The
blood-brain
barrier
(BBB)
is
critical
for
maintaining
brain
homeostasis
but
susceptible
to
inflammatory
dysfunction.
While
transporter-dependent
efflux
of
some
lipophilic
substrates
across
the
BBB
shows
circadian
variation
due
rhythmic
transporter
expression,
basal
transporter-independent
permeability
and
leakage
nonrhythmic.
Whether
daily
timing
influences
in
response
inflammation
unknown.
Here,
we
induced
systemic
through
repeated
LPS
injections
either
morning
(ZT1)
or
evening
(ZT13)
under
standard
lighting
conditions;
then
examined
a
polar
molecule
that
not
substrate,
sodium
fluorescein.
We
observed
clear
diurnal
permeability,
with
striking
increase
paracellular
leak
specifically
following
injection.
Evening
led
persisting
glia
activation
as
well
was
periphery.
exaggerated
neuroinflammation
disruption
were
suppressed
by
microglial
depletion
keeping
mice
constant
darkness.
Our
data
show
rhythms
responses
drive
variability
breakdown
reveal
time
day
key
regulator
disruption.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Апрель 14, 2024
Abstract
The
blood-brain
barrier
(BBB)
is
critical
for
maintaining
brain
homeostasis
but
susceptible
to
inflammatory
dysfunction.
Permeability
of
the
BBB
lipophilic
molecules
shows
circadian
variation
due
rhythmic
transporter
expression,
while
basal
permeability
polar
non-rhythmic.
Whether
daily
timing
influences
in
response
inflammation
unknown.
Here,
we
induced
systemic
through
repeated
lipopolysaccharide
(LPS)
injections
either
morning
(ZT1)
or
evening
(ZT13)
under
standard
lighting
conditions,
then
examined
a
molecule,
sodium
fluorescein.
We
observed
clear
diurnal
permeability,
with
striking
increase
paracellular
leak
across
specifically
following
LPS
injection.
Evening
led
persisting
glia
activation
and
that
was
not
periphery.
exaggerated
neuroinflammation
disruption
were
suppressed
by
microglial
depletion
keeping
mice
constant
darkness.
Our
data
show
rhythms
responses
drive
variability
breakdown
reveals
time-of-day
as
key
regulator
disruption.
Cell Reports,
Год журнала:
2025,
Номер
unknown, С. 115176 - 115176
Опубликована: Янв. 1, 2025
Microglia,
the
resident
macrophages
of
brain,
are
derived
from
yolk
sac
and
colonize
brain
before
blood-brain
barrier
forms.
Once
established,
they
expand
locally
require
Colony-stimulating-factor-1
receptor
(CSF1R)
signaling
for
their
development
maintenance.
CSF1R
inhibitors
have
been
used
extensively
to
deplete
microglia
in
healthy
diseased
brain.
In
this
study,
we
demonstrated
sex-dependent
differences
microglial
response
inhibitor
PLX3397.
Male
mice
exhibited
greater
depletion
compared
females.
Transcriptomic
flow
cytometry
analysis
revealed
sex-specific
remaining
population,
with
female
upregulating
autophagy
proteostasis
pathways
while
male
increased
mitobiogenesis.
Furthermore,
manipulating
key
receptors
by
using
different
transgenic
mouse
lines
resulted
changes
efficacies
that
were
also
sex
dependent.
These
findings
suggest
survival
mechanisms,
which
might
contribute
well-documented
various
neurological
disorders.
Brain and Behavior,
Год журнала:
2025,
Номер
15(3)
Опубликована: Март 1, 2025
Despite
extensive,
cross-disciplinary
research
revealing
a
relationship
between
early
life
stress
(ELS)
and
an
increased
risk
for
neuropsychiatric
disorders,
the
underlying
processes
mediating
this
are
not
fully
understood.
Further,
majority
of
preclinical
studies
investigating
have
taken
sex
differences
into
consideration.
A
growing
body
work
suggests
that
microglia,
resident
immune
cells
brain,
impacted
by
ELS
contribute
to
some
maladaptive
behavioral
phenotypes
in
adulthood.
Here,
we
utilized
adolescent
social
isolation
(aSI)
model
female
rats
test
role
microglia
effects
on
anxiety-related
behaviors.
The
present
study
sought
determine
whether
ablation
during
aSI
could
prevent
anxiety-like
behaviors
Long
Evans
rats.
colony-stimulating
factor
1
receptor
(CSF1-r)
inhibitor,
PLX3397,
was
provided
chow
ablate
at
start
period
(postnatal
day
(P)
21-42).
During
period,
animals
performed
battery
assays
including
open
field
test,
elevated
plus
maze,
successive
alleys
test.
Following
completion
assays,
brain
tissue
collected
confirm
efficacy
PLX3397
identify
changes
population
density.
Relative
group-housed
(GH)
controls,
showed
locomotor
activity
higher
closed-arm
entries
maze.
Although
effectively
ablated
across
all
animals,
treatment
had
minimal
observed
aSI-associated
phenotypes.
Together,
these
data
suggest
required
adaptations
promoted
aSI.
Future
will
be
needed
assess
Widespread
delivery
of
therapeutic
proteins
to
the
brain
remains
challenging.
To
determine
whether
human
induced
pluripotent
stem
cell
(iPSC)-microglia
(iMG)
could
enable
brain-wide
and
pathology-responsive
cargo,
we
utilized
CRISPR
gene
editing
engineer
iMG
express
Aβ-degrading
enzyme
neprilysin
under
control
plaque-responsive
promoter,
CD9.
further
increased
engraftment
enhances
efficacy,
a
CSF1R-inhibitor
resistance
approach.
Interestingly,
both
localized
in
Alzheimer's
disease
(AD)
mice
reduced
multiple
biochemical
measures
pathology.
However,
within
plaque-dense
subiculum,
reductions
plaque
load,
dystrophic
neurites,
astrogliosis
preservation
neuronal
density
were
only
achieved
following
widespread
microglial
engraftment.
Lastly,
examined
chimeric
models
breast
cancer
metastases
demyelination,
demonstrating
that
adopt
diverse
transcriptional
responses
differing
neuropathologies,
which
be
harnessed
therapeutics
CNS.
Investigative Ophthalmology & Visual Science,
Год журнала:
2025,
Номер
66(4), С. 45 - 45
Опубликована: Апрель 17, 2025
To
investigate
the
role
of
microglial
subtypes
in
mouse
visual
cortex
development,
focusing
on
ocular
dominance
plasticity
and
interactions
with
GABAergic
neurons
extracellular
matrix.
Immunofluorescence
single-nucleus
RNA-sequencing
(snRNA-seq)
were
used
to
study
microglia
binocular
primary
(V1)
from
postnatal
day
(P)
11
P42.
Gene
ontology
(GO)
analysis
assessed
synapse
organization,
impact
disruption
was
examined.
Visual
evoked
potentials
miniature
postsynaptic
current
recordings
are
monitor
functional
changes
V1.
Microglia
underwent
a
marked
expansion
between
P11
P21
stabilized
after
P35,
coinciding
notable
gene
expression
that
aligned
synaptic
remodeling.
GO
at
P14
P28
revealed
significant
enrichment
organization
linked
microglia.
Single-nucleus
RNA
sequencing
identified
six
distinct
clusters,
among
which
two
functionally
relevant
subpopulations
closely
cortical
plasticity.
One
cluster,
enriched
inflammatory
responses
endocytosis,
peaked
P21,
whereas
another
associated
signaling,
exhibited
dynamic
eye
opening
during
critical
period,
significantly
influencing
In
parallel,
perineuronal
nets
(PNNs)
PV(+)
interneuron
populations
increased
reached
steady
levels
by
P42,
suggesting
help
coordinate
timing
inhibitory
circuit
maturation.
Disrupting
function
period
impaired
plasticity,
but
this
effect
reversed
treatment
cessation.
Mechanistically,
depletion
enhanced
numbers,
elevated
PNN
expression,
altered
development.
Our
findings
highlight
specific
as
key
regulators
development
through
their
interneurons
PNNs.
These
insights
advance
our
understanding
contributions
provide
potential
avenues
for
targeting
modulate
Lipofuscin
is
indigestible
garbage
that
accumulates
in
the
autophagic
vesicles
and
cytosol
of
post-mitotic
cells
with
age.
Drs.
Brunk
Terman
postulated
lipofuscin
accumulation
main
or
at
least
a
major
driving
factor
aging.
They
even
posited
evolution
memory
reason
why
we
get
all,
as
stable
synaptic
connections
must
be
maintained
over
time,
meaning
somas
neurons
also
remain
same
locale.
In
other
words,
they
cannot
dilute
out
their
time
through
cell
division.
Mechanistically,
position
certainly
makes
sense
given
rendering
large
percentage
cell’s
lysosomes
useless
almost
negatively
affect
surrounding
microenvironment.
It
may
case
issue
regard
to
current
age-related
disease.
Degradation
situ
an
insurmountable
task
currently.
However,
method
systemic
removal
discussed
herein.
Organ
shortage
is
one
of
the
most
pressing
issues
with
regard
to
human
mortality.
This
issue
further
complicated
by
fact
that
HLA
matching
required
for
patients,
leading
restricted
choices
transplant.
If
organs
or
tissues
from
non-
partially-HLA–matched
donors
could
be
edited
such
they
evade
cytotoxic
T
cells
as
well
natural
killer
cells,
it
would
ameliorate
organ
problem.
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Авг. 30, 2024
Microglia
are
resident
immune
cells
in
the
central
nervous
system,
including
retina
that
surveil
environment
for
damage
and
infection.
Following
retinal
damage,
microglia
undergo
morphological
changes,
migrate
to
site
of
express
secrete
pro-inflammatory
signals.
In
zebrafish
retina,
inflammation
induces
reprogramming
proliferation
Müller
glia
regeneration
neurons
following
or
injury.
Immunosuppression
pharmacological
ablation
reduce
abolish
proliferation.
We
evaluated
architecture
adult
irf8
mutants,
which
have
significantly
depleted
numbers
microglia.
show
mutants
normal
structure
at
3
months
post
fertilization
(mpf)
6
mpf
but
fewer
cone
photoreceptors
by
10
mpf.
Surprisingly,
light-induced
photoreceptor
induced
rod
regeneration.
Light-damaged
retinas
from
both
wild-type
upregulated
expression
mmp-9,
il8,
tnfβ
cytokines.
Our
data
demonstrate
can
regenerate
normally
acute
These
findings
suggest
may
not
be
essential
other
mechanisms
compensate
reduction
numbers.
