Proceedings of the National Academy of Sciences,
Journal Year:
2025,
Volume and Issue:
122(15)
Published: April 8, 2025
Various
strategies
targeting
spinal
locomotor
circuitry
have
been
associated
with
functional
improvements
after
cord
injury
(SCI).
However,
the
neuronal
populations
mediating
beneficial
effects
remain
largely
unknown.
Using
a
combination
therapy
in
mouse
model
of
complete
SCI,
we
show
that
virally
delivered
brain-derived
neurotrophic
factor
(BDNF)
(AAV-BDNF)
activates
hindlimb
stepping
and
causes
hyperreflexia,
whereas
submotor
threshold
epidural
stimulation
(ES)
reduces
BDNF-induced
hyperreflexia.
Given
their
role
gating
proprioceptive
afferents
as
potential
convergence
point
BDNF
ES,
hypothesized
an
enhanced
excitability
inhibitory
RORβ
neurons
would
be
improvements.
Ex
vivo
slice
recordings
from
mice
range
hyperreflexia
scores
revealed
was
related
to
outcome
post-SCI.
Mice
poor
function
SCI
had
less
excitable
neurons,
but
similar
between
uninjured
“best
stepping”
groups.
Further,
chemogenetic
activation
reduced
improved
stepping,
ES.
Our
findings
identify
target
population
limit
enhance
SCI.
Journal of Neuroinflammation,
Journal Year:
2025,
Volume and Issue:
22(1)
Published: March 10, 2025
Abstract
Spinal
cord
injury
(SCI)
can
cause
permanent
dysfunction
proceeding
from
multifaceted
neuroinflammatory
processes
that
contribute
to
damage
and
repair.
Fidgetin-like
2
(FL2),
a
microtubule-severing
enzyme
negatively
regulates
axon
growth,
microglial
functions,
wound
healing,
has
emerged
as
potential
therapeutic
target
for
central
nervous
system
injuries
neuroinflammation.
To
test
the
hypothesis
FL2
knockdown
increases
acute
neuroinflammation
improves
recovery
after
SCI,
we
examined
effects
of
nanoparticle-encapsulated
siRNA
treatment
moderate
contusion
SCI
in
rats.
significantly
increased
expression
lesion
site
rostral
1
day
post-injury
(dpi).
A
single
led
modestly
improved
locomotor
consistent
with
preservation
corticospinal
tract
function,
accompanied
by
reduced
inflammation
presence
oligodendrocytes.
In
determining
treatment,
RNA
sequencing
gene
set
enrichment
analyses
revealed
modulates
early
cellular
responses,
including
chemokine
signaling,
both
pro-
anti-inflammatory
immune
reactions,
neurotransmitter
signaling
pathways
at
1,
4,
7
dpi.
Follow-up
4
dpi
using
dual
situ
hybridization
immunohistochemistry
demonstrated
mRNA
was
colocalized
microglia/macrophages.
downregulation
resulted
marked
accumulation
microglia
site,
inflammatory
markers
(IL-1β,
TGF-β1,
CD68).
The
results
suggest
induces
an
increase
undermines
responses
well
spinal
integrity
growth.
Overall,
our
study
suggests
targeting
holds
promise
strategy
treating
SCI.
Proceedings of the National Academy of Sciences,
Journal Year:
2025,
Volume and Issue:
122(15)
Published: April 8, 2025
Various
strategies
targeting
spinal
locomotor
circuitry
have
been
associated
with
functional
improvements
after
cord
injury
(SCI).
However,
the
neuronal
populations
mediating
beneficial
effects
remain
largely
unknown.
Using
a
combination
therapy
in
mouse
model
of
complete
SCI,
we
show
that
virally
delivered
brain-derived
neurotrophic
factor
(BDNF)
(AAV-BDNF)
activates
hindlimb
stepping
and
causes
hyperreflexia,
whereas
submotor
threshold
epidural
stimulation
(ES)
reduces
BDNF-induced
hyperreflexia.
Given
their
role
gating
proprioceptive
afferents
as
potential
convergence
point
BDNF
ES,
hypothesized
an
enhanced
excitability
inhibitory
RORβ
neurons
would
be
improvements.
Ex
vivo
slice
recordings
from
mice
range
hyperreflexia
scores
revealed
was
related
to
outcome
post-SCI.
Mice
poor
function
SCI
had
less
excitable
neurons,
but
similar
between
uninjured
“best
stepping”
groups.
Further,
chemogenetic
activation
reduced
improved
stepping,
ES.
Our
findings
identify
target
population
limit
enhance
SCI.
