Challenges and Opportunities in Exploring Non‐Motor Symptoms in 6‐Hydroxydopamine Models of Parkinson's Disease: A Systematic Review
Journal of Neurochemistry,
Год журнала:
2025,
Номер
169(2)
Опубликована: Фев. 1, 2025
ABSTRACT
Parkinson's
disease
(PD)
is
a
neurodegenerative
disorder
characterized
by
the
progressive
loss
of
midbrain
dopaminergic
neurons,
leading
to
motor
symptoms
such
as
tremors,
rigidity,
and
bradykinesia.
Non‐motor
symptoms,
including
depression,
hyposmia,
sleep
disturbances,
often
emerge
in
early
stages
PD,
but
their
mechanisms
remain
poorly
understood.
The
6‐hydroxydopamine
(6‐OHDA)
rodent
model
well‐established
tool
for
preclinical
research,
replicating
key
non‐motor
PD.
In
this
review,
we
systematically
analyzed
135
studies
that
used
6‐OHDA
models
PD
investigate
symptoms.
review
process
adhered
Preferred
Reporting
Items
Systematic
Reviews
Meta‐Analyses
(PRISMA)
guidelines.
Our
analysis
highlights
growing
use
experimental
research
It
also
reveals
significant
variability
methodologies,
choices
brain
target,
toxin
dosage,
lesion
verification
strategies,
behavioral
assessment
reporting.
Factors
hinder
reproducibility
comparability
findings
across
studies.
We
highlight
need
standardization
6‐OHDA‐based
with
particular
emphasis
on
consistent
evaluation
extent
reporting
co‐occurrence
By
fostering
methodological
coherence,
framework
aims
enhance
reproducibility,
reliability,
translational
value
symptom
research.
image
Язык: Английский
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
Опубликована: Март 5, 2025
Several
studies
have
revealed
that
midbrain
dopamine
(DA)
neurons,
even
within
a
single
neuroanatomical
area,
display
heterogeneous
properties.
In
parallel,
using
cell
profiling
techniques
begun
to
cluster
DA
neurons
into
subtypes
based
on
their
molecular
signatures.
Recent
work
has
shown
molecularly
defined
the
substantia
nigra
(SNc)
distinctive
anatomic
and
functional
properties,
differential
vulnerability
in
Parkinson’s
disease
(PD).
Based
these
provocative
results,
granular
understanding
of
putative
alterations
PD
models,
is
imperative.
We
developed
an
optimized
pipeline
for
single-nuclear
RNA
sequencing
(snRNA-seq)
generated
high-resolution
hierarchically
organized
map
revealing
20
distinct
neuron
belonging
three
main
families.
integrated
this
data
with
spatial
MERFISH
technology
map,
high
definition,
location
mouse
midbrain,
heterogeneity
sub-structures.
Finally,
we
demonstrate
preclinical
LRRK2
G2019S
knock-in
model
PD,
subtype
organization
proportions
are
preserved.
Transcriptional
occur
many
including
those
localized
ventral
tier
SNc,
where
expression
observed
synaptic
pathways,
which
might
account
previously
described
release
deficits
model.
Our
provides
advancement
current
taxonomic
schemes
subtypes,
view
locations,
prodromal
PD.Teaser:
Using
snRNASeq
identified
mapped
location,
Язык: Английский
Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model
eLife,
Год журнала:
2023,
Номер
12
Опубликована: Авг. 14, 2023
Midbrain
dopamine
(mDA)
neurons
comprise
diverse
cells
with
unique
innervation
targets
and
functions.
This
is
illustrated
by
the
selective
sensitivity
of
mDA
substantia
nigra
compacta
(SNc)
in
patients
Parkinson’s
disease,
while
those
ventral
tegmental
area
(VTA)
are
relatively
spared.
Here,
we
used
single
nuclei
RNA
sequencing
(snRNA-seq)
approximately
70,000
mouse
midbrain
to
build
a
high-resolution
atlas
neuron
diversity
at
molecular
level.
The
results
showed
that
differences
between
groups
could
best
be
understood
as
continuum
without
sharp
subtypes.
Thus,
assigned
several
‘territories’
‘neighborhoods’
within
shifting
gene
expression
landscape
where
boundaries
gradual
rather
than
discrete.
Based
on
enriched
patterns
these
territories
neighborhoods,
were
able
localize
them
adult
midbrain.
Moreover,
because
underlying
mechanisms
for
variable
sensitivities
pathological
insults
not
well
understood,
analyzed
surviving
after
partial
6-hydroxydopamine
(6-OHDA)
lesions
unravel
correlate
vulnerability
resilience.
Together,
this
provides
basis
further
studies
neurophysiological
role
health
disease.
Язык: Английский
Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity
Neuron,
Год журнала:
2024,
Номер
112(20), С. 3470 - 3485.e12
Опубликована: Авг. 16, 2024
The
globus
pallidus
externus
(GPe)
is
a
central
component
of
the
basal
ganglia
circuit
that
acts
as
gatekeeper
cocaine-induced
behavioral
plasticity.
However,
molecular
and
mechanisms
underlying
this
function
are
unknown.
Here,
we
show
GPe
parvalbumin-positive
(GPe
Язык: Английский
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
Опубликована: Ноя. 21, 2024
Several
studies
have
revealed
that
midbrain
dopamine
(DA)
neurons,
even
within
a
single
neuroanatomical
area,
display
heterogeneous
properties.
In
parallel,
using
cell
profiling
techniques
begun
to
cluster
DA
neurons
into
subtypes
based
on
their
molecular
signatures.
Recent
work
has
shown
molecularly
defined
the
substantia
nigra
(SNc)
distinctive
anatomic
and
functional
properties,
differential
vulnerability
in
Parkinson’s
disease
(PD).
Based
these
provocative
results,
granular
understanding
of
putative
alterations
PD
models,
is
imperative.
We
developed
an
optimized
pipeline
for
single-nuclear
RNA
sequencing
(snRNA-seq)
generated
high-resolution
hierarchically
organized
map
revealing
20
distinct
neuron
belonging
three
main
families.
integrated
this
data
with
spatial
MERFISH
technology
map,
high
definition,
location
mouse
midbrain,
heterogeneity
sub-structures.
Finally,
we
demonstrate
preclinical
LRRK2
G2019S
knock-in
model
PD,
subtype
organization
proportions
are
preserved.
Transcriptional
occur
many
including
those
localized
ventral
tier
SNc,
where
expression
observed
synaptic
pathways,
which
might
account
previously
described
release
deficits
model.
Our
provides
advancement
current
taxonomic
schemes
subtypes,
view
locations,
prodromal
PD.
Язык: Английский
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019Smodel of Parkinson’s disease
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 8, 2024
Abstract
Several
studies
have
revealed
that
midbrain
dopamine
(DA)
neurons,
even
within
a
single
neuroanatomical
area,
display
heterogeneous
properties.
In
parallel,
using
cell
profiling
techniques
begun
to
cluster
DA
neurons
into
subtypes
based
on
their
molecular
signatures.
Recent
work
has
shown
molecularly
defined
the
substantia
nigra
(SNc)
distinctive
anatomic
and
functional
properties,
differential
vulnerability
in
Parkinson’s
disease
(PD).
Based
these
provocative
results,
granular
understanding
of
putative
alterations
PD
models,
is
imperative.
We
developed
an
optimized
pipeline
for
single-nuclear
RNA
sequencing
(snRNA-seq)
generated
high-resolution
hierarchically
organized
map
revealing
20
distinct
neuron
belonging
three
main
families.
integrated
this
data
with
spatial
MERFISH
technology
map,
high
definition,
location
mouse
midbrain,
heterogeneity
sub-structures.
Finally,
we
demonstrate
preclinical
LRRK2
G2019S
knock-in
model
PD,
subtype
organization
proportions
are
preserved.
Transcriptional
occur
many
including
those
localized
ventral
tier
SNc,
where
expression
observed
synaptic
pathways,
which
might
account
previously
described
release
deficits
model.
Our
provides
advancement
current
taxonomic
schemes
subtypes,
view
locations,
prodromal
PD.
Teaser:
Using
snRNASeq
identified
mapped
location,
Язык: Английский
VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Ноя. 8, 2024
Abstract
Alzheimer’s
disease
(AD)
patients
exhibit
neuropsychiatric
symptoms
that
extend
beyond
classical
cognitive
deficits,
suggesting
involvement
of
subcortical
areas.
Here,
we
investigated
the
role
midbrain
dopamine
(DA)
neurons
in
AD
using
amyloid
+
tau-driven
3xTg-AD
mouse
model.
We
found
deficits
reward-based
operant
learning
mice,
possible
VTA
DA
neuron
dysregulation.
Physiological
assessment
revealed
hyperexcitability
and
disrupted
firing
caused
by
reduced
activity
small-conductance
calcium-activated
potassium
(SK)
channels.
RNA
sequencing
from
contents
single
patch-clamped
(Patch-seq)
identified
up-regulation
SK
channel
modulator
casein
kinase
2
(CK2),
which
corroborated
immunohistochemical
protein
analysis.
Pharmacological
inhibition
CK2
restored
normal
patterns
mice.
These
findings
identify
a
mechanism
ion
dysregulation
could
contribute
to
behavioral
abnormalities
AD,
paving
way
for
novel
treatment
strategies.
Язык: Английский
Sox9 and Nfi transcription factors regulate the timing of neurogenesis and ependymal maturation in dopamine progenitors
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 14, 2024
Abstract
Correct
timing
of
neurogenesis
is
critical
for
both
generating
the
correct
number
and
subtypes
glia
neurons
in
embryo,
as
well
preventing
tumours
depletion
stem
cell
pools
adults.
Here
we
analyse
how
midbrain
dopamine
neuron
(mDA)
progenitors
transition
into
cycle
arrest
(G0)
begin
to
mature
ependymal
cells.
The
comparison
mDA
from
different
embryonic
stages
revealed
upregulation
Nfi
Sox9
transcription
factors
during
development.
Their
conditional
inactivation
early
leads
delayed
G0
entry
maturation,
reduced
gliogenesis,
increased
generation
neurons,
including
neurons.
In
contrast,
their
late
embryogenesis
does
not
result
mitotic
re-entry,
suggesting
that
these
are
necessary
induction,
but
its
maintenance.
Our
characterisation
mDA-progenitor-derived
adult
cells
by
single-cell
RNA
sequencing
histology
show
they
retain
several
progenitor
features
also
secrete
neuropeptides
contact
neighbouring
blood
vessels,
indicating
may
form
a
novel
part
circumventricular
organ
system.
Язык: Английский
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
Опубликована: Ноя. 21, 2024
Several
studies
have
revealed
that
midbrain
dopamine
(DA)
neurons,
even
within
a
single
neuroanatomical
area,
display
heterogeneous
properties.
In
parallel,
using
cell
profiling
techniques
begun
to
cluster
DA
neurons
into
subtypes
based
on
their
molecular
signatures.
Recent
work
has
shown
molecularly
defined
the
substantia
nigra
(SNc)
distinctive
anatomic
and
functional
properties,
differential
vulnerability
in
Parkinson’s
disease
(PD).
Based
these
provocative
results,
granular
understanding
of
putative
alterations
PD
models,
is
imperative.
We
developed
an
optimized
pipeline
for
single-nuclear
RNA
sequencing
(snRNA-seq)
generated
high-resolution
hierarchically
organized
map
revealing
20
distinct
neuron
belonging
three
main
families.
integrated
this
data
with
spatial
MERFISH
technology
map,
high
definition,
location
mouse
midbrain,
heterogeneity
sub-structures.
Finally,
we
demonstrate
preclinical
LRRK2
G2019S
knock-in
model
PD,
subtype
organization
proportions
are
preserved.
Transcriptional
occur
many
including
those
localized
ventral
tier
SNc,
where
expression
observed
synaptic
pathways,
which
might
account
previously
described
release
deficits
model.
Our
provides
advancement
current
taxonomic
schemes
subtypes,
view
locations,
prodromal
PD.Teaser:
Using
snRNASeq
identified
mapped
location,
Язык: Английский
In vivo multiplex imaging of dynamic neurochemical networks with designed far-red dopamine sensors
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 23, 2024
Neurochemical
signals
like
dopamine
(DA)
play
a
crucial
role
in
variety
of
brain
functions
through
intricate
interactions
with
other
neuromodulators
and
intracellular
signaling
pathways.
However,
studying
these
complex
networks
has
been
hindered
by
the
challenge
detecting
multiple
neurochemicals
vivo
simultaneously.
To
overcome
this
limitation,
we
developed
single-protein
chemigenetic
DA
sensor,
HaloDA1.0,
which
combines
cpHaloTag-chemical
dye
approach
G
protein-coupled
receptor
activation-based
(GRAB)
strategy,
providing
high
sensitivity
for
DA,
sub-second
response
kinetics,
an
extensive
spectral
range
from
far-red
to
near-infrared.
When
used
together
existing
green
red
fluorescent
neuromodulator
sensors,
Ca2+
indicators,
cAMP
optogenetic
tools,
HaloDA1.0
provides
versatility
multiplex
imaging
cultured
neurons,
slices,
behaving
animals,
facilitating
in-depth
studies
dynamic
neurochemical
networks.
Язык: Английский