phase theory,
brain stem respiratory activity results from the
sequential activation of at least six neuronal
populations, leading to two fast phaseswitching
transitions and three relatively long
respiratory phases. Each process is conditioned
by the previous one and initiates the next. A
major problem requiring our future attention is
the determination of how, in contrast to
intermittent motor activity, this sequence of
respiratory rhythm-generating processes is
maintained throughout life.
