Download Pontine control of breathing

DR MATHIAS DUTSCHMANN
Respiratory research
Dr Mathias Dutschmann discusses how his research into pontine respiratory areas
and neural dysfunctions is forging new insights into neurogenic breathing disorders
centres before translational research could
become a logical next step.
As the neural phase of respiration that
occurs after the inspiration of air into the
lungs, can you expand on the function of
postinspiration?
Could you outline your professional and
academic background and inspirations?
During my civil service in Germany I worked
as a paramedic, which sparked my strong
motivation to study respiration and control
of the autonomic function. The job of a
paramedic is to secure the vital functions
and this made me realise that I wanted to
understand how the brain controls these
essential functions. After studying zoology
and neurophysiology at the University of
Tübingen, Germany, I completed my postdoc
at the University of Göttingen, Germany, and
the University of Bristol, UK. I have since held
lecturer positions in Göttingen, Marseille
and Leeds.
Over the course of my career I have had
many inspirational teachers and mentors
including my PhD supervisor Professor Horst
Herbert from the University of Tübingen,
Professor Julian Paton at the University of
Bristol, Professor Diethelm Richter from the
University of Göttingen and Dr Gerard Hilaire
at the Université Paul Cezanne in Marseille.
What are you centring your research
efforts on at present?
I focus on the pontine control of breathing.
My main research efforts at present surround
the role the pontine respiratory areas – that
is, the parabrachial complex and KöllikerFuse nucleus – in neurogenic breathing
disorders. However, it has taken more than
10 years to establish the fundamental role
of these often neglected pontine breathing
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The function of postinspiratory activity
is to transiently constrict the larynx, that
counteracts the mechanical recoil force of the
expanded lung (which is highest right after
inspiration), and increases the time period
for gas exchange in the lungs. The same
activity occurs during vocalisation and speech.
Moreover, postinspiration is also critical for
the protection of the lungs – for instance,
the postinspiratory system closes the larynx
during swallowing. In this instance it prevents
the aspiration of food or fluids into the lung
by sealing the trachea.
The brainstem – the core unit of the brain
– controls the movement of the tongue
muscle and directs airflow patterning
required for vocalisation. What led you to
focus your studies in this area?
Firstly, I find the brainstem, with its respiratory
control circuits, the most attractive research
subject in the mammalian brain. It is always
active, from the first breath at birth to the
last breath before death. Unsurprisingly, its
huge importance means that this network is
extremely robust and can be studied in its
entirety from a cellular to a complex
network level – with a large variety
of experimental techniques
being capable of analysing its
functions. Because of the
robustness and anatomical
compactness of this
brainstem circuit, the
respiratory network could
be the first neural network
that is understood in detail.
Secondly, while respiration is
often studied in the context
of its role as a vital function,
the fact that breathing is
also used for vocalisation
in animals and speech in
humans is somewhat more
neglected. For me, one of
the most exciting research
questions is to ask how
a rhythmogenic neural
network – which is constantly producing
muscle contractions to draw air in and out
of the lungs – is adapted and used by other
brain areas to produce sound and, ultimately,
vocalisation and speech.
DR MATHIAS DUTSCHMANN
Breathing easy
Building on an extensive body of research into neural systems,
researchers at the Florey Institute of Neuroscience and Mental Health
are conducting novel studies that aim to advance diagnoses and therapies
Looking back on your research, what have
been your greatest successes to date?
The biggest achievements have definitely
been putting the respiratory control centres
of the pontines back on the scientific
map and linking the neural dysfunction
of these pontine circuits to neurogenic
breathing disorders.
How do you envisage respiratory
research developing in the coming years?
Do you have any plans for future projects
on the horizon?
The most exciting project is being supported
by funds from the Florey Institute of
Neuroscience and Mental Health and
the Australian Research Council (ARC)
which tackles a fundamental research
question. Basically, we want to visualise
the activity of a population of up to 100
nerve cells in the pontines during learning
and memory of breathing patterns. We are
currently extending our established imaging
techniques to paradigms for this and hope
to be able to visualise learning and memory
processes online and in real-time within the
next two to three years.
NEUROLOGICAL DISORDERS ARE prevalent
throughout the world, representing a source of
substantial suffering for both patients and carers.
The extension of life expectancy, together with
ageing populations in developed and developing
countries alike, means that degenerative
neurological conditions are projected to become
increasingly more widespread in future. This is
likely to impose an increased economic burden
on societies across the world, signifying the
paramount importance of therapeutic research
for disorders of the nervous system.
However, the discovery of cures for neurological
disorders is dependent on achieving a more
robust understanding of how neural systems
work. One prominent researcher operating on
this principle is Dr Mathias Dutschmann. Based
at the Florey Institute of Neuroscience and
Mental Health in Melbourne, Australia, he has
devoted the past 15 years of his research to the
study of the organisation of the postinspiratory
system, exploring its intrinsic link to learning
and memory. The respiratory network found
in the brainstem is highly complex; as the
most active area of the brain, it continually
generates and regulates breathing activity,
as well as controlling the movement of the
tongue muscles and airflow patterns necessary
for vocalisation.
Crucially, Dutschmann’s fundamental research
into the postinspiratory system has prepared
the groundwork for the implementation of
novel and topical translational studies. Drawing
on the detailed knowledge they have garnered
throughout the course of their research, he and
his team are currently conducting three projects
that aim to translate their research findings
into practical applications for the diagnosis
and treatment of three common neurological
disorders: aspiration pneumonia, dementia and
obstructive sleep apnoea (OSA).
DIAGNOSING DEMENTIA
Dementia is a growing healthcare challenge,
with early diagnosis still proving difficult.
However, a growing body of evidence suggests
that one early symptom of dementia is impaired
olfaction, or a reduced ability to detect odours.
Importantly, odours can be grouped into several
different classes: trigeminal odours, which have
a direct neural pathway to brainstem respiratory
centres, and non-trigeminal odours, which
are linked to cortical function. With research
strongly suggesting that neurodegeneration in
dementia starts in the brainstem, one possible
diagnostic tool for the early detection of the
disease would be to test the patient’s ability
to detect trigeminal odours in comparison
to non-trigeminal odours by monitoring
their respiration.
In response to this, Dutschmann and his team
are investigating brain activity markers in
mice with a progressive dementia phenotype.
Promisingly, their initial results demonstrate
that certain olfactory impairments correlate
with marked changes in the activity of specific
brain areas: “We hope that an atlas of detailed
brain impairments, linked to well-defined
olfactory dysfunctions, will translate into a
general guideline for the diagnosis of early
dementia in humans,” Dutschmann elucidates.
“Our approach could also promote tailored
therapy for the affected brain areas.”
ADDRESSING ASPIRATION PNEUMONIA
Aspiration pneumonia, an illness caused by the
accidental inhalation of food or fluid, is common
in those with dementia. Dutschmann and his team
are therefore using transgenic mouse models
to conduct detailed studies into the central
mechanisms that underpin dementia-related
swallowing disorders. They have pinpointed a
pontine brainstem area that is central to airway
protection during swallowing, which shows severe
tauopathy – that is, neurodegeneration – in mice
that display swallowing disorders. Importantly,
autopsies on human patients who died as a
result of aspiration have revealed signs of severe
tauopathy in the same area of the brainstem.
The objective of Dutschmann’s translational
research in this field is threefold: firstly, to
discover the impact of tauopathy on the
synaptic function of pontine airway protective
neurons; secondly, to examine the tauopathyinduced chemical changes that occur in these
neurons; and lastly, to determine whether
the same chemical changes occur in human
dementia patients with a history of aspiration.
It is hoped that this will pave the way for
the implementation of circuit therapy for
swallowing disorders in dementia patients,
improving their safety when eating and helping
to restore their quality of life.
EXPELLING OBSTRUCTIVE SLEEP APNOEA
OSA causes disrupted breathing during sleep,
and is linked to a variety of neurodegenerative
disorders. One of the key characteristics of this
condition is the relaxation of the muscles and
soft tissues in the upper airways during sleep
– and, importantly, muscle tone in the upper
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PONTINE CONTROL OF BREATHING
OBJECTIVE
To understand the neurophysiological
principles of respiratory network function
TEAM MEMBERS
Dr Davor Stanic; Dr Tara G Bautista; Sarah
E Jones, The Florey Institute of Neuroscience
and Mental Health, Victoria, Australia
KEY COLLABORATORS
Professor Robin McAllen; Professor Steven
Petrou; Professor Andrew Gundlach;
Professor Chris Reid; Dr David Farmer;
Dr Davide Martelli, The Florey Institute
of Neuroscience and Mental Health,
Victoria, Australia • Professor Julian Paton,
University of Bristol, Bristol, UK • Professor
Veronica Egger, University of Regensburg,
Regensburg, Germany • Professor Swen
Hülsmann, University of Göttingen,
Göttingen, Germany • Professor Thomas
Dick, Case Western Reserve University, Ohio,
USA • Professor Hiroshi Onimaru, Showa
University, Shinagawa-ku, Tokyo, Japan •
Professor Richard Wilson, University of
Calgary, Calgary, Canada • Professor Eugene
Nalivaiko, University of Newcastle, New
South Wales, Australia
respiratory tract is determined by motor neurons
in the brainstem. While previous OSA studies
have explored how motor neurons change their
activity during sleep, Dutschmann and his team
have focused on the role of pre-motor circuits – a
component that has previously been overlooked:
“These motor circuits are one level higher up
in the upper airway motor control system,” he
reveals. “We have found the first sets of selective
cell markers for a specific and important premotor control area of the tongue. This will allow
us to target these pre-motor cells specifically with
genetically-engineered tools or pharmacology.”
At present, the researchers are planning to
develop a rodent model for OSA that will allow
them to investigate the role of these pre-motor
cells in more detail. The goal is that this will
lead to the identification of drugs that target
pre-motor neurons on the tongue, and hence
restore tongue muscle tone during sleep. This
would represent a substantial achievement,
pinpointing and targeting the root cause of OSA
while avoiding unnecessary side effects
A FULLER UNDERSTANDING
Dutschmann’s extensive research into the
postinspiratory system has broken significant
ground for practical applications that could lead
to better health outcomes for patients suffering
with neurological conditions. Looking ahead,
he is keen to continue working on translational
projects in the areas of dementia, aspiration
and OSA. In addition, Dutschmann plans to
target why the areas of the brain in which
learning and memory processes occur seem
to be more susceptible to neurodegenerative
diseases. Ultimately, the hope is that a broader
understanding of neurological disorders will
lead to earlier diagnoses, better treatments and
an improved quality of life for patients.
FUNDING
Australian Research Council (ARC) Future
Fellowship • Kenneth Myer Fellowship from
the Florey Institute of Neuroscience and
Mental Health
CONTACT
Dr Mathias Dutschmann
The Florey Institute of Neuroscience and
Mental Health
30 Royal Parade (corner Genetics Lane)
Parkville, Victoria 3052
Australia
T +61 3 9035 6789
E [email protected]
www.florey.edu.au
MATHIAS DUTSCHMANN studied biology
(zoology and neurophysiology) at the
Eberhard Karls University of Tübingen where
he obtained his PhD in 1998, and DSc in
2004. His European research career has
encompassed academic positions (teaching
and/or research) at the universities of
Göttingen (Germany), Bristol (UK), Leeds
(UK) and the Université Paul Cezanne
(France). Dutschmann is now Principal
Research Fellow at the Florey Institute of
Neuroscience and Mental Health.
POSTINSPIRATION
In order to ventilate the lungs, specific pressure gradients are needed between the atmosphere
and the lungs themselves. This is facilitated by continuous rhythmic contractions of the
striated muscles which enable the efficient flow of air into and out of the lungs. This process of
ventilation consists of a two-phase cycle of inspiration and expiration. Conversely, the central
circuits that generate and control breathing movements comprise of a respiratory cycle that has
three distinct stages: inspiration, postinspiration and expiration.
While it is easy to link the neural expression of inspiration and expiration to the physical acts
of lung inflation and deflation, the function of postinspiration is often misunderstood and
underappreciated. It is much more obvious in reptiles, where the breath-hold following inspiration
completely arrests ventilation until expiration starts again. In mammals, postinspiration merges
into the early stage of expiration, where it slows the expiratory airflow without completely
arresting lung ventilation.
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