Background:
Angiotensin
receptor
blockade
(ARB)
has
been
linked
to
aspects
of
aversive
learning
and
memory
formation,
the
prevention
post-traumatic
stress
disorder
symptom
development.
Methods:
We
investigate
influence
ARB
losartan
on
Pavlovian
conditioning
using
a
probabilistic
paradigm.
In
double-blind,
randomised
placebo-controlled
design,
we
tested
45
(18
female)
healthy
volunteers
during
Baseline
session,
after
application
or
placebo
(Drug
session)
Follow-up
session.
On
each
participants
engaged
in
task
where
they
had
predict
probability
an
electrical
stimulation
every
trial
while
true
shock
contingencies
repeatedly
switched
between
phases
high
low
threat.
Computational
reinforcement
models
were
used
dynamics.
Results:
Acute
administration
significantly
reduced
participants’
adjustment
both
low-to-high
high-to-low
threat
changes.
This
was
driven
by
rates
group
drug
session
compared
baseline.
The
50mg
dose
did
not
induce
reduction
blood
pressure
change
reaction
times,
ruling
out
general
attention
engagement.
Decreased
expectations
maintained
follow
up
24hrs
later.Conclusions:
study
shows
that
acutely
reduces
environments.
Such
decreased
may
explain
previously
reported
preventive
role
development
anxiety
symptoms.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(8)
Опубликована: Фев. 13, 2024
Accumulating
evidence
suggests
that
the
brain
renin
angiotensin
system
(RAS)
plays
a
pivotal
role
in
regulation
of
cognition
and
behavior
as
well
neuropathology
neurological
mental
disorders.
The
II
type
1
receptor
(AT1R)
mediates
most
functional
neuropathology-relevant
actions
associated
with
central
RAS.
However,
an
overarching
comprehension
to
guide
translation
utilize
therapeutic
potential
RAS
humans
is
currently
lacking.
We
conducted
comprehensive
characterization
using
innovative
combination
transcriptomic
gene
expression
mapping,
image-based
behavioral
decoding,
pre-registered
randomized
controlled
discovery–replication
pharmacological
resting-state
magnetic
resonance
imaging
(fMRI)
trials
(N
=
132)
selective
AT1R
antagonist.
exhibited
particular
dense
subcortical
network
encompassing
thalamus,
striatum,
amygdalo-hippocampal
formation.
Behavioral
decoding
map
showed
association
memory,
stress,
reward,
motivational
processes.
Transient
blockade
further
decreased
neural
activity
systems
characterized
by
high
expression,
while
increasing
connectivity
cortico-basal
ganglia-thalamo-cortical
circuitry.
Effects
on
level
were
specifically
signatures
dopaminergic,
opioid,
acetylcholine,
corticotropin-releasing
hormone
signaling
systems.
robustness
results
was
supported
independent
fMRI
trial.
These
findings
present
biologically
informed
pathways
their
relevance
humans.
Brain,
Год журнала:
2024,
Номер
147(9), С. 3083 - 3098
Опубликована: Май 29, 2024
Abstract
Comprehensive
understanding
of
the
neural
circuits
involving
ventral
tegmental
area
is
essential
for
elucidating
anatomofunctional
mechanisms
governing
human
behaviour,
in
addition
to
therapeutic
and
adverse
effects
deep
brain
stimulation
neuropsychiatric
diseases.
Although
has
been
targeted
successfully
with
different
diseases,
axonal
connectivity
region
not
fully
understood.
Here,
using
fibre
microdissections
cadaveric
hemispheres,
population-based
high-definition
tractography
previously
reported
hotspots,
we
find
that
participates
an
intricate
network
serotonergic
pontine
nuclei,
basal
ganglia,
limbic
system,
forebrain
prefrontal
cortex,
which
implicated
treatment
obsessive–compulsive
disorder,
major
depressive
Alzheimer’s
disease,
cluster
headaches
aggressive
behaviours.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Март 21, 2023
Abstract
The
brain
renin
angiotensin
II
system
plays
a
pivotal
role
in
cognition
and
neuropathology
via
the
central
type
1
receptor
(AT1R),
yet
lack
of
biologically
informed
framework
currently
impedes
translational
therapeutic
progress.
We
combined
imaging
transcriptomic
meta-analyses
with
pharmaco-resting
state
fMRI
employing
selective
AT1R
antagonist
discovery-replication
design
(n=132
individuals).
was
densely
expressed
subcortical
systems
engaged
reward,
motivation,
stress,
memory.
Pharmacological
target
engagement
suppressed
spontaneous
neural
activity
high
expression
enhanced
functional
network
integration
cortico-basal
ganglia-thalamo-cortical
circuits.
AT1R-regulation
on
further
mediated
by
dopaminergic,
opioid
corticotrophin-releasing
hormone
pathways.
Overall,
this
work
provides
first
comprehensive
characterization
architecture
function
indicating
that
AT1R-mediates
human
behavior
regulating
specific
circuits
interacting
classical
transmitter
systems.
Biological Psychiatry,
Год журнала:
2024,
Номер
96(4), С. 247 - 255
Опубликована: Фев. 2, 2024
BackgroundAngiotensin
receptor
blockade
(ARB)
has
been
linked
to
aspects
of
aversive
learning
and
memory
formation,
the
prevention
post-traumatic
stress
disorder
symptom
development.MethodsWe
investigate
influence
ARB
losartan
on
Pavlovian
conditioning
using
a
probabilistic
paradigm.
In
double-blind,
randomised
placebo-controlled
design,
we
tested
45
(18
female)
healthy
volunteers
during
Baseline
session,
after
application
or
placebo
(Drug
session)
Follow-up
session.
On
each
participants
engaged
in
task
where
they
had
predict
probability
an
electrical
stimulation
every
trial
while
true
shock
contingencies
repeatedly
switched
between
phases
high
low
threat.
Computational
reinforcement
models
were
used
dynamics.ResultsAcute
administration
significantly
reduced
participants'
adjustment
both
low-to-high
high-to-low
threat
changes.
This
was
driven
by
rates
group
drug
session
compared
baseline.
The
50mg
dose
did
not
induce
reduction
blood
pressure
change
reaction
times,
ruling
out
general
attention
engagement.
Decreased
expectations
maintained
follow
up
24hrs
later.ConclusionsThis
study
shows
that
acutely
reduces
environments,
highlighting
potential
role
renin-angiotensin
system
anxiety
development.
