The Role of Microglia in Sex- and Region-Specific Blood-Brain Barrier Integrity During Nicotine Withdrawal.
The Role of Microglia in Sex- and Region-Specific Blood-Brain Barrier Integrity During Nicotine Withdrawal.
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DOI：
10.1016/j.bpsgos.2023.08.019
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发表时间：
2024-01
期刊：
影响因子：
--
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中科院分区：
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--
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吸烟是美国最大的可预防的死亡和疾病原因，只有不到5%的戒烟尝试成功。奖赏神经回路中的小胶质细胞活化和促炎性神经免疫信号传导与尼古丁戒断病理学有关。小胶质细胞也是血脑屏障（BBB）功能的整体调节剂;然而，尼古丁戒断对小胶质细胞功能的影响是否会影响BBB的完整性尚不清楚。用慢性尼古丁（12 mg/kg/天）处理小鼠，并使其经历48小时尼古丁戒断。区域血脑屏障通透性，连同信使RNA和蛋白质表达的紧密连接蛋白，进行了评估。使用PLX 5622饲料消耗小胶质细胞以评价小胶质细胞在调节BBB完整性和尼古丁戒断病理学中的作用。雌性小鼠在前额皮质和海马中的基线BBB渗透性高于雄性小鼠。尼古丁戒断进一步加剧了BBB渗透性选择性在前额叶皮质的女性。这些影响与前额叶皮质紧密连接蛋白亚组的改变同时发生，女性尼古丁戒断后促炎反应增加。通过PLX 5622处理的小胶质细胞耗竭防止了所有这些分子效应，并减弱了雌性小鼠中戒断诱导的焦虑样行为。这些结果首次显示了尼古丁戒断期间区域BBB渗透性的性别差异。这可能与女性戒烟成功率降低和女性吸烟相关神经血管疾病风险增加有关。此外，这些发现为针对女性尼古丁戒断期间小胶质细胞和BBB功能障碍的性别特异性治疗开辟了一条途径。
Smoking is the largest preventable cause of death and disease in the United States, with <5% of quit attempts being successful. Microglia activation and proinflammatory neuroimmune signaling in reward neurocircuitry are implicated in nicotine withdrawal symptomology. Microglia are integral regulators of blood-brain barrier (BBB) functionality as well; however, whether the effects of nicotine withdrawal on microglia function impact BBB integrity is unknown. Mice were treated with chronic nicotine (12 mg/kg/day) and subjected to 48 hours nicotine withdrawal. Regional BBB permeability, together with messenger RNA and protein expression of tight junction proteins, were assessed. PLX5622 chow was used to deplete microglia to evaluate the role of microglia in regulating BBB integrity and nicotine withdrawal symptomology. Female mice had higher baseline BBB permeability in the prefrontal cortex and hippocampus than males. Nicotine withdrawal further exacerbated the BBB permeability selectively in the prefrontal cortex of females. These effects were concurrent with prefrontal cortex alterations in a subset of tight junction proteins with increased proinflammatory responses following nicotine withdrawal in females. Depletion of microglia via PLX5622 treatment prevented all these molecular effects and attenuated withdrawal-induced anxiety-like behavior in female mice. These results are the first to show sex differences in regional BBB permeability during nicotine withdrawal. This represents a possible link to both the reduced smoking cessation success seen in women and women’s increased risk for smoking-related neurovascular disorders. Furthermore, these findings open an avenue for sex-specific therapeutics that target microglia and BBB dysfunction during nicotine withdrawal in women.
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影响因子：
4.7
作者：
Barko, Kelly;Shelton, Micah;Xue, Xiangning;Afriyie-Agyemang, Yvette;Puig, Stephanie;Freyberg, Zachary;Tseng, George C.;Logan, Ryan W.;Seney, Marianne L.
通讯作者：
Seney, Marianne L.
影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre
DOI：
10.1073/pnas.1922788117
发表时间：
2020-09-22
影响因子：
11.1
作者：
Lei F;Cui N;Zhou C;Chodosh J;Vavvas DG;Paschalis EI
通讯作者：
Paschalis EI
影响因子：
8
作者：
Berndt, Philipp;Winkler, Lars;Haseloff, Reiner F.
通讯作者：
Haseloff, Reiner F.
影响因子：
16.6
作者：
Dion-Albert L;Cadoret A;Doney E;Kaufmann FN;Dudek KA;Daigle B;Parise LF;Cathomas F;Samba N;Hudson N;Lebel M;Signature Consortium;Campbell M;Turecki G;Mechawar N;Menard C
通讯作者：
Menard C