Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence

项目摘要/摘要 内侧前额叶皮质(MPFC)是参与脑功能恢复的关键脑区之一。 寻找酒精的行为。我们实验室的最新发现表明，mPFC 祖细胞(干细胞的后代，以有限的自我更新为特征)，能增殖、成熟和 分化为早髓鞘和髓鞘少突胶质祖细胞(OPC)，并生成 少突胶质髓鞘形成。最值得注意的是，在慢性酒精中毒期间，酒精自身给药增加 间歇性酒精蒸气吸入(依赖期间饮酒；CIE)减少新生的OPC 酒精体验。然而，退出CIE和强制禁欲在CIE产生反弹效应 新生mPFC OPC的增殖和存活，可见早髓鞘细胞数量的增加 OPC和髓鞘少突胶质细胞，这些变化与髓鞘表达增加有关 相关蛋白质。CIE大鼠的这些变化也预示着酒精寻求行为的增强， 这表明CIE动物的依赖样行为在细胞内产生了深刻的变化 MPFC的组成可能是复发倾向增强的危险因素。 我们还证明，在CIE强制禁欲期间，新生OPC的生成增加 大鼠血小板内皮细胞黏附分子-1(PECAM-1， CD-31；神经炎性反应的标志物)和增强的恢复倾向 寻找乙醇。此外，来自电生理学研究的初步全细胞膜片钳数据 在CIE大鼠强制戒断期间进行的研究表明，mPFC OPC的生成增加，并且 髓鞘相关蛋白和PECAM-1的表达与基底突触增强相关 2/3mPFC层锥体神经元的传递和神经元兴奋性提示超兴奋性和 增强mPFC的谷氨酸能传递。根据我们公布的和试点的数据，我们希望 促进mPFC中OPC增强生成与PECAM-1表达的机制联系 谷氨酸能神经元的超兴奋性与对酒精寻求的增强复发性。我们建议 抑制新生OPC、髓鞘相关蛋白和PECAM-1反应的异常生成 在强制戒断期间，将保留mPFC内的神经元功能，从而减少恢复 寻找乙醇。我们的研究结合了酒精成瘾和复发的强大行为模型，细胞 而mPFC的生化改变结合功能电生理研究提供了一个 强大的机制背景，以更好地了解与增强的 旧病复发。

Project Summary/Abstract The medial prefrontal cortex (mPFC) is one of the key brain regions implicated in reinstatement of ethanol-seeking behaviors. Recent findings from our laboratory demonstrates that the mPFC harbors progenitors (progeny of stem cells that are characterized by limited self-renewal) that proliferate, mature and differentiate into premyelinating and myelinating oligodendrocyte progenitor cells (OPCs), and generate myelinating oligodendroglia. Most notable is that increased ethanol self-administration during chronic intermittent ethanol vapor inhalation (drinking during dependence; CIE) reduce newly born OPCs during ethanol experience. However, withdrawal and forced abstinence from CIE produces a rebound effect in the proliferation and survival of newly born mPFC OPCs, visualized as increases in the number of premyelinating OPCs and myelinating oligodendroglia and these changes are associated with increased expression of myelin associated proteins. These alterations in CIE rats also predicted enhanced ethanol seeking behaviors, indicating that dependence-like behavior in CIE animals produced profound alterations in the cellular composition of mPFC which could be a risk factor for enhanced propensity for relapse. We also demonstrate that increased generation of newly born OPCs during forced abstinence in CIE rats positively correlate with enhanced expression of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD-31; a marker of neuroinflammatory response) in the mPFC and enhanced propensity for reinstatement of ethanol seeking. Furthermore, preliminary whole-cell patch-clamp data from electrophysiology studies performed during forced abstinence in CIE rats demonstrate that enhanced generation of mPFC OPCs, and expression of myelin associated proteins and PECAM-1 is associated with enhanced basal synaptic transmission and neuronal excitability of layer 2/3 mPFC pyramidal neurons indicating hyperexcitability and enhanced glutamatergic transmission in the mPFC. Based on our published and pilot data we hope to mechanistically link enhanced generation of OPCs and expression of PECAM-1 in the mPFC in promoting hyperexcitability of glutamatergic neurons and enhanced relapse to ethanol seeking. We propose that inhibiting the aberrant generation of newly born OPCs, myelin associated proteins and PECAM-1 response during forced abstinence will preserve neuronal function within the mPFC and thus reduce reinstatement of ethanol seeking. Our studies combining robust behavioral models of alcohol addiction and relapse, cellular and biochemical alterations in the mPFC in combination with functional electrophysiological studies offer a powerful mechanistic context to better understand the factors associated with enhanced propensity for relapse.