Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Alcohol Clin Exp Res. 2022 May;46(5):759-769. doi: 10.1111/acer.14810. Epub 2022 Apr 1.
Binge alcohol exposure during adolescence results in long-lasting alterations in the brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) that surround some interneurons, particularly PV+ interneurons, further regulate cellular plasticity. The effect of AIE exposure on the expression of these markers within the PFC is not well understood.
The present study tested the hypothesis that AIE exposure reduces the expression of PV+ and choline acetyltransferase (ChAT)+ interneurons in the adult PFC and striatum and increases the related expression of PNNs (marked by binding of Wisteria floribunda agglutinin lectin) in adulthood. Male rats were exposed to AIE (5 g/kg/day, 2-days-on/2-days-off, i.e., P25 to P54) or water (CON), and brain tissue was harvested in adulthood (>P80). Immunohistochemistry and co-immunofluorescence were used to assess the expression of ChAT, PV, and PNNs within the adult PFC and striatum following AIE exposure.
ChAT and PV interneuron densities in the striatum and PFC were unchanged after AIE exposure. However, PNN density in the PFC of AIE-exposed rats was greater than in CON rats. Moreover, significantly more PV neurons were surrounded by PNNs in AIE-exposed subjects than controls in both PFC subregions assessed: orbitofrontal cortex (CON = 34%; AIE = 40%) and medial PFC (CON = 10%; AIE = 14%).
These findings indicate that, following AIE exposure, PV interneuron expression in the adult PFC and striatum is unaltered, while PNNs surrounding these neurons are increased. This increase in PNNs may restrict the plasticity of the ensheathed neurons, thereby contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.
青春期大量饮酒会导致大脑和行为长期改变。例如，在啮齿动物中，青少年间歇性乙醇（AIE）暴露会导致前额叶皮层（PFC）和纹状体区域之间的功能连接长期丧失，以及各种神经化学、分子和表观遗传改变。PFC 和纹状体中的中间神经元在行为灵活性和功能连接中发挥关键作用。例如，已知 Parvalbumin（PV）中间神经元有助于神经同步，胆碱能中间神经元有助于策略选择。此外，包围一些中间神经元的细胞外周细胞网络（PNNs），特别是 PV+中间神经元，进一步调节细胞可塑性。AIE 暴露对 PFC 中这些标志物表达的影响尚不清楚。
本研究测试了以下假设：AIE 暴露会降低成年 PFC 和纹状体中 PV+和胆碱乙酰转移酶（ChAT）+中间神经元的表达，并增加成年时相关的 PNNs（用 Wisteria floribunda agglutinin lectin 结合标记）的表达。雄性大鼠接受 AIE（5 g/kg/天，2 天 ON/2 天 OFF，即 P25 至 P54）或水（CON）暴露，成年后（>P80）收获脑组织。免疫组织化学和共免疫荧光用于评估 AIE 暴露后成年 PFC 和纹状体中 ChAT、PV 和 PNNs 的表达。
AIE 暴露后纹状体和 PFC 中的 ChAT 和 PV 中间神经元密度没有变化。然而，AIE 暴露大鼠 PFC 中的 PNN 密度大于 CON 大鼠。此外，与 CON 组相比，AIE 暴露组中 PFC 的两个亚区（眶额皮层（CON=34%；AIE=40%）和内侧 PFC（CON=10%；AIE=14%））中，更多的 PV 神经元被 PNN 包围。
这些发现表明，在 AIE 暴露后，成年 PFC 和纹状体中的 PV 中间神经元表达没有改变，而围绕这些神经元的 PNN 增加。PNNs 的这种增加可能会限制包被神经元的可塑性，从而导致额纹状体连接的微电路受损，并导致相关的行为障碍。
