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bioRxiv · 10.1101/2025.10.14.682478

Adolescent Alcohol Exposure Disrupts Astrocyte-Synaptic Structural And Functional Coupling In The Male Dorsal Hippocampus

Coulter, O. R.·Walker, C. D.·Muck, T.·Sexton, H. G.·Denvir, J.·Risher, C.·Henderson, B. J.·Risher, M.-L.
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Abstract

Adolescence is a window of heightened vulnerability to the neurotoxic effects of binge ethanol exposure. Adolescent intermittent ethanol (AIE) exposure has been shown to induce long-lasting cognitive and behavioral impairments in patients and rodent models that increase the risk of developing alcohol use disorder (AUD). Our previous work shows that these behavioral deficits coincide with persistent astrocyte dysfunction. Here, we aim to understand how astrocyte-synaptic structural and functional crosstalk are disrupted following AIE to provide better mechanistic understanding of why behavioral impairments persist into adulthood. Male Sprague-Dawley rats received AIE, a variety of adeno-associated viruses encoding astrocyte-specific sensors, and fiber implantation in the dorsal hippocampal (dHipp) for in vivo photometry. A subset of rats received hM3D(Gq) to chemogenetically activate astrocytes. Following AIE and a forced abstinence period that allowed growth into adulthood, rats underwent assessment in the contextual fear conditioning (CFC) task with simultaneous fiber photometry recordings. By combining immunohistochemistry (IHC), Stimulated Emission Depletion (STED) microscopy, fiber photometry, chemogenetics, and slice physiology, we show that AIE induces structural and functional decoupling of astrocytes from synapses and astrocyte dysregulation that persists into adulthood. Remarkably, stimulating astrocytic calcium signaling via chemogenetic activation partially attenuates heightened fear responding and increases gliotransmitter availability. These findings highlight a critical role for astrocyte-synaptic crosstalk in regulating fear learning and underscore the untapped therapeutic potential of targeting astrocytes to improve behavioral outcomes following substance use.

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Coulter, O. R., Walker, C. D., Muck, T., Sexton, H. G., Denvir, J., Risher, C., Henderson, B. J., Risher, M.-L.. 2025-10-15. Adolescent Alcohol Exposure Disrupts Astrocyte-Synaptic Structural And Functional Coupling In The Male Dorsal Hippocampus. https://doi.org/10.1101/2025.10.14.682478

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