Influence of biological sex and age on alcohol modulation of synaptic gating in nucleus accumbens core medium spiny neurons

BACKGROUND: In the nucleus accumbens (NAc), a brain region known for its role in reward, medium spiny neurons (MSNs) receive glutamatergic inputs from the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), two brain regions implicated in mediating alcohol's effects. Previously, we reported that in 8-week-old male C57Bl/6j mice, mPFC and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other presynaptically in a strict time-dependent manner, a phenomenon called synaptic gating. However, the influence of sex and age on synaptic gating and its sensitivity to binge alcohol drinking remained unknown. METHODS: This study investigates the effects of alcohol, age, and sex on BLA-mPFC and mPFC-BLA synaptic gating. To investigate this biological question, we performed whole-cell recordings from NAc core MSNs while independently optogenetically stimulating BLA and mPFC inputs in succession, using interstimulus intervals of 40, 65, 115, and 165 ms, in 6-, 8-, and 12-week-old male and female C57Bl/6j mice. RESULTS: We found that, in alcohol-naïve mice, the ability of cortical inputs to inhibit the transmission of information from the BLA region changes with age. Regarding the influence of sex, mPFC gating of BLA synaptic transmission was significantly stronger in 8-week-old males compared with age-matched females, a difference that disappeared in 12-week-old mice. Interestingly, the observed synaptic gating sex difference disappeared in binge alcohol drinking mice. Furthermore, binge alcohol drinking had a greater effect on BLA → mPFC gating in older (12-week-old) than in younger (8-week-old) mice. CONCLUSIONS: Overall, our results show that age and sex influence how NAc MSNs process cortical and amygdala information through synaptic gating, a phenomenon disrupted by binge alcohol drinking.