Stressor controllability and anxiety: role of serotonin and prefrontal cortex.

描述（由申请人提供）：先前的研究和人类文献表明，应对或控制的感知通常会减轻压力经历的后果，但在压力下缺乏控制可能会导致病理反应。在大鼠中，人们对调节可控和不可控压力源影响的基本神经机制了解甚多。重要的是，不可控的应激源会引起5 -羟色胺能中缝背核的激活，而可控的应激源通过腹内侧前额叶皮层的抑制调节来阻止这种激活（PFC; Maier et al., 2006）。在此基础上，拟议的研究将确定这些机制如何与杏仁核相互作用，杏仁核是焦虑状态的关键结构。该提案的具体目标将使人们了解压力和应对如何在行为和神经水平上影响焦虑，并为NIMH神经科学和基础行为科学部6个高优先级研究领域中的3个做出贡献。这些目标与情感和社会行为项目有重要的相关性，因为应激源可控性和焦虑的行为和神经成分与人类创伤后应激障碍患者的情况相似。在这些患者中，PFC活动减少，杏仁核活动增加，这为即使是轻微的情绪刺激也会产生高焦虑反应提供了一种机制（Bremner et al, 1997）。这项研究的结果可以促进治疗、诊断和预防人类创伤后应激障碍的进展。研究设计：简而言之，将大鼠暴露在压力源中，然后使用社会探索测试测试其焦虑程度。在焦虑状态下，社会探索会减少。将使用多种方法来确定选定的脑核的贡献，包括：应激时兴奋性或抑制性化合物的显微注射，体内微透析，使用逆行示踪的功能解剖和细胞活性标记的免疫组织化学。总之，这些方法提供了对焦虑和神经系统成分的多层次分析，这些神经系统成分介导了可控或不可控压力源的后果。相关性：根据NIMH出版物OM-99 4157（修订版），3.6%的美国成年人患有PTSD。创伤性事件包括军事冲突、飓风、恐怖主义行为、疾病、伤害、身体虐待和犯罪暴力。然而，这些经历并不是所有的受害者都患有创伤后应激障碍。这项拟议的研究将提供关键的见解，以了解应对的关键心理变量如何有助于创伤性事件后焦虑/PTSD的发展或预防。

DESCRIPTION (provided by applicant): Prior research and human literature indicate that coping or the perception of control often mitigates the consequences of stressful experiences, but lack or control during stress may result in pathological responses. In the rat, much is known about the basic neural mechanisms that mediate the effects of controllable and uncontrollable stressors. Importantly, uncontrollable stressors cause activation of the serotonergic dorsal raphe nucleus while controllable stressors prevent this activation via inhibitory modulation from the ventromedial prefrontal cortex (PFC; Maier et al., 2006). Building upon this knowledge, the proposed research will determine how these mechanisms interact with the amygdala, a structure critical to anxiety states. The specific aims of this proposal will inform the basic understanding of how stress and coping affect anxiety on behavioral and neural levels and contribute to 3 of the 6 high-priority research areas of the NIMH Division of Neuroscience and Basic Behavioral Science. The aims have significant relevance to the Affect and Social Behavior program because the behavioral and neural components of stressor controllability and anxiety are similar to the condition in human PTSD patients. In these patients PFC activity is reduced and amygdala activity is increased, providing a mechanism for hyperanxiogenic responses to even mildly-emotional stimuli (Bremner et al., 1997). The results of this research could facilitate advancements in treatment, diagnosis and prevention of PTSD in humans. Research Design: In brief, rats will be exposed to a stressor and then tested for anxiety using a social exploration test. Social exploration is reduced under anxiogenic conditions. A variety of methods will be used to determine the contributions of selected brain nuclei, including: microinjection of excitatory or inhibitory compounds during stress, in vivo microdialysis, functional anatomy using retrograde tracing and immunohistochemistry for cellular activity markers. Together, these methods provide multiple levels of analysis of anxiety and the components of the neural systems that mediate the consequences of controllable or uncontrollable stressors. Relevance: According to NIMH publication OM-99 4157 (Revised), 3.6 % of American adults suffer from PTSD. Traumatic events include military conflict, hurricanes, acts of terrorism, illness, injury, physical abuse and criminal violence. However, these experiences do not leave all victims crippled with PTSD. The proposed research will provide critical insight to how the key psychological variable of coping contributes to the development or prevention of anxiety/PTSD after a traumatic event.