Persistent loss of hippocampal neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol exposure.
Persistent loss of hippocampal neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol exposure.
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DOI：
10.1159/000362874
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发表时间：
2014
影响因子：
2.9
通讯作者：
Spear LP
中科院分区：
文献类型：
--
作者：
Broadwater MA;Liu W;Crews FT;Spear LP
虽然青春期是开始饮酒的常见年龄，但在大脑相当成熟的这个时期暴露于酒精的长期后果在很大程度上是未知的。在利用啮齿类动物的研究中，行为证据开始出现，表明海马可能会持续受到青春期反复酒精暴露的影响，但成年期的酒精暴露则不会。本系列实验的目的是探索在青春期暴露于乙醇的成年人海马功能障碍的潜在机制。考虑到成年神经发生的中断已被报道会损害被认为与神经系统相关的任务的表现，我们使用免疫组织化学来评估双皮质素（DCX）的水平，DCX是未成熟神经元的内源性标志物，在青少年（P28 - 48）或成人（P70 - 90）间歇性暴露于4 g/kg乙醇后3 - 4周，海马齿状回（DG）中的kg乙醇灌胃。我们还研究了另一个神经源性小生境，脑室下区（SVZ），以确定乙醇暴露的影响是否具有区域特异性。还通过分别评估Ki67和裂解的半胱天冬酶-3免疫反应性来检查DG中的细胞增殖和细胞死亡水平。与对照同龄动物相比，暴露后约4周，在青少年（而非成年）乙醇暴露动物的DG中观察到DCX显著减少。青少年乙醇对DCX免疫反应性的影响是特定的海马，没有显着的暴露影响出现在SVZ。在DG和SVZ有一个显着的年龄相关的下降，神经发生的DCX指数。青少年乙醇暴露对DG中DCX减少的持续影响似乎与细胞死亡的显著增加有关，与对照组相比，在青少年乙醇组中观察到更多的裂解半胱天冬酶-3阳性免疫反应性，但在Ki67指数化时细胞增殖没有改变。这些结果表明，青少年乙醇暴露史导致分化神经元的水平降低，可能至少部分是由于未成熟神经元的细胞死亡增加。这些影响是明显的，在成年期，周后终止的慢性暴露，并可能有助于以前报告的行为缺陷后，慢性暴露的露营相关的任务。
Although adolescence is a common age to initiate alcohol consumption, long-lasting consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally-related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3–4 weeks after adolescent (P28–48) or adult (P70–90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if effects of ethanol exposure were region-specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol exposed animals ~4 weeks post-exposure when these animals were compared to control age-mates. Effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both DG and SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3 positive immunoreactivity observed in the adolescent ethanol group compared to controls, but no alterations in cell proliferation when indexed by Ki67. These results suggest that a history of adolescent ethanol exposure results in lowered levels of differentiating neurons, likely due at least in part to increased cell death of immature neurons. These effects were evident in adulthood, weeks following termination of the chronic exposure, and may contribute to previously reported behavioral deficits on hippocampal-related tasks after the chronic exposure.
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影响因子：
3.5
作者：
Morris, Stephanie A.;Eaves, David W.;Smith, Aleksander R.;Nixon, Kimberly
通讯作者：
Nixon, Kimberly
乙醇暴露对提示和上下文恐惧条件和灭绝的后果因青春期或成年期暴露时间而有所不同。
影响因子：
2.7
作者：
Broadwater, Margaret;Spear, Linda P.
通讯作者：
Spear, Linda P.
影响因子：
--
作者：
Harrington, Heather A.;Ho, Kenneth L.;Tung, K. C.
通讯作者：
Tung, K. C.
影响因子：
2.5
作者：
Brown, JP;Couillard-Després, S;Kuhn, HG
通讯作者：
Kuhn, HG
影响因子：
2.5
作者：
McClain, Justin A.;Hayes, Dayna M.;Morris, Stephanie A.;Nixon, Kimberly
通讯作者：
Nixon, Kimberly