Glutamatergic dysfunction of astrocytes in paraventricular nucleus of thalamus contributes to adult anxiety susceptibility in adolescent ethanol exposed mice

Repeated ethanol exposure during adolescence increases adult anxiety risk, but the underlying mechanisms remain unclear. The paraventricular nucleus of the thalamus (PVT) has been considered a hub for controlling anxiety and is affected by experiences from early life. Thus, this study investigated how adolescent intermittent repeated ethanol exposure (AIE) affects the PVT activities and anxiety-related behaviors in adulthood. We found that AIE triggers anxiety-like behaviors and parallelly exhibited elevated firing rates and increased calcium signaling in the PVT neurons compared to control counterpart mice. Chemogenetic inhibition of PVT neurons reduced anxiety-like behaviors in AIE-treated animals, confirming PVT's role in adolescent alcohol-induced adult anxiety. The increased PVT neuronal activities were mediated, at least partly, by the reduced GLT1, an astrocyte dominant glutamate transporter (also known as EAAT2, slc1a2). Magnetic resonance spectroscopy showed the higher glutamate/GABA ratios in the thalamus of GLT1 knockdown mice, which also exhibited heightened anxiety-like behaviors. Importantly, the selective GLT1 deletion in the PVT astrocytes of alcohol-naïve mice elicited anxiety-like behaviors, whereas GLT1 enhancement in PVT astrocytes of AIE-treated mice ameliorated AIE-induced anxiety-like behaviors. These findings highlight the significant role of PVT astrocytic GLT1 in the anxiogenic phenotype in adulthood induced by adolescent intermittent ethanol exposure, suggesting that GLT1 in the PVT could serve as a therapeutic target for alcohol use disorder and comorbid emotional disorders.