The transcription factor, ΔFOSB, acting in the nucleus accumbens (NAc), has been shown to control transcriptional and behavioral responses to opioids and other drugs of abuse. However, circuit-level consequences of ΔFOSB induction on the rest of the brain-required for its regulation of complex behavior-remain unknown.
We used an epigenetic approach in mice to suppress or activate the endogenous Fosb gene, and therefore decrease or increase, respectively, levels of ΔFOSB selectively in D1-type medium spiny neurons of the NAc, and tested whether these modifications affect the organization of functional connectivity (FC) in the brain. We acquired fMRI images at rest and in response to a morphine challenge, and analyzed both stationary and dynamic FC patterns.
The two manipulations markedly and differently modified brain wide communication. ΔFOSB down- and up-regulation had overlapping effects on prefrontal- and retrosplenial cortex-centered networks, but also generated specific FC signatures for epithalamus (habenula) and dopaminergic/serotonergic centers, respectively. Analysis of dynamic FC patterns showed that increasing ΔFOSB essentially altered responsivity to morphine, and uncovered striking modifications of epithalamus and amygdala roles in brain communication, particularly upon ΔFOSB down-regulation.
These novel findings illustrate how it is possible to link activity of a transcription factor within a single cell type of an identified brain region to consequent changes in circuit function brain-wide by use of fMRI, and pave the way for fundamental advances in bridging the gap between transcriptional and brain connectivity mechanisms underlying opioid addiction.
Copyright © 2023. Published by Elsevier Inc.
