AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli.
AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli.
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DOI：
10.1016/j.biopsych.2008.06.003
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发表时间：
2008-10-15
影响因子：
10.6
通讯作者：
Nestler, Eric J.
中科院分区：
文献类型：
--
作者：
Krishnan, Vaishnav;Han, Ming-Hu;Mazei-Robison, Michelle;Iniguez, Sergio D.;Ables, Jessica L.;Vialou, Vincent;Berton, Olivier;Ghose, Subroto;Covington, Herbert E., III;Wiley, Matthew D.;Henderson, Ross P.;Neve, Rachael L.;Eisch, Amelia J.;Tamminga, Carol A.;Russo, Scott J.;Bolanos, Carlos A.;Nestler, Eric J.
只有少数暴露在压力下的人患上精神疾病的神经生物学机制在很大程度上仍不清楚。最近的证据表明，腹侧被盖区(VTA)的多巴胺能神经元在应激易损性的表现中起关键作用。使用社交失败范式，我们将易感小鼠(社交回避)与不易感小鼠(社交互动)分开，并检查VTA击打神经营养信号的变化。利用一系列病毒载体，我们试图将这些神经营养变化与回避行为的发展因果联系起来。对社会失败的易感性与VTA内活性/磷酸化AKT(胸腺瘤病毒原癌基因)水平显著降低有关，而慢性抗抑郁治疗(在小鼠和人类中)增加了活性AKT水平。在易感的小鼠中，这种失败诱导的AKT激活的减少既是必要的，也是足以概括与易感性相关的抑郁行为的。AKT活性的药理学降低也显著提高了VTA多巴胺神经元的放电频率，这是易感表型的重要电生理标志。这些研究强调了VTA AKT信号减少的关键作用，它是慢性应激适应不良细胞和行为反应的关键中介。
The neurobiological mechanisms by which only a minority of stress-exposed individuals develop psychiatric diseases remain largely unknown. Recent evidence suggests that dopaminergic neurons of the ventral tegmental area (VTA) play a key role in the manifestation of stress vulnerability. Using a social defeat paradigm, we segregated susceptible mice (socially avoidant) from unsusceptible mice (socially interactive) and examined VTA punches for changes in neurotrophic signaling. Employing a series of viral vectors, we sought to causally implicate these neurotrophic changes in the development of avoidance behavior. Susceptibility to social defeat was associated with a significant reduction in levels of active/phosphorylated AKT (thymoma viral proto-oncogene) within the VTA, whereas chronic antidepressant treatment (in mice and humans) increased active AKT levels. This defeat-induced reduction in AKT activation in susceptible mice was both necessary and sufficient to recapitulate depressive behaviors associated with susceptibility. Pharmacologic reductions in AKT activity also significantly raised the firing frequency of VTA dopamine neurons, an important electrophysiologic hallmark of the susceptible phenotype. These studies highlight a crucial role for decreases in VTA AKT signaling as a key mediator of the maladaptive cellular and behavioral response to chronic stress.
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影响因子：
3.4
作者：
Lucki, I;Dalvi, A;Mayorga, AJ
通讯作者：
Mayorga, AJ
影响因子：
--
作者：
KESSLER, RC;SONNEGA, A;NELSON, CB
通讯作者：
NELSON, CB
影响因子：
17.7
作者：
Kendler, KS;Karkowski, LM;Prescott, CA
通讯作者：
Prescott, CA
DOI：
10.1073/pnas.172091899
发表时间：
2002-08-20
影响因子：
11.1
作者：
Barrot, M;Olivier, JDA;Nestler, EJ
通讯作者：
Nestler, EJ
影响因子：
3.4
作者：
Cryan, JF;Page, ME;Lucki, I
通讯作者：
Lucki, I