Abstract
Background
High-level alcohol consumption causes neuroplastic changes in the brain that promote
pathological drinking behavior. Some of these changes have been characterized in defined
brain circuits and cell types, but unbiased approaches are needed to explore broader
patterns of adaptations.
Methods
We used whole-brain c-Fos mapping and network analysis to assess patterns of neuronal
activity during alcohol withdrawal and following reaccess in a well-characterized
model of alcohol dependence. Mice underwent 4 cycles of chronic intermittent ethanol
to increase voluntary alcohol consumption, and a subset underwent forced swim stress
to further escalate consumption. Brains were collected either 24 hours (withdrawal)
or immediately following a 1-hour period of alcohol reaccess. c-fos counts were obtained
for 110 brain regions using iDISCO and ClearMap. Then, we classified mice as high
or low drinkers and used graph theory to identify changes in network properties associated
with high-drinking behavior.
Results
During withdrawal, chronic intermittent ethanol mice displayed widespread increased
c-Fos expression relative to air-exposed mice, independent of forced swim stress.
Reaccess drinking reversed this increase. Network modularity, a measure of segregation
into communities, was increased in high-drinking mice after alcohol reaccess relative
to withdrawal. The cortical amygdala showed increased cross-community coactivation
during withdrawal in high-drinking mice, and cortical amygdala silencing in chronic
intermittent ethanol mice reduced voluntary drinking.
Conclusions
Alcohol withdrawal in dependent mice causes changes in brain network organization
that are attenuated by reaccess drinking. Olfactory brain regions, including the cortical
amygdala, drive some of these changes and may play an important but underappreciated
role in alcohol dependence.
Keywords
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Article info
Publication history
Published online: January 31, 2023
Accepted:
January 23,
2023
Received in revised form:
January 6,
2023
Received:
September 6,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Society of Biological Psychiatry.
