Neuromodulators
affect
cognition
and
behavior
via
their
actions
on
brain
wide
neural
networks.
The
locus
coeruleus
norepinephrine
(LC-NE)
system
is
one
of
the
brain’s
major
neuromodulatory
systems.
Aging
neurological
diseases
lead
to
changes
in
structure
that
impact
normal
functioning
networks
Although
precise
nature
this
impact,
its
diagnosis
quantification
remain
a
challenge,
recent
studies
humans
animal
models
have
started
reveal
details
about
effects
intrinsic
neuromodulators
behavior.
These
findings
are
beginning
suggest
how
systems
neuroscience
approaches
might
help
develop
new
tests
supplement
range
established
clinical
assays
for
testing
cognitive
deficits
due
aging
Alzheimer’s
disease.
Here,
I
will
review
what
we
know
perform
computations
driving
perception
action
these
affected
by
activation
LC-NE
system.
examine
known
disease
related
resulting
action.
discuss
relationships
between
pupil
size,
recently
explored
with
precision
models.
how,
when
combined
perceptual
or
tests,
provide
basis
exploring
use
pupillometry
as
non-invasive
assay
age-
disease-related
decline
neuromodulatoryfunction.
Nature Aging,
Journal Year:
2023,
Volume and Issue:
3(9), P. 1128 - 1143
Published: Aug. 31, 2023
Abstract
Changes
in
dopaminergic
neuromodulation
play
a
key
role
adult
memory
decline.
Recent
research
has
also
implicated
noradrenaline
shaping
late-life
memory.
However,
it
is
unclear
whether
these
two
neuromodulators
have
distinct
roles
age-related
cognitive
changes.
Here,
combining
longitudinal
MRI
of
the
substantia
nigra–ventral
tegmental
area
(SN-VTA)
and
noradrenergic
locus
coeruleus
(LC)
younger
(
n
=
69)
older
251)
adults,
we
found
that
integrity
are
differentially
associated
with
performance.
While
LC
was
related
to
better
episodic
across
several
tasks,
SN-VTA
linked
working
Longitudinally,
age
more
negative
change
integrity.
Notably,
changes
reliably
predicted
future
These
differential
associations
nuclei
decline
potential
clinical
utility,
given
their
degeneration
age-associated
diseases.
Nature Aging,
Journal Year:
2024,
Volume and Issue:
4(5), P. 625 - 637
Published: April 25, 2024
Abstract
Autopsy
studies
indicated
that
the
locus
coeruleus
(LC)
accumulates
hyperphosphorylated
tau
before
allocortical
regions
in
Alzheimer’s
disease.
By
combining
vivo
longitudinal
magnetic
resonance
imaging
measures
of
LC
integrity,
positron
emission
tomography
and
cognition
with
autopsy
data
transcriptomic
information,
we
examined
whether
changes
precede
deposition
specific
genetic
features
underlie
LC’s
selective
vulnerability
to
tau.
We
found
integrity
preceded
medial
temporal
lobe
accumulation,
together
these
processes
were
associated
lower
cognitive
performance.
Common
gene
expression
profiles
between
LC–medial
lobe–limbic
map
biological
functions
protein
transport
regulation.
These
findings
advance
our
understanding
spatiotemporal
patterns
initial
spreading
from
disease
pathology.
can
be
a
promising
indicator
for
identifying
time
window
when
individuals
are
at
risk
progression
underscore
importance
interventions
mitigating
spread.
Psychophysiology,
Journal Year:
2025,
Volume and Issue:
62(1)
Published: Jan. 1, 2025
ABSTRACT
The
decline
in
noradrenergic
(NE)
locus
coeruleus
(LC)
function
aging
is
thought
to
be
implicated
episodic
memory
decline.
Transcutaneous
auricular
vagus
nerve
stimulation
(taVNS),
which
supports
LC
function,
might
serve
preserve
or
improve
aging.
However,
taVNS
effects
are
generally
very
heterogeneous,
and
it
currently
unclear
whether
has
an
effect
on
memory.
In
this
study,
emotional
task
with
negative
events
involving
the
LC‐NE
system
was
combined
short
burst
of
event‐related
(3
s)
younger
adults
(
N
=
24).
aim
investigate
taVNS‐induced
changes
pupil
dilation
during
encoding
possible
improvements
(emotional)
performance
for
early
delayed
(24
h)
recognition.
Negative
were
associated
increased
better
performance.
Additionally,
real
as
compared
sham
no
selectively
events.
Short
bursts
stimulation,
sham,
led
increase
improvement
over
time,
likely
due
attention‐inducing
sensory
modulation
electrical
stimulation.
Alzheimer s Research & Therapy,
Journal Year:
2025,
Volume and Issue:
17(1)
Published: Feb. 27, 2025
Abstract
Background
Alzheimer’s
disease
(AD)
is
the
leading
cause
of
dementia,
and
early
detection
disease-associated
changes
allows
interventions.
The
locus
coeruleus
(LC)
has
been
reported
to
be
first
brain
region
develop
tau
pathology
in
AD.
However,
functional
network
LC
both
healthy
aging
AD
largely
unknown
due
technical
difficulties
associated
with
small
size
LC.
In
this
study,
we
used
measurement
spontaneous
pupil
constriction/dilation
as
a
surrogate
for
activity
study
during
aging.
Methods
Thirty-seven
younger
thirty-nine
older
adults
were
included
from
Emory
Healthy
Brain
Study
underwent
resting-state
MRI
while
simultaneously
tracking
diameter.
measurements
diameter
dynamics
reference
signals
connectivity
analysis.
identified
networks
was
then
compared
between
participants.
Correlations
regions
neuropsychological
assessments
cerebrospinal
fluid
(CSF)
biomarkers
also
evaluated.
Results
A
20
clusters
identified,
including
well
functionally
connected
found
positively
correlate
salience
negatively
central
executive
network.
Functional
decreased
within
memory,
executive,
visuospatial
functioning.
CSF
total
closely
correlated
Conclusions
Pupil
provide
valuable
insights
into
LC-related
processes.
While
they
are
not
solely
influenced
by
activity,
constrictor/dilatory
shows
promise
non-invasive
approach
probe
warrants
further
studies
evaluate
its
value
an
biomarker
Molecular Psychiatry,
Journal Year:
2023,
Volume and Issue:
28(6), P. 2412 - 2422
Published: April 5, 2023
Abstract
Autopsy
data
indicate
that
the
locus
coeruleus
(LC)
is
one
of
first
sites
in
brain
to
accumulate
hyperphosphorylated
tau
pathology,
with
rostral
part
possibly
being
more
vulnerable
earlier
stages
disease.
Taking
advantage
recent
developments
ultra-high
field
(7
T)
imaging,
we
investigated
whether
imaging
measures
LC
also
reveal
a
specific
anatomic
correlation
using
novel
plasma
biomarkers
different
species
tau,
how
early
adulthood
these
associations
can
be
detected
and
if
are
associated
worse
cognitive
performance.
To
validate
correlations,
tested
rostro-caudal
gradient
pathology
at
autopsy
from
Rush
Memory
Aging
Project
(MAP).
We
found
higher
phosphorylated
particular
ptau
231
,
correlated
negatively
dorso-rostral
integrity,
whereas
correlations
for
neurodegenerative
markers
(neurofilament
light,
total
tau)
were
scattered
throughout
including
middle
caudal
sections.
In
contrast,
Aβ
42/40
ratio,
amyloidosis,
did
not
correlate
integrity.
These
findings
observed
when
entire
or
hippocampus.
Furthermore,
MAP
data,
than
tangle
density
LC,
independent
disease
stage.
The
vivo
LC-phosphorylated
became
significant
midlife,
earliest
effect
starting
about
age
55.
Finally,
interactions
between
lower
integrity
concentrations
predicted
Together,
demonstrate
vulnerability
dedicated
magnetic
resonance
measures,
highlighting
promise
as
an
marker
AD-related
processes.
Neurobiology of Disease,
Journal Year:
2023,
Volume and Issue:
187, P. 106294 - 106294
Published: Sept. 13, 2023
Interictal
spikes
(IIS)
are
a
common
type
of
abnormal
electrical
activity
in
Alzheimer's
disease
(AD)
and
preclinical
models.
The
brain
regions
where
IIS
largest
not
known
but
important
because
such
data
would
suggest
sites
that
contribute
to
generation.
Because
hippocampus
cortex
exhibit
altered
excitability
AD
models,
we
asked
which
areas
dominate
the
during
along
cortical-CA1-dentate
gyrus
(DG)
dorso-ventral
axis.
medial
septal
(MS)
cholinergic
neurons
overactive
when
typically
occur,
also
tested
novel
hypothesis
silencing
MS
selectively
reduce
IIS.
We
used
mice
simulate
aspects
AD:
Tg2576
mice,
presenilin
2
(PS2)
knockout
Ts65Dn
mice.
To
silence
neurons,
were
bred
with
choline-acetyltransferase
(ChAT)-Cre
offspring
injected
AAV
encoding
inhibitory
designer
receptors
exclusively
activated
by
drugs
(DREADDs).
recorded
local
field
potentials
cortical-CA1-DG
axis
using
silicon
probes
wakefulness,
slow-wave
sleep
(SWS)
rapid
eye
movement
(REM)
sleep.
detected
all
transgenic
or
age-matched
controls.
detectable
throughout
occurred
primarily
REM
In
3
mouse
lines,
amplitudes
significantly
greater
DG
granule
cell
layer
vs.
CA1
pyramidal
overlying
cortex.
Current
source
density
analysis
showed
robust
early
current
sources
DG,
additional
also.
Selective
chemogenetic
reduced
rate
without
affecting
overall
duration,
number
bouts,
latency
sleep,
theta
power
REM.
Notably,
two
control
interventions
no
effects.
Consistent
maximal
amplitude
strong
is
remarkably
active
addition,
reducing
tone,
at
times
hyperactive,
could
be
new
strategy
AD.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: June 3, 2024
Abstract
The
neuromodulatory
subcortical
nuclei
within
the
isodendritic
core
(IdC)
are
earliest
sites
of
tauopathy
in
Alzheimer’s
disease
(AD).
They
project
broadly
throughout
brain’s
white
matter.
We
investigated
relationship
between
IdC
microstructure
and
whole-brain
matter
to
better
understand
early
neuropathological
changes
AD.
Using
multiparametric
quantitative
magnetic
resonance
imaging
we
observed
two
covariance
patterns
133
cognitively
unimpaired
older
adults
(age
67.9
±
5.3
years)
with
familial
risk
for
integrity
related
1)
neurite
density,
2)
orientation
dispersion
tracts
known
be
affected
Pattern
2
was
associated
CSF
concentration
phosphorylated-tau,
indicating
AD
specificity.
Apolipoprotein-E4
carriers
expressed
both
more
strongly
than
non-carriers.
variation
is
reflected
matter,
particularly
AD-affected
tracts,
highlighting
an
mechanism
pathological
development.
