bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 2, 2024
Abstract
Cue
reactivity
is
the
maladaptive
neurobiological
and
behavioral
response
upon
exposure
to
drug
cues
a
major
driver
of
relapse.
The
leading
hypothesis
that
dopamine
release
by
addictive
drugs
represents
persistently
positive
reward
prediction
error
causes
runaway
enhancement
responses
cues,
their
pathological
overvaluation
compared
non-drug
alternatives.
However,
this
has
not
been
directly
tested.
Here
we
developed
Pavlovian
operant
procedures
measure
firing
responses,
within
same
neurons,
versus
natural
which
found
be
similarly
enhanced
predicting
rewards
in
drug-naïve
controls.
This
was
associated
with
increased
cue,
suggesting
still
critical
cue
reactivity,
albeit
as
previously
hypothesized.
These
results
challenge
prevailing
warranting
new
models
dopaminergic
function
addiction,
provide
insights
into
neurobiology
potential
implications
for
relapse
prevention.
Drugs
of
abuse
are
thought
to
promote
addiction
in
part
by
“hijacking”
brain
reward
systems,
but
the
underlying
mechanisms
remain
undefined.
Using
whole-brain
FOS
mapping
and
vivo
single-neuron
calcium
imaging,
we
found
that
drugs
augment
dopaminoceptive
ensemble
activity
nucleus
accumbens
(NAc)
disorganize
overlapping
responses
natural
rewards
a
cell
type–specific
manner.
Combining
FOS-Seq,
CRISPR-perturbation,
single-nucleus
RNA
sequencing,
identified
Rheb
as
molecular
substrate
regulates
signal
transduction
NAc
while
enabling
suppress
consumption.
Mapping
NAc-projecting
regions
activated
revealed
input-specific
effects
on
These
findings
characterize
dynamic,
circuit
basis
common
pathway,
wherein
interfere
with
fulfillment
innate
needs.
Cell Metabolism,
Год журнала:
2025,
Номер
37(3), С. 723 - 741.e6
Опубликована: Март 1, 2025
Similar
to
most
humans
with
obesity,
diet-induced
obese
(DIO)
mice
have
high
leptin
levels
and
fail
respond
the
exogenous
hormone,
suggesting
that
their
obesity
is
caused
by
resistance,
pathogenesis
of
which
unknown.
We
found
treatment
reduced
plasma
leucine
methionine,
mTOR-activating
ligands,
leading
us
hypothesize
chronic
mTOR
activation
might
reduce
signaling.
Rapamycin,
an
inhibitor,
fat
mass
increased
sensitivity
in
DIO
but
not
defects
Rapamycin
restored
leptin's
actions
on
POMC
neurons
failed
weight
melanocortin
whereas
POMC-specific
mutations
activators
decreased
gain
mice.
Thus,
activity
necessary
sufficient
for
development
resistance
mice,
establishing
a
key
pathogenic
mechanism
obesity.
Hedonic
eating
is
defined
as
food
consumption
driven
by
palatability
without
physiological
need.
However,
neural
control
of
palatable
intake
poorly
understood.
We
discovered
that
hedonic
controlled
a
pathway
from
the
peri–locus
ceruleus
to
ventral
tegmental
area
(VTA).
Using
photometry-calibrated
optogenetics,
we
found
VTA
dopamine
(VTA
DA
)
neurons
encode
bidirectionally
regulate
consumption.
neuron
responsiveness
was
suppressed
during
semaglutide,
glucagon-like
peptide
receptor
1
(GLP-1R)
agonist
used
an
antiobesity
drug.
Mice
recovered
appetite
and
activity
repeated
semaglutide
treatment,
which
reversed
consumption-triggered
inhibition.
Thus,
activates
neurons,
sustain
further
consumption,
mechanism
opposes
reduction
semaglutide.
Drugs
of
abuse
activate
defined
neuronal
populations
in
reward
structures
such
as
the
nucleus
accumbens
(NAc),
which
promote
enduring
synaptic,
circuit,
and
behavioral
consequences
drug
exposure.
While
molecular
cellular
effects
arising
from
experience
with
drugs
like
cocaine
are
increasingly
well
understood,
mechanisms
that
dictate
NAc
recruitment
remain
unknown.
Here,
we
leveraged
unbiased
single-nucleus
transcriptional
profiling
targeted
situ
detection
to
identify
Reln
(encoding
secreted
glycoprotein,
Reelin)
a
marker
cocaine-activated
within
rat
NAc.
A
CRISPR
interference
approach
enabling
selective
knockdown
adult
altered
expression
calcium
signaling
genes,
promoted
trajectory
consistent
loss
sensitivity,
decreased
MSN
excitability.
Behaviorally,
prevented
locomotor
sensitization,
abolished
place
preference
memory,
self-administration
behavior.
These
results
Reelin
critical
mechanistic
link
between
activation
cocaine-induced
adaptations.
Frontiers in Psychiatry,
Год журнала:
2025,
Номер
15
Опубликована: Янв. 14, 2025
Behavioral
addictive
disorders
(BADs)
have
become
a
significant
societal
challenge
over
time.
The
central
feature
of
BADs
is
the
loss
control
engaging
in
and
continuing
behaviors,
even
when
facing
negative
consequences.
neurobiological
underpinnings
primarily
involve
impairments
reward
circuitry,
encompassing
ventral
tegmental
area,
nucleus
accumbens
striatum,
prefrontal
cortex.
These
brain
regions
form
networks
that
communicate
through
neurotransmitter
signaling,
leading
to
changes
individuals
with
behavioral
addictions.
While
dopamine
has
long
been
associated
process,
recent
research
highlights
role
other
key
neurotransmitters
like
serotonin,
glutamate,
endorphins
BADs'
development.
interact
within
creating
potential
targets
for
therapeutic
intervention.
This
improved
understanding
systems
provides
foundation
developing
targeted
treatments
helps
clinicians
select
personalized
approaches.
