Bray Jennifer G, Roberts Amanda J, Gruol Donna L
Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
Neuroscience. 2017 Jun 23;354:88-100. doi: 10.1016/j.neuroscience.2017.04.009. Epub 2017 Apr 19.
Emerging research provides strong evidence that activation of CNS glial cells occurs in neurological diseases and brain injury and results in elevated production of neuroimmune factors. These factors can contribute to pathophysiological processes that lead to altered CNS function. Recently, studies have also shown that both acute and chronic alcohol consumption can produce activation of CNS glial cells and the production of neuroimmune factors, particularly the chemokine ligand 2 (CCL2). The consequences of alcohol-induced increases in CCL2 levels in the CNS have yet to be fully elucidated. Our studies focus on the hypothesis that increased levels of CCL2 in the CNS produce neuroadaptive changes that modify the actions of alcohol on the CNS. We utilized behavioral testing in transgenic mice that express elevated levels of CCL2 to test this hypothesis. The increased level of CCL2 in the transgenic mice involves increased astrocyte expression. Transgenic mice and their non-transgenic littermate controls were subjected to one of two alcohol exposure paradigms, a two-bottle choice alcohol drinking procedure that does not produce alcohol dependence or a chronic intermittent alcohol procedure that produces alcohol dependence. Several behavioral tests were carried out including the Barnes maze, Y-maze, cued and contextual conditioned fear test, light-dark transfer, and forced swim test. Comparisons between alcohol naïve, non-dependent, and alcohol-dependent CCL2 transgenic and non-transgenic mice show that elevated levels of CCL2 in the CNS interact with alcohol in tests for alcohol drinking, spatial learning, and associative learning.
新兴研究提供了强有力的证据，表明中枢神经系统（CNS）胶质细胞的激活发生在神经疾病和脑损伤中，并导致神经免疫因子的产生增加。这些因子可促成导致中枢神经系统功能改变的病理生理过程。最近，研究还表明，急性和慢性饮酒均可导致中枢神经系统胶质细胞的激活以及神经免疫因子的产生，尤其是趋化因子配体2（CCL2）。酒精诱导中枢神经系统中CCL2水平升高的后果尚未完全阐明。我们的研究聚焦于这样一个假设，即中枢神经系统中CCL2水平的升高会产生神经适应性变化，从而改变酒精对中枢神经系统的作用。我们利用行为测试对表达高水平CCL2的转基因小鼠进行测试，以验证这一假设。转基因小鼠中CCL2水平的升高涉及星形胶质细胞表达的增加。转基因小鼠及其非转基因同窝对照接受两种酒精暴露模式之一，一种是不会产生酒精依赖的双瓶选择饮酒程序，另一种是会产生酒精依赖的慢性间歇性酒精程序。进行了多项行为测试，包括巴恩斯迷宫测试、Y迷宫测试、线索性和情境性条件恐惧测试、明暗转换测试以及强迫游泳测试。对未接触酒精、非依赖酒精和依赖酒精的CCL2转基因小鼠与非转基因小鼠进行比较，结果显示，中枢神经系统中CCL2水平的升高在酒精饮用、空间学习和联想学习测试中与酒精相互作用。
