Franklin Janay P, Testen Anze, Mieczkowski Piotr A, Hepperla Austin, Crynen Gogce, Simon Jeremy M, Wood Jonathan D, Harder Eden V, Bellinger Tania J, Witt Emily A, Powell N LaShae, Reissner Kathryn J
Neuroscience Center, University of North Carolina at Chapel Hill.
Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill.
bioRxiv. 2024 Aug 5:2024.08.05.606656. doi: 10.1101/2024.08.05.606656.
In recent years, astrocytes have been increasingly implicated in cellular mechanisms of substance use disorders (SUD). Astrocytes are structurally altered following exposure to drugs of abuse; specifically, astrocytes within the nucleus accumbens (NAc) exhibit significantly decreased surface area, volume, and synaptic colocalization after operant self-administration of cocaine and extinction or protracted abstinence (45 days). However, the mechanisms that elicit these morphological modifications are unknown. The current study aims to elucidate the molecular modifications that lead to observed astrocyte structural changes in rats across cocaine abstinence using astrocyte-specific RiboTag and RNA-seq, as an unbiased, comprehensive approach to identify genes whose transcription or translation change within NAc astrocytes following cocaine self-administration and extended abstinence. Using this method, our data reveal cellular processes including cholesterol biosynthesis that are altered specifically by cocaine self-administration and abstinence, suggesting that astrocyte involvement in these processes is changed in cocaine-abstinent rats. Overall, the results of this study provide insight into astrocyte functional adaptations that occur due to cocaine exposure or during cocaine withdrawal, which may pinpoint further mechanisms that contribute to cocaine-seeking behavior.
近年来，星形胶质细胞在物质使用障碍（SUD）的细胞机制中所起的作用越来越受到关注。暴露于滥用药物后，星形胶质细胞的结构会发生改变；具体而言，在可卡因操作性自我给药、消退或长期禁欲（45天）后，伏隔核（NAc）内的星形胶质细胞表面积、体积和突触共定位显著减少。然而，引发这些形态学改变的机制尚不清楚。本研究旨在通过星形胶质细胞特异性RiboTag和RNA测序，阐明导致可卡因戒断大鼠星形胶质细胞结构变化的分子修饰，这是一种无偏倚、全面的方法，用于识别可卡因自我给药和长期禁欲后伏隔核星形胶质细胞内转录或翻译发生变化的基因。通过这种方法，我们的数据揭示了包括胆固醇生物合成在内的细胞过程，这些过程因可卡因自我给药和禁欲而发生特异性改变，表明可卡因戒断大鼠星形胶质细胞在这些过程中的参与情况发生了变化。总体而言，本研究结果深入了解了因接触可卡因或在可卡因戒断期间发生的星形胶质细胞功能适应性变化，这可能有助于确定导致觅药行为的进一步机制。
