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bioRxiv · 10.64898/2025.12.19.695484

Selective dysregulation of serotonin dynamics in the anterior cingulate cortex and central amygdala following binge alcohol consumption

Ritchie, J. L.·Eberle, M. R.·Roland, A. V.·Taxier, L. R.·Campeau, M. R.·George, B. E.·Kooyman, L. S.·Kash, T. L.
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Abstract

Serotonin (5HT) is a critical modulator of brain function and behavior that is dysregulated in alcohol use disorder (AUD). The anterior cingulate cortex (ACC) and central nucleus of the amygdala (CeA) play distinct roles in AUD and undergo functional changes in 5HT signaling following binge drinking, but our understanding of real-time 5HT dynamics in these structures is lacking. We hypothesized that binge drinking would elicit brain-region specific dysfunction in 5HT dynamics during appetitive and aversive stimuli processing. Using fiber photometry with the GRAB5HT sensor, we identified distinct reward and aversion 5HT signaling motifs in the ACC and CeA. Consumption of alcohol and other tastants elicited a suppression of GRAB5HT signal in the ACC and an increase in 5HT signal in the CeA. In contrast, aversive stimuli similarly increased 5HT in both structures. The effect of binge drinking on 5HT function was surprisingly non-uniform, producing brain-region, sex-, and stimulus-specific dysfunction in 5HT signaling that dramatically shifted across weeks of alcohol experience. This suggests that adaptations in 5HT signaling are specific to neural circuits underlying discrete functions. Optogenetically stimulating 5HT terminals in the ACC and CeA increased avoidance behavior without being overtly rewarding or aversive, and stimulating 5HT release in the ACC blunted alcohol drinking. Together, these data identify distinct 5HT reward and aversion signaling motifs in the ACC and CeA and highlight early binge drinking as a critical stage of 5HT adaptation and a potential window for therapeutic intervention.

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Ritchie, J. L., Eberle, M. R., Roland, A. V., Taxier, L. R., Campeau, M. R., George, B. E., Kooyman, L. S., Kash, T. L.. 2025-12-22. Selective dysregulation of serotonin dynamics in the anterior cingulate cortex and central amygdala following binge alcohol consumption. https://doi.org/10.64898/2025.12.19.695484

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