Background

We previously reported that a single injection of ketamine prior to stress protects against the onset of depressive-like behavior and attenuates learned fear. However, the molecular pathways and brain circuits underlying ketamine-induced stress resilience are still largely unknown.

Methods

Here, we tested if prophylactic ketamine administration altered neural activity in the prefrontal cortex (PFC) and/or hippocampus (HPC). Mice were injected with saline or ketamine (30 mg/kg) one week before social defeat (SD). Following behavioral tests assessing depressive-like behavior, mice were sacrificed and brains were processed to quantify ΔFosB expression. In a second set of experiments, mice were stereotaxically injected with viral vectors into ventral CA3 (vCA3) in order to silence or overexpress ΔFosB prior to prophylactic ketamine administration. In a third set of experiments, ArcCreER^T2 mice, a line that allows for the indelible labeling of neural ensembles activated by a single experience, were used to quantify memory traces representing a contextual fear conditioning (CFC) experience following prophylactic ketamine administration.

Results

Prophylactic ketamine administration increased ΔFosB expression in the ventral dentate gyrus (vDG) and vCA3 of SD mice but not of Ctrl mice. Transcriptional silencing of ΔFosB activity in vCA3 inhibited prophylactic ketamine efficacy, while overexpression of ΔFosB mimicked and occluded ketamine’s prophylactic effects. In the ArcCreER^T2 mice, ketamine administration altered memory traces representing the CFC experience in vCA3, but not in vDG.

Conclusions

Our data indicate that prophylactic ketamine may be protective against a stressor by altering neural activity, specifically the neural ensembles representing an individual stressor in vCA3.

中文翻译：

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腹侧CA3激活介导氯胺酮预防应激诱导的抑郁样行为的功效。

背景

我们以前曾报道过，在压力前单次注射氯胺酮可防止抑郁症发作，并减轻学习中的恐惧感。然而，氯胺酮诱导的应激弹性的分子途径和大脑回路仍是未知之数。

方法

在这里，我们测试了氯胺酮的预防给药是否改变了前额叶皮层（PFC）和/或海马（HPC）中的神经活动。在社交失败（SD）前一周，给小鼠注射生理盐水或氯胺酮（30 mg / kg）。在评估抑郁症样行为的行为测试之后，处死小鼠并处理大脑以量化ΔFosB表达。在第二组实验中，在给予预防性的氯胺酮之前，将病毒载体立体定向注射到腹侧CA3（vCA3）中，以沉默或过表达ΔFosB。在第三组实验中，ArcCreER ^T2 小鼠是一条允许对单一经历激活的神经团进行不可磨灭标记的线，用于量化预防性氯胺酮给药后代表情境恐惧调节（CFC）经历的记忆痕迹。

结果

预防性氯胺酮治疗可增加SD小鼠腹侧齿状回（vDG）和vCA3中的ΔFosB表达，而Ctrl小鼠则不。vCA3中ΔFosB活性的转录沉默抑制了氯胺酮的预防功效，而ΔFosB的过表达模仿和阻断了氯胺酮的预防作用。在ArcCreER ^T2小鼠中，氯胺酮的给药改变了记忆痕迹，代表了vCA3中CFC的经历，而vDG中没有。

结论

我们的数据表明，预防性的氯胺酮可以通过改变神经活动来保护应激源，特别是在vCA3中代表单个应激源的神经团。