Reprogramming of mPFC transcriptome and function in alcohol dependence.
Reprogramming of mPFC transcriptome and function in alcohol dependence.
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DOI：
10.1111/gbb.12344
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Sommer WH
中科院分区：
文献类型：
--
作者：
Heilig M;Barbier E;Johnstone AL;Tapocik J;Meinhardt MW;Pfarr S;Wahlestedt C;Sommer WH
尽管其有限的即时强化价值，酒精有一个强大的能力，以诱导神经适应，促进其激励显着性，自愿饮酒量的升级和厌恶酒精寻求。这些特征的集合，统称为“后依赖性”，出现在大脑暴露于反复的中毒和戒断循环之后。内侧前额叶皮层（mPFC）及其分支对接近和回避行为（包括那些导致酒精摄入的行为）进行自上而下的调节。在这里，我们回顾了一个新兴的文献表明，mPFC功能的重新编程发生与长期暴露的大脑酒精中毒和戒断周期。这种重编程导致分子失调，导致后依赖综合征。汇聚的证据已经确定了神经适应性改变，从而改变了神经递质和BDNF介导的信号传导，并且对于这些通路，已经获得了机制作用的直接证据。其他证据表明，钙稳态和神经递质释放的途径失调。最近的研究结果表明，全球DNA超甲基化是依赖史后mPFC基因组重新编程的关键因素。作为这种表观遗传重塑的结果之一，几种组蛋白修饰表观遗传酶被抑制。其中，PR结构域锌指蛋白2，一种甲基转移酶，选择性单甲基化组蛋白H3在赖氨酸9已被功能验证驱动酒精依赖的分子和行为的长期后果。mPFC内的信息处理涉及动态神经元网络的形成，或由转录反应形成的功能集合。我们的分子研究发现的表观遗传失调可能会以多种方式改变这种动态处理。总之，随着酒精中毒的发展，mPFC中的表观遗传分子开关似乎被打开。逆转这些过程的策略可能为疾病改善治疗提供目标。
Despite its limited immediate reinforcement value, alcohol has a potent ability to induce neuroadaptations that promote its incentive salience, escalation of voluntary alcohol intake and aversion-resistant alcohol seeking. A constellation of these traits, collectively called ‘post-dependent’, emerges following brain exposure to repeated cycles of intoxication and withdrawal. The medial prefrontal cortex (mPFC) and its subdivisions exert top-down regulation of approach and avoidance behaviors, including those that lead to alcohol intake. Here, we review an emerging literature which indicates that a reprogramming of mPFC function occurs with prolonged exposure of the brain to cycles of alcohol intoxication and withdrawal. This reprogramming results in molecular dysregulations that contribute to the post-dependent syndrome. Convergent evidence has identified neuroadaptations resulting in altered glutamatergic and BDNF-mediated signaling, and for these pathways, direct evidence for a mechanistic role has been obtained. Additional evidence points to a dysregulation of pathways involving calcium homeostasis and neurotransmitter release. Recent findings indicate that global DNA hypermethylation is a key factor in reprogramming the mPFC genome after a history of dependence. As one of the results of this epigenetic remodeling, several histone modifying epigenetic enzymes are repressed. Among these, PR-domain zinc-finger protein 2, a methyltransferase that selectively mono-methylates histone H3 at lysine 9 has been functionally validated to drive several of the molecular and behavioral long-term consequences of alcohol dependence. Information processing within the mPFC involves formation of dynamic neuronal networks, or functional ensembles that are shaped by transcriptional responses. The epigenetic dysregulations identified by our molecular studies are likely to alter this dynamic processing in multiple ways. In summary, epigenetic molecular switches in the mPFC appear to be turned on as alcoholism develops. Strategies to reverse these processes may offer targets for disease-modifying treatments.
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影响因子：
10.6
作者：
Caprioli D;Venniro M;Zeric T;Li X;Adhikary S;Madangopal R;Marchant NJ;Lucantonio F;Schoenbaum G;Bossert JM;Shaham Y
通讯作者：
Shaham Y
影响因子：
25
作者：
Bossert, Jennifer M.;Stern, Anna L.;Theberge, Florence R. M.;Cifani, Carlo;Koya, Eisuke;Hope, Bruce T.;Shaham, Yavin
通讯作者：
Shaham, Yavin
影响因子：
5.3
作者：
Gehlert, Donald R.;Cippitelli, Andrea;Heilig, Markus
通讯作者：
Heilig, Markus
影响因子：
7.6
作者：
Cannella, Nazzareno;Halbout, Briac;Spanagel, Rainer
通讯作者：
Spanagel, Rainer
影响因子：
5.3
作者：
Baptista, MAS;Martin-Fardon, R;Weiss, F
通讯作者：
Weiss, F