Clark Sarah M, Sand Joseph, Francis T Chase, Nagaraju Anitha, Michael Kerry C, Keegan Achsah D, Kusnecov Alexander, Gould Todd D, Tonelli Leonardo H
Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States; Research and Development Service, Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, United States.
Laboratory of Behavioral Neuroimmunology, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States.
Brain Behav Immun. 2014 May;38:192-201. doi: 10.1016/j.bbi.2014.02.001. Epub 2014 Feb 10.
Significant evidence suggests that exposure to traumatic and/or acute stress in both mice and humans results in compromised immune function that in turn may affect associated brain processes. Additionally, recent studies in mouse models of immune deficiency have suggested that adaptive immunity may play a role during traumatic stress exposure and that impairments in lymphocyte function may contribute to increased susceptibility to various psychogenic stressors. However, rodent studies on the relationship between maladaptive stress responses and lymphocyte deficiency have been complicated by the fact that genetic manipulations in these models may also result in changes in CNS function due to the expression of targeted genes in tissues other than lymphocytes, including the brain. To address these issues we utilized mice with a deletion of recombination-activating gene 2 (Rag2), which has no confirmed expression in the CNS; thus, its loss should result in the absence of mature lymphocytes without altering CNS function directly. Stress responsiveness of immune deficient Rag2(-/-) mice on a BALB/c background was evaluated in three different paradigms: predator odor exposure (POE), fear conditioning (FC) and learned helplessness (LH). These models are often used to study different aspects of stress responsiveness after the exposure to an acute stressor. In addition, immunoblot analysis was used to assess hippocampal BDNF expression under both stressed and non-stressed conditions. Subsequent to POE, Rag2(-/-) mice exhibited a reduced acoustic startle response compared to BALB/c mice; no significant differences in behavior were observed in either FC or LH. Furthermore, analysis of hippocampal BDNF indicated that Rag2(-/-) mice have elevated levels of the mature form of BDNF compared to BALB/c mice. Results from our studies suggest that the absence of mature lymphocytes is associated with increased resilience to stress exposure in the POE and does not affect behavioral responses in the FC and LH paradigms. These findings indicate that lymphocytes play a specific role in stress responsiveness dependent upon the type, nature and intensity of the stressor.
大量证据表明，小鼠和人类暴露于创伤性和/或急性应激会导致免疫功能受损，进而可能影响相关的大脑过程。此外，最近在免疫缺陷小鼠模型中的研究表明，适应性免疫可能在创伤性应激暴露期间发挥作用，淋巴细胞功能受损可能导致对各种心理性应激源的易感性增加。然而，啮齿动物关于适应不良应激反应与淋巴细胞缺乏之间关系的研究因以下事实而变得复杂：这些模型中的基因操作也可能由于淋巴细胞以外的组织（包括大脑）中靶向基因的表达而导致中枢神经系统功能的变化。为了解决这些问题，我们使用了重组激活基因2（Rag2）缺失的小鼠，该基因在中枢神经系统中没有确认的表达；因此，其缺失应导致成熟淋巴细胞的缺失，而不会直接改变中枢神经系统功能。在三种不同的范式中评估了BALB/c背景下免疫缺陷的Rag2(-/-)小鼠的应激反应性：捕食者气味暴露（POE）、恐惧条件反射（FC）和习得性无助（LH）。这些模型通常用于研究暴露于急性应激源后应激反应性的不同方面。此外，免疫印迹分析用于评估应激和非应激条件下海马脑源性神经营养因子（BDNF）的表达。在POE之后，与BALB/c小鼠相比，Rag2(-/-)小鼠表现出降低的听觉惊吓反应；在FC或LH中均未观察到行为上的显著差异。此外，海马BDNF的分析表明，与BALB/c小鼠相比，Rag2(-/-)小鼠成熟形式的BDNF水平升高。我们的研究结果表明，成熟淋巴细胞的缺失与POE中对应激暴露的恢复力增加有关，并且不影响FC和LH范式中的行为反应。这些发现表明，淋巴细胞在应激反应性中发挥特定作用，这取决于应激源的类型、性质和强度。
