bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: Oct. 19, 2023
Abstract
The
pigment
neuromelanin,
produced
in
the
locus
coeruleus
(LC)
as
a
byproduct
of
catecholamine
synthesis,
gives
“blue
spot”
its
name,
and
both
identifies
LC
neurons
is
thought
to
play
an
important
yet
complex
role
normal
pathological
aging.
Using
neuromelanin-sensitive
T1-weighted
turbo
spin
echo
MRI
scans
we
characterized
volume
neuromelanin
signal
intensity
96
participants
between
ages
19
86.
Although
did
not
change
significantly
throughout
lifespan,
increased
from
early
adulthood,
peaked
around
age
60
precipitously
declined
thereafter.
Neuromelanin
was
greater
caudal
relative
rostral
extent
women
men.
With
regard
function,
associated
with
fluid
cognition
older
adults
(60+)
only
those
above
50th
percentile
cognitive
ability
for
age.
gradual
accumulation
across
sudden
dissipation
later
life,
relation
preserved
consistent
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: June 8, 2024
Selective
manipulation
of
neural
circuits
using
optogenetics
and
chemogenetics
holds
great
translational
potential
but
requires
genetic
access
to
neurons.
Here,
we
demonstrate
a
general
framework
for
identifying
tool-independent,
pharmacological
strategies
circuit-selective
modulation.
We
developed
an
economically
accessible
calcium
imaging-based
approach
large-scale
scans
endogenous
receptor-mediated
activity.
As
testbed
this
approach,
used
the
mouse
locus
coeruleus
due
combination
its
widespread,
modular
efferent
circuitry
wide
variety
endogenously
expressed
GPCRs.
Using
machine
learning-based
action
deconvolution
retrograde
tracing,
identified
agonist
cocktail
that
selectively
inhibits
medial
prefrontal
cortex-projecting
Acta Neuropathologica Communications,
Journal Year:
2025,
Volume and Issue:
13(1)
Published: Feb. 28, 2025
The
locus
coeruleus
(LC)
has
been
identified
as
a
site
that
develops
phosphorylated
tau
pathology
earlier
than
cerebral
cortex.
We
present
data
using
high-resolution
postmortem
MRI
and
validated
histopathology
in
controls
the
earliest
Braak
(BB)
stages
(BBI-BBII)
LC.
ex
vivo
provides
3D
volume
(quantitative),
while
histology
reveals
specificity
severity
burden
(semi-quantitative).
mapped
our
highly
regionally
specific
LC
onto
reconstructions
of
same
samples
used
(n
=
11).
noted
significant
structural
subatrophy
between
BB
0
II
(30.0%
smaller
volumes,
p
0.0381),
trend
which
primarily
affected
rostral-most
(49.2%
average
volume,
0.0381).
show
on
both
neighboring
dorsal
raphe
caudal
(DRc),
were
assessed
at
multiple
rostrocaudal
levels
with
sensitive
spatial
matrices.
observed
accumulation
I
(37.6%
increase,
<
0.0001),
may
reflect
change
prior
to
presumptive
cognitive
impairment
III.
Tau
was
most
severe
middle
portion
(11.3%
greater
compared
rostral
LC,
0.0289)
when
including
gradient
DRc
(58.2%
decrease
DRc,
suggesting
selective
regional
vulnerabilities
nuclei.
Our
study
represents
rigorous
approach
investigating
pathology,
having
sections
per
sublevel
measure
whole
without
missing
slices
histological
only
approach.
Taken
together,
findings
provide
novel
demonstrate
occurring
during
preclinical
AD
stages,
alongside
will
serve
valuable
references
for
imaging.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2023,
Volume and Issue:
unknown
Published: March 10, 2023
Abstract
The
locus
coeruleus
(LC),
the
major
source
of
norepinephrine
(NE)
in
brain,
is
an
early
site
pathology
both
Alzheimer’s
disease
(AD)
and
Parkinson’s
(PD),
it
undergoes
catastrophic
degeneration
later
disorders.
Dysregulation
LC
thought
to
contribute
prodromal
symptoms
AD
PD
such
as
anxiety
sleep
disturbances,
while
frank
LC-NE
loss
promotes
cognitive
decline.
However,
mechanisms
responsible
for
its
selective
vulnerability
are
unknown.
among
only
structures
brain
that
produces
appreciable
amounts
neuromelanin
(NM),
a
dark
cytoplasmic
pigment.
It
has
been
proposed
NM
initially
plays
protective
role
by
sequestering
toxic
catecholamine
metabolites
heavy
metals,
but
may
become
harmful
during
aging
overwhelms
cellular
machinery
released
neurodegeneration.
Rodents
do
not
naturally
produce
NM,
limiting
study
causal
relationships
between
pathology.
Adapting
viral-mediated
approach
expression
human
tyrosinase,
enzyme
peripheral
melanin
production,
we
successfully
promoted
pigmentation
mouse
neurons
recapitulates
key
ultrastructural
features
endogenous
found
primates.
Pigment
results
neuron
hyperactivity,
reduced
tissue
NE
levels,
transcriptional
changes,
novelty-induced
phenotypes
1-week
post-injection.
By
6-10
weeks,
accumulation
associated
with
severe
neurodegeneration
microglial
engulfment
pigment
granules,
anxiety-like
behavior
abated.
These
reminiscent
dysfunction
cell
death
PD,
validating
this
model
studying
consequences
relates
neurodegenerative
disease.
Brain,
Journal Year:
2023,
Volume and Issue:
146(12), P. 4794 - 4795
Published: Nov. 15, 2023
This
scientific
commentary
refers
to
‘Neuromelanin
accumulation
drives
endogenous
synucleinopathy
in
non-human
primates’
by
Chocarro
et
al.
(https://doi.org/10.1093/brain/awad331).
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: May 23, 2024
Whole-brain
intrinsic
activity
as
detected
by
resting-state
fMRI
can
be
summarized
three
primary
spatiotemporal
patterns.
These
patterns
have
been
shown
to
change
with
different
brain
states,
especially
arousal.
The
noradrenergic
locus
coeruleus
(LC)
is
a
key
node
in
arousal
circuits
and
has
extensive
projections
throughout
the
brain,
giving
it
neuromodulatory
influence
over
coordinated
of
structurally
separated
regions.
In
this
study,
we
used
optogenetic-fMRI
rats
investigate
impact
LC
stimulation
on
global
signal
We
report
small,
spatially
specific
changes
distribution
result
tonic
stimulation,
well
regional
at
5
Hz
15
phasic
stimulation.
also
found
that
had
little
no
effect
complex
principal
component
analysis.
results
show
effects
BOLD
may
small
regionally
concentrated,
opposed
widespread
globally
acting.
