Tuesday, April 1, 2025
4/1/2025
Extended Amygdala Regulation of Dorsal Raphe Function in Ethanol Self-Administration - Abstract Alcohol use disorder (AUD) is an enormous public health problem. While there have been gains in our knowledge of this disorder, we lack fundamental knowledge pertaining to the biological mechanisms that drive aberrant behavior associated with AUD. Ethanol exposure modifies signaling across brain regions, and these changes are thought to underlie persistent alterations in behavior. The serotonin (5HT) system has been implicated in the pathophysiology of AUD and represents a potential avenue for therapeutic intervention. In the previous funding period, we examined how ethanol exposure could divergently impact anatomically defined dorsal raphe 5HT systems, focusing on cortical and subcortical 5HT signaling. We found that alcohol drinking leads to a suppression of 5HT function in the orbitofrontal cortex, and that disrupting 5HT function there led to increased alcohol consumption. We found that sub-cortical 5HT signaling was engaged, in the BNST and the lateral habenula, and led to disrupted social behavior and heightened arousal response via 5HT2C-R activation. Previous studies from the lab had found that 5HT2C-R activation was coupled to CRF function. Because of this, as well as previous work from the lab showing BNST CRF neurons are involved in alcohol consumption, we examined the role of BNST CRF in alcohol drinking. Specifically, we found that genetic deletion of CRF from the BNST led to a robust decrease in alcohol self-administration. BNST CRF neurons project to the dorsal raphe, and CRF signaling in the DR can both regulate alcohol consumption and inhibit 5HT release in the cortex. These data serve as the basis for our model in which alcohol withdrawal leads to engagement of CRF neurons in the BNST that project to the DR to drive long lasting suppression of activity in cortically-projecting 5HT neurons, driving escalated and aversion resistant alcohol consumption.
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