Research Square (Research Square),
Год журнала:
2022,
Номер
unknown
Опубликована: Июль 26, 2022
Abstract
Square-wave
bursting
is
an
activity
pattern
common
to
a
variety
of
neuronal
and
endocrine
cell
models
that
has
been
linked
central
generation
for
respiration
other
physiological
functions.
Many
the
reduced
mathematical
exhibit
square-wave
yield
transitions
alternative
pseudo-plateau
with
small
parameter
changes.
This
susceptibility
change
could
represent
problematic
feature
in
settings
where
release
events
triggered
by
spike
production
are
necessary
function.
In
this
work,
we
analyze
how
model
burst
patterns
vary
changes
conductance
fast
inward
current.
Using
numerical
simulations
dynamical
systems
methods,
such
as
fast-slow
decomposition
bifurcation
phase-plane
analysis,
demonstrate
explain
presence
slow
negative
feedback
associated
gradual
reduction
current
these
helps
maintain
spikes
within
active
phases
bursts.
Therefore,
although
not
production,
find
its
generates
robustness
may
be
important
The
rates
of
opioid
overdose
in
the
United
States
quadrupled
between
1999
and
2017,
reaching
a
staggering
130
deaths
per
day.
This
health
epidemic
demands
innovative
solutions
that
require
uncovering
key
brain
areas
cell
types
mediating
cause
overdose-
opioid-induced
respiratory
depression.
Here,
we
identify
two
primary
changes
to
murine
breathing
after
administering
opioids.
These
implicate
brainstem's
circuitry
which
confirm
by
locally
eliminating
µ-Opioid
receptor.
We
find
critical
site
is
preBötzinger
Complex,
where
rhythm
originates,
use
genetic
tools
reveal
just
70-140
neurons
this
region
are
responsible
for
its
sensitivity
Future
characterization
these
may
lead
novel
therapies
prevent
depression
while
sparing
analgesia.Opioids
such
as
morphine
or
fentanyl
powerful
substances
used
relieve
pain
medical
settings.
However,
taken
too
high
dose
they
can
depress
–
other
words,
slow,
shallow
breaths
cannot
sustain
life.
In
States,
misuse
drugs
has
been
soaring
past
decades,
about
people
die
each
day
from
overdose.
Pinpointing
exact
opioids
act
on
could
help
create
safer
painkillers
do
not
have
deadly
effect.
While
previous
studies
proposed
several
regions
be
involved,
able
results,
determine
area
plays
biggest
role.
Opioids
influence
animals
(including
humans)
attaching
proteins
known
receptors
present
at
surface
neurons.
Bachmutsky
et
al.
genetically
engineered
mice
lack
specific
control
breathing.
were
then
exposed
opioids,
their
was
closely
monitored.
experiments
showed
small
becoming
depressed
under
with
most
impact
also
happens
rhythms
originate.
There,
group
50
140
Crucially,
cells
necessary
drugs’
ability
pain.
Overall,
work
highlights
whose
role
creating
deserves
further
attention.
It
opens
possibility
targeting
would
painkillers.
The Journal of Physiology,
Год журнала:
2022,
Номер
600(9), С. 2049 - 2075
Опубликована: Март 16, 2022
Abstract
Twenty‐five
years
ago,
a
new
physiological
preparation
called
the
working
heart–brainstem
(WHBP)
was
introduced
with
claim
it
would
provide
platform
allowing
studies
not
possible
before
in
cardiovascular,
neuroendocrine,
autonomic
and
respiratory
research.
Herein,
we
review
some
of
progress
made
WHBP,
advantages
disadvantages
along
potential
future
applications,
photographs
technical
drawings
all
customised
equipment
used
for
preparation.
Using
mice
or
rats,
WHBP
is
an
situ
experimental
model
that
perfused
via
extracorporeal
circuit
benefitting
from
unprecedented
surgical
access,
mechanical
stability
brain
whole
cell
recording
uncompromised
use
pharmacological
agents
akin
to
vitro
approaches.
The
has
revealed
novel
mechanistic
insights
into,
example,
generation
distinct
rhythms,
neurogenesis
sympathetic
activity,
coupling
between
respiration
heart
circulation,
hypothalamic
spinal
control
mechanisms,
peripheral
central
chemoreceptor
mechanisms.
Insights
have
been
gleaned
into
diseases
such
as
hypertension,
failure
sleep
apnoea.
Findings
ratified
conscious
vivo
animals
when
tested
translated
humans.
We
conclude
by
discussing
applications
including
two‐photon
imaging
nervous
systems
adoption
pharmacogenetic
tools
will
improve
our
understanding
mechanisms
reveal
may
guide
treatment
strategies
cardiorespiratory
diseases.
image
The Journal of Physiology,
Год журнала:
2024,
Номер
602(5), С. 809 - 834
Опубликована: Фев. 14, 2024
Abstract
Breathing
behaviour
involves
the
generation
of
normal
breaths
(eupnoea)
on
a
timescale
seconds
and
sigh
order
minutes.
Both
rhythms
emerge
in
tandem
from
single
brainstem
site,
but
whether
how
cell
population
can
generate
two
disparate
remains
unclear.
We
posit
that
recurrent
synaptic
excitation
concert
with
depression
cellular
refractoriness
gives
rise
to
eupnoea
rhythm,
whereas
an
intracellular
calcium
oscillation
is
slower
by
orders
magnitude
rhythm.
A
mathematical
model
capturing
these
dynamics
simultaneously
generates
frequencies,
which
be
separately
regulated
physiological
parameters.
experimentally
validated
key
predictions
regarding
signalling.
All
vertebrate
brains
feature
network
oscillator
drives
breathing
pump
for
regular
respiration.
However,
air‐breathing
mammals
compliant
lungs
susceptible
collapse,
rhythmogenic
may
have
refashioned
ubiquitous
signalling
systems
produce
second
rhythm
(for
sighs)
prevents
atelectasis
without
impeding
eupnoea.
image
Key
points
simplified
activity‐based
preBötC
inspiratory
neuron
population.
Inspiration
attributable
canonical
excitatory
mechanism.
Sigh
emerges
The
predicts
perturbations
uptake
release
across
endoplasmic
reticulum
counterintuitively
accelerate
decelerate
rhythmicity,
respectively,
was
validated.
Vertebrate
evolution
adapted
existing
mechanisms
slow
oscillations
needed
optimize
pulmonary
function
mammals.
How
mammalian
neural
circuits
generate
rhythmic
activity
in
motor
behaviors,
such
as
breathing,
walking,
and
chewing,
remains
elusive.
For
rhythm
generation
is
localized
to
a
brainstem
nucleus,
the
preBötzinger
Complex
(preBötC).
Rhythmic
preBötC
population
consists
of
strong
inspiratory
bursts,
which
drive
motoneuronal
activity,
weaker
burstlets,
we
hypothesize
reflect
an
emergent
rhythmogenic
process.
If
burstlets
underlie
rhythmogenesis,
respiratory
depressants,
opioids,
should
reduce
burstlet
frequency.
Indeed,
medullary
slices
from
neonatal
mice,
μ-opioid
receptor
(μOR)
agonist
DAMGO
slowed
generation.
Genetic
deletion
μORs
glutamatergic
subpopulation
abolished
opioid-mediated
depression,
neuropeptide
Substance
P,
but
not
blockade
inhibitory
synaptic
transmission,
reduced
opioidergic
effects.
We
conclude
that
rhythmogenesis
process,
modulated
by
does
rely
on
bursts
associated
with
output.
These
findings
also
point
strategies
for
ameliorating
opioid-induced
depression
breathing.
The Journal of Physiology,
Год журнала:
2020,
Номер
598(21), С. 4969 - 4994
Опубликована: Июль 4, 2020
Contraction
of
abdominal
muscles
at
the
end
expiration
during
metabolic
challenges
(such
as
hypercapnia
and
hypoxia)
improves
pulmonary
ventilation.
The
emergence
this
active
expiratory
pattern
requires
recruitment
oscillator
located
on
ventral
surface
medulla
oblongata.
Here
we
show
that
an
inhibitory
circuitry
in
Bötzinger
complex
is
important
source
drive
to
oscillator.
This
circuitry,
mediated
by
GABAergic
glycinergic
synapses,
provides
inhibition
restrains
under
resting
condition
regulates
formation
activity
expiration.
By
combining
experimental
modelling
approaches,
propose
organization
connections
within
respiratory
network
control
changes
breathing
associated
with
elevated
demand.The
neurons
(BötC)
provide
inputs
network,
which,
eupnoea,
are
critically
for
phase
transition
duration
control.
Here,
investigated
how
BötC
interact
parafacial
group
(pFRG)
Using
decerebrated,
arterially
perfused
situ
preparations
juvenile
rats,
recorded
performed
pharmacological
manipulations
pFRG
or
after
exposure
short-term
sustained
hypoxia
-
conditions
generate
data
were
integrated
a
mathematical
model
gain
new
insights
into
connectome
central
generator.
Our
results
indicate
may
establish
mutual
pFRG,
providing
first
stage
receiving
excitatory
late
Moreover,
found
application
antagonists
caused
opposing
effects
activity,
suggesting
BötC.
modelling,
its
interactions
restrain
contribute
observed
hypoxia.
Inspiratory
breathing
rhythms
arise
from
synchronized
neuronal
activity
in
a
bilaterally
distributed
brainstem
structure
known
as
the
preBötzinger
complex
(preBötC).
In
vitro
slice
preparations
containing
preBötC,
extracellular
potassium
must
be
elevated
above
physiological
levels
(to
7–9
mM)
to
observe
regular
rhythmic
respiratory
motor
output
hypoglossal
nerve
which
preBötC
projects.
Reexamination
of
how
K
+
affects
has
revealed
that
low-amplitude
oscillations
persist
at
levels.
These
oscillatory
events
are
subthreshold
standpoint
transmission
and
dubbed
burstlets.
Burstlets
neural
rhythmogenic
subpopulation
within
some
instances
may
fail
recruit
larger
network
events,
or
bursts,
required
generate
output.
The
fraction
(burstlet
fraction)
decreases
sigmoidally
with
increasing
potassium.
observations
underlie
burstlet
theory
rhythm
generation.
Experimental
computational
studies
have
suggested
recruitment
non-rhythmogenic
component
population
requires
intracellular
Ca
2+
dynamics
activation
calcium-activated
nonselective
cationic
current.
this
study,
we
show
calcium
driven
by
synaptically
triggered
influx
well
release/uptake
endoplasmic
reticulum
conjunction
current
can
reproduce
offer
an
explanation
for
many
key
properties
associated
Altogether,
our
modeling
work
provides
mechanistic
basis
unify
wide
range
experimental
findings
on
generation
preBötC.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(19)
Опубликована: Май 1, 2024
How
breathing
is
generated
by
the
preBötzinger
complex
(preBötC)
remains
divided
between
two
ideological
frameworks,
and
a
persistent
sodium
current
(I