Berton Olivier, Covington Herbert E, Ebner Karl, Tsankova Nadia M, Carle Tiffany L, Ulery Paula, Bhonsle Akshay, Barrot Michel, Krishnan Vaishnav, Singewald Georg M, Singewald Nicolas, Birnbaum Shari, Neve Rachael L, Nestler Eric J
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Neuron. 2007 Jul 19;55(2):289-300. doi: 10.1016/j.neuron.2007.06.033.
We analyzed the influence of the transcription factor DeltaFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a deficit in escape behavior. Repeated IS induces DeltaFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit-with the strongest DeltaFosB induction observed in the most resilient animals. Induction of DeltaFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for DeltaFosB, is downregulated upon DeltaFosB induction. Local overexpression of DeltaFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.
我们分析了转录因子DeltaFosB对习得性无助的影响，习得性无助是一种情感障碍动物模型，其中一部分暴露于不可逃避应激（IS）的小鼠会出现逃避行为缺陷。反复的IS诱导腹外侧导水管周围灰质（vlPAG）中的DeltaFosB，该蛋白水平高度预测个体随后的行为缺陷——在最具恢复力的动物中观察到最强的DeltaFosB诱导。IS诱导的DeltaFosB在vlPAG中P物质阳性神经元中占主导，并且P物质基因是DeltaFosB的直接靶点，在DeltaFosB诱导后会下调。使用病毒介导的基因转移在vlPAG中局部过表达DeltaFosB可显著减少抑郁样行为，并抑制应激诱导的P物质释放。这些结果表明，IS诱导的DeltaFosB在vlPAG中的积累使该区域丰富的P物质神经元脱敏，并通过促进主动防御反应来对抗行为绝望。
