敲除雌性大鼠前边缘皮层的神经元选择性 HCN 通道可模拟慢性乙醇暴露的影响

IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Benjamin A. Hughes , Todd K. O'Buckley , Giorgia Boero , A. Leslie Morrow
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引用次数: 0

摘要

我们的实验室以前曾发现,慢性乙醇暴露会增强雌性成年 Sprague-Dawley 大鼠的工作记忆能力,而雄性大鼠则不会,这表明大脑皮层的可塑性存在根本性的性别差异。最近的研究进一步发现,雌性大鼠在长期接触乙醇后,抑制性马丁诺蒂中间神经元中 HCN 介导的通道活性明显降低,而雄性大鼠则没有类似现象。根据这些观察结果,我们推测酒精会通过下调这些通道在中间神经元中的活性来促进工作记忆的表现。为了验证这一假设,我们采用了一种与 Pol-II 兼容的 shRNA 表达系统,有针对性地敲除这些细胞中的 HCN 通道活性,并在延迟非匹配抽样(NMS)T-迷宫测试中测量其表现,以评估其对工作记忆表现的影响。在敲除HCN通道后,工作记忆的基线表现明显增强,这表明神经元间表达的HCN在认知要求较高的任务中对维持最佳皮层网络活动起着关键作用。与之前的观察结果一致,乙醇暴露会导致 NMS T 迷宫表现增强,但在施用酒精后,scram 和 hcn-shRNA 感染组都观察到了工作记忆表现的提升。因此,我们得出结论,尽管神经元间表达的 HCN 通道在大脑皮层 HCN 总表达量中仅占一小部分,但它们对维持工作记忆过程做出了重大贡献。不过,下调的 HCN 通道活性似乎并不足以单独表现出酒精诱导的雌性大鼠在急性戒断期工作记忆能力的增强。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Interneuron-selective HCN channel knockdown in prelimbic cortex of female rats mimics effects of chronic ethanol exposure

Our laboratory has previously shown that chronic ethanol exposure elicits enhanced working memory performance in female, but not male, adult Sprague–Dawley rats, indicative of a fundamental sex difference in cortical plasticity. Recent studies have furthermore revealed that females display markedly reduced HCN-mediated channel activity in inhibitory Martinotti interneurons after chronic ethanol exposure that is similarly not observed in males. From these observations we hypothesized that alcohol induces facilitated working memory performance via down-regulation of these channels’ activity specifically within interneurons. To test this hypothesis, we employed a Pol-II compatible shRNA expression system to elicit targeted knockdown of HCN channel activity in these cells, and measured performance on a delayed Non-Match-to-Sample (NMS) T-maze test to gauge effects on working memory performance. A significant baseline enhancement of working memory performance with HCN channel knockdown was observed, indicative of a critical role for interneuron-expressed HCNs in maintaining optimal cortical network activity during cognitively-demanding tasks. Consistent with previous observations, ethanol exposure resulted in enhanced NMS T-maze performance, however elevated working memory performance was observed in both scram- and hcn-shRNA infected groups after alcohol administration. We therefore conclude that interneuron-expressed HCN channels, despite representing a minor population of total cortical HCN expression, contribute substantially to maintaining working memory processes. Downregulated HCN channel activity, though, does not alone appear sufficient to manifest alcohol-induced enhancement of working memory performance observed in female rats during acute withdrawal.

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来源期刊
Alcohol
Alcohol 医学-毒理学
CiteScore
4.60
自引率
4.30%
发文量
74
审稿时长
15.6 weeks
期刊介绍: Alcohol is an international, peer-reviewed journal that is devoted to publishing multi-disciplinary biomedical research on all aspects of the actions or effects of alcohol on the nervous system or on other organ systems. Emphasis is given to studies into the causes and consequences of alcohol abuse and alcoholism, and biomedical aspects of diagnosis, etiology, treatment or prevention of alcohol-related health effects. Intended for both research scientists and practicing clinicians, the journal publishes original research on the neurobiological, neurobehavioral, and pathophysiological processes associated with alcohol drinking, alcohol abuse, alcohol-seeking behavior, tolerance, dependence, withdrawal, protracted abstinence, and relapse. In addition, the journal reports studies on the effects alcohol on brain mechanisms of neuroplasticity over the life span, biological factors associated with adolescent alcohol abuse, pharmacotherapeutic strategies in the treatment of alcoholism, biological and biochemical markers of alcohol abuse and alcoholism, pathological effects of uncontrolled drinking, biomedical and molecular factors in the effects on liver, immune system, and other organ systems, and biomedical aspects of fetal alcohol spectrum disorder including mechanisms of damage, diagnosis and early detection, treatment, and prevention. Articles are published from all levels of biomedical inquiry, including the following: molecular and cellular studies of alcohol''s actions in vitro and in vivo; animal model studies of genetic, pharmacological, behavioral, developmental or pathophysiological aspects of alcohol; human studies of genetic, behavioral, cognitive, neuroimaging, or pathological aspects of alcohol drinking; clinical studies of diagnosis (including dual diagnosis), treatment, prevention, and epidemiology. The journal will publish 9 issues per year; the accepted abbreviation for Alcohol for bibliographic citation is Alcohol.
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