Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 2, 2025
Protein/protein
interactions
(PPI)
play
crucial
roles
in
neuronal
functions.
Yet,
their
potential
as
drug
targets
for
brain
disorders
remains
underexplored.
The
fibroblast
growth
factor
14
(FGF14)/voltage-gated
Na+
channel
1.6
(Nav1.6)
complex
regulates
excitability
of
medium
spiny
neurons
(MSN)
the
nucleus
accumbens
(NAc),
a
central
hub
reward
circuitry
that
controls
motivated
behaviors.
Here,
we
identified
compound
1028
(IUPAC:
ethyl
3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate),
brain-permeable
small
molecule
FGF14R117,
critical
residue
located
within
druggable
pocket
at
FGF14/Nav1.6
PPI
interface.
We
found
modulates
assembly
and
depolarizes
voltage-dependence
Nav1.6
inactivation
with
nanomolar
potency
by
modulating
intramolecular
interaction
between
III-IV
linker
C-terminal
domain
channel.
Consistent
compound's
effects
on
inactivation,
enhances
MSN
ex
vivo
accumbal
neuron
firing
rate
murine
models.
Systemic
administration
maintains
behavioral
motivation
preferentially
during
motivationally
deficient
conditions
These
were
abrogated
gene
silencing
Fgf14
NAc
accompanied
selective
reduction
dopamine
levels
consumption
findings
underscore
to
selectively
regulate
behaviors
associated
neuropsychiatric
through
targeting
PPIs
neurons.
interfaces
have
emerged
develop
medications
less
side
effects.
Dvorak
et
al.
show
is
an
approach
psychiatric
discovery.
Harvard Review of Psychiatry,
Год журнала:
2020,
Номер
28(6), С. 371 - 394
Опубликована: Ноя. 1, 2020
Abstract
Initiating
and
maintaining
behavior
change
is
key
to
the
prevention
treatment
of
most
preventable
chronic
medical
psychiatric
illnesses.
The
cultivation
mindfulness,
involving
acceptance
nonjudgment
present-moment
experience,
often
results
in
transformative
health
change.
Neural
systems
involved
motivation
learning
have
an
important
role
play.
A
theoretical
model
mindfulness
that
integrates
these
mechanisms
with
cognitive,
emotional,
self-related
processes
commonly
described,
while
applying
integrated
change,
needed.
This
integrative
review
(1)
defines
describes
mindfulness-based
intervention
movement,
(2)
synthesizes
neuroscience
within
a
mindful
self-regulation
for
understanding
complex
effects
on
(3)
current
clinical
research
evaluating
interventions
targeting
behaviors
relevant
care.
provides
insight
into
limitations
proposes
potential
be
tested
future
targeted
practice
enhance
impact
Physiological Reviews,
Год журнала:
2020,
Номер
101(1), С. 213 - 258
Опубликована: Июнь 11, 2020
Chronic,
pathological
pain
remains
a
global
health
problem
and
challenge
to
basic
clinical
sciences.
A
major
obstacle
preventing,
treating,
or
reverting
chronic
has
been
that
the
nature
of
neural
circuits
underlying
diverse
components
complex,
multidimensional
experience
is
not
well
understood.
Moreover,
involves
maladaptive
plasticity
processes,
which
have
decoded
mechanistically
in
terms
involvement
specific
cause-effect
relationships.
This
review
aims
discuss
recent
advances
our
understanding
circuit
connectivity
mammalian
brain
at
level
regional
contributions
cell
types
acute
pain.
focus
placed
on
functional
dissection
sub-neocortical
using
optogenetics,
chemogenetics,
imaging
technological
tools
rodent
models
with
view
towards
decoding
sensory,
affective,
motivational-cognitive
dimensions
The
summarizes
breakthroughs
insights
structure-function
properties
nociceptive
higher
order
modulatory
involved
aversion,
learning,
reward,
mood
their
modulation
by
endogenous
GABAergic
inhibition,
noradrenergic,
cholinergic,
dopaminergic,
serotonergic,
peptidergic
pathways.
knowledge
dynamic
regulation
via
structural
will
be
beneficial
designing
improving
targeted
therapies.
Cell Reports,
Год журнала:
2023,
Номер
42(2), С. 112069 - 112069
Опубликована: Фев. 1, 2023
The
nucleus
accumbens
(NAc)
plays
an
important
role
in
motivation
and
reward
processing.
Recent
studies
suggest
that
different
NAc
subnuclei
differentially
contribute
to
reward-related
behaviors.
However,
how
is
encoded
individual
neurons
remains
unclear.
Using
vivo
single-cell
resolution
calcium
imaging,
we
find
diverse
patterns
of
encoding
the
medial
lateral
shell
subdivision
(NAcMed
NAcLat,
respectively).
Reward
consumption
increases
NAcLat
activity
but
decreases
NAcMed
activity,
albeit
with
high
variability
among
neurons.
heterogeneity
could
be
attributed
differences
their
synaptic
inputs
transcriptional
profiles.
Specific
optogenetic
activation
Nts-positive
promotes
positive
reinforcement,
while
Cartpt-positive
induces
behavior
aversion.
Collectively,
our
study
shows
organizational
subregions
provides
a
framework
for
future
dissection
physiological
pathological
conditions.
Cachexia,
a
severe
wasting
syndrome
associated
with
inflammatory
conditions,
often
leads
to
multiorgan
failure
and
death.
Patients
cachexia
experience
extreme
fatigue,
apathy,
clinical
depression,
yet
the
biological
mechanisms
underlying
these
behavioral
symptoms
their
relationship
disease
remain
unclear.
In
mouse
cancer
model,
specifically
induced
increased
effort-sensitivity,
apathy-like
through
cytokine-sensing
brainstem-to-basal
ganglia
circuit.
This
neural
circuit
detects
elevated
interleukin-6
(IL-6)
at
onset
translates
signals
into
decreased
mesolimbic
dopamine,
thereby
increasing
effort
sensitivity.
We
alleviated
by
targeting
key
nodes:
administering
an
anti–IL-6
antibody
treatment,
ablating
cytokine
sensing
in
brainstem,
optogenetically
or
pharmacologically
boosting
dopamine.
Our
findings
uncovered
central
that
senses
systemic
inflammation
orchestrates
changes,
providing
mechanistic
insights
connection
between
chronic
depressive
symptoms.
