Department of Psychiatry, Weill Cornell Medicine, New York, NY, 10065, USA.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
Transl Psychiatry. 2022 Aug 25;12(1):346. doi: 10.1038/s41398-022-02116-4.
Fear generalization is a conserved survival mechanism that can become maladaptive in the face of traumatic situations, a feature central to certain anxiety disorders including posttraumatic stress disorder (PTSD). However, the neural circuitry and molecular mechanisms underlying fear generalization remain unclear. Recent studies have shown that prophylactic treatment with (R,S)-ketamine confers protective effects in stress-induced depressive behaviors and enhances contextual fear discrimination, but the extent to which these effects extend to fear generalization after auditory fear conditioning remains unclear. Here, we build on this work by using a behavioral model of fear generalization in mice involving foot shocks with differential intensity levels during auditory fear conditioning. We find that prophylactic (R,S)-ketamine treatment exerts protective effects that results in enhanced fear discrimination in wild type mice. As the growth factor, brain-derived neurotrophic factor (BDNF), has been shown to mediate the rapid antidepressant actions of (R,S)-ketamine, we used a loss-of-function BDNF mouse line (BDNF Val66Met) to determine whether BDNF is involved in (R,S)-ketamine's prophylactic effects on fear generalization. We found that BDNF Val66Met mice were resistant to the protective effects of prophylactic (R,S)-ketamine administration on fear generalization and extinction. We then used fiber photometry to parse out underlying neural activity and found that in the ventral hippocampus there were significant fear generalization-dependent patterns of activity for wild type and BDNF Val66Met mice that were altered by prophylactic (R,S)-ketamine treatment. Overall, these findings indicate a role for the ventral hippocampus and BDNF signaling in modulating the mitigating effects of prophylactic (R,S)-ketamine treatment on generalized fear.
恐惧泛化是一种保守的生存机制，在面对创伤性情境时可能会变得适应不良，这是某些焦虑症（包括创伤后应激障碍[PTSD]）的核心特征。然而，恐惧泛化的神经回路和分子机制仍不清楚。最近的研究表明，（R，S）-氯胺酮的预防性治疗在应激诱导的抑郁行为中具有保护作用，并增强了情境恐惧辨别力，但这些作用在听觉恐惧条件反射后是否扩展到恐惧泛化尚不清楚。在这里，我们在涉及听觉恐惧条件反射期间使用不同强度水平的脚部电击的小鼠恐惧泛化行为模型中，构建了这项工作。我们发现预防性（R，S）-氯胺酮治疗具有保护作用，可导致野生型小鼠的恐惧辨别力增强。由于脑源性神经营养因子（BDNF）作为生长因子，已被证明介导了（R，S）-氯胺酮的快速抗抑郁作用，我们使用了一种 BDNF 基因缺失功能小鼠品系（BDNF Val66Met）来确定 BDNF 是否参与（R，S）-氯胺酮对恐惧泛化的预防性作用。我们发现 BDNF Val66Met 小鼠对预防性（R，S）-氯胺酮给药对恐惧泛化和消退的保护作用具有抗性。然后，我们使用光纤光度法解析出潜在的神经活动，发现野生型和 BDNF Val66Met 小鼠的腹侧海马体中存在显著的恐惧泛化相关活动模式，这些模式因预防性（R，S）-氯胺酮治疗而改变。总体而言，这些发现表明腹侧海马体和 BDNF 信号在调节预防性（R，S）-氯胺酮治疗对泛化恐惧的减轻作用中起作用。
