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Endocannabinoid control of the insular-bed nucleus of the stria terminalis
circuit regulates negative affective behavior associated with alcohol
Authors Centanni SW, Morris BD, Luchsinger JR, Bedse G, Fetterly TL, Patel S, Winder DG
Submitted By Submitted Externally on 6/24/2019
Status Published
Journal Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Year 2019
Date Published 2/1/2019
Volume : Pages 44 : 526 - 537
PubMed Reference 30390064
Abstract Negative affect is a core symptom domain associated with an array of
neurological and psychiatric disorders and is only partially targeted by current
therapies, highlighting the need for better, more targeted treatment options.
This study focuses on negative affective symptoms associated with prolonged
alcohol abstinence, one of the leading causes of relapse. Using a mouse model of
chronic alcohol consumption followed by forced abstinence (CDFA), prolonged
alcohol abstinence increased c-fos expression and spontaneous glutamatergic
neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a
region heavily implicated in negative affect in both humans and rodents.
Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184
prevents abstinence-induced increases in dBNST neuronal activity, underscoring
the therapeutic potential of drugs targeting the brain's eCB system. Next, we
used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs
to the dBNST that could contribute to CDFA-induced negative affect. We
identified the insular cortex (insula), a region involved in regulating
interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a
chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the
insula strongly influences the CDFA behavioral phenotype and dBNST neuronal
activity. Lastly, we used an anterograde strategy for transynaptic targeting of
Cre expression in combination with a Gq-DREADD to selectively recruit dBNST
neurons receiving insula projections. Chemogenetic recruitment of these neurons
mimicked behavioral and c-fos responses observed in CDFA. Collectively, this
study supports a role for the insula-BNST neural circuit in negative affective
disturbances and highlights the therapeutic potential of the eCB system for
treating negative affective disorders.


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