Estrogen signaling in the dorsal raphe regulates binge-like drinking in mice

Abstract

The ovarian hormone estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms for estrogen-induced binge drinking are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We used the drinking in the dark (DID) behavioral test in mice to mimic binge drinking in humans. We found that female mice drank more alcohol than male mice in chronic DID tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor alpha (ERalpha) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling in binge alcohol drinking. In supporting this view, 5-HTDRN neurons from naive male mice had lower baseline neuronal firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naive female mice. Notably, this higher sensitivity was blunted by 17bata-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERalpha and ERbeta are expressed in 5-HTDRN neurons, whereas ERalpha agonist propyl pyrazole triol (PPT) depolarizes 5-HTDRN neurons and ERbeta agonist diarylpropionitrile (DPN) hyperpolarizes 5-HTDRN neurons. Notably, both PPT and DPN treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, despite the fact that they have antagonistic effects on the activity dynamics of 5-HTDRN neurons. These results suggest that the inhibitory effects of ERs on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERalpha- or ERbeta-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERalpha/beta to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

“…Sex differences have been reported in the severity of AD neuropathology, with women typically having more NFTs, greater cognitive decline, and accelerated disease progression relative to men [5, 24, 30, 38]. The DRN is a sexually dimorphic region that in enriched in both types of estrogen receptors (ERα and Erβ)[66], so we might expect to observe sex differences in behavioral manifestations of DRN neuropathology. We observed a significant reduction in social interaction in female P301L-tau DRN mice relative to controls (F 1,28 =24.79, p<0.0001, stranger x tau interaction).…”