∆FosB: a transcriptional regulator of stress and antidepressant responses.
∆FosB: a transcriptional regulator of stress and antidepressant responses.
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DOI：
10.1016/j.ejphar.2014.10.034
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发表时间：
2015-04-15
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
作者：
FosB是Δ转录因子家族的成员。虽然其他家族成员对一系列急性刺激的反应迅速但短暂，但ΔFosB的独特之处在于，由于其不同寻常的蛋白质稳定性，它在重复刺激时积累。在药物成瘾动物模型中，研究最多的是伏隔核内ΔFosB的长期诱导，大量证据表明ΔFosB促进奖励和动机，并作为药物敏化和增加药物自我给药的机制。最近几年，在慢性给予某些形式的应激反应中，也观察到在NAC内长时间诱导ΔFosB。越来越多的证据表明，这种诱导代表了对慢性应激的积极的、动态平衡的适应，因为ΔFosB在这个大脑区域的过度表达促进了对应激的弹性，而阻断其活动则促进了应激的敏感性。长期服用几种抗抑郁药物也会在NAc中诱导ΔFosB，这种诱导是这些药物在小鼠模型中发挥类似治疗作用所必需的。对这些啮齿动物发现的验证表明，在尸检中，抑郁的人在新AC中显示出ΔFosB水平的降低。作为一种转录因子，ΔFosB通过调节特定靶基因的表达来产生这种行为表型，目前正在进行研究。这些对ΔFosB的研究为抑郁症和抗抑郁作用的分子基础提供了新的见解，这为可能的治疗开发定义了许多新的靶点。
ΔFosB is a member of the Fos family of transcription factors. While other family members are induced rapidly but transiently in response to a host of acute stimuli, ΔFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability. Such prolonged induction of ΔFosB, within nucleus accumbens (NAc), a key brain reward region, has been most studied in animal models of drug addiction, with considerable evidence indicating that ΔFosB promotes reward and motivation and serves as a mechanism of drug sensitization and increased drug self-administration. In more recent years, prolonged induction of ΔFosB has also been observed within NAc in response to chronic administration of certain forms of stress. Increasing evidence indicates that this induction represents a positive, homeostatic adaptation to chronic stress, since overexpression of ΔFosB in this brain region promotes resilience to stress, whereas blockade of its activity promotes stress susceptibility. Chronic administration of several antidepressant medications also induces ΔFosB in the NAc, and this induction is required for the therapeutic-like actions of these drugs in mouse models. Validation of these rodent findings is the demonstration that depressed humans, examined at autopsy, display reduced levels of ΔFosB within the NAc. As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes, which are under current investigation. These studies of ΔFosB are providing new insight into the molecular basis of depression and antidepressant action, which is defining a host of new targets for possible therapeutic development.
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DOI：
10.1523/jneurosci.1758-09.2009
发表时间：
2009-09-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
通讯作者：
Nestler EJ
影响因子：
4.7
作者：
Nestler EJ
通讯作者：
Nestler EJ
DOI：
10.1073/pnas.1221742110
发表时间：
2013-01-29
影响因子：
11.1
作者：
Grueter, Brad A.;Robison, Alfred J.;Malenka, Robert C.
通讯作者：
Malenka, Robert C.
影响因子：
3.4
作者：
Carle, Tiffany L.;Ohnishi, Yoshinori N.;Nestler, Eric J.
通讯作者：
Nestler, Eric J.
影响因子：
5.3
作者：
Cates, Hannah M.;Thibault, Mackenzie;Robison, Alfred J.
通讯作者：
Robison, Alfred J.