Behavioral Control, the Medial Prefrontal Cortex, and Resilience in the Face of C

描述（由申请人提供）：本申请涉及挑战领域15（转化科学）。特定挑战主题15-MH-109前额皮质对高级大脑功能和复杂行为的调节。 人们越来越重视了解什么可能产生对压力的行为和神经影响的弹性，应对因素被认为起着关键作用。对压力源的行为控制是应对的一个关键方面，并且控制的存在不仅减弱了被控制的压力源的影响（Maier等人，2006），而且还减少甚至消除了由随后的应激源产生的行为和神经化学变化，即使随后的应激源在行为上是不可控制的（Amat等人，2006年）。也就是说，控制一个强有力的急性应激源的经验似乎可以使生物体对后来（急性）应激的影响“免疫”。重要的是，腹内侧前额叶皮层（vmPFC）已被证明介导行为控制的即时和主动保护作用。控制的存在已被证明激活对应激反应性脑干和边缘结构的自上而下的vmPFC抑制控制，从而减少应激源的神经化学影响，以及这些结构激活的行为后遗症（Amat等人，2005年）。此外，对有效应激源的控制体验以这样的方式改变vmPFC，使得不可控的后续应激源现在激活vmPFC抑制性控制，从而导致针对后续应激源暴露的保护（Amat等人，2006; Baratta等人，2008）。探索控制的顺从性诱导特性以及vmPFC在压力恢复中的作用的研究完全集中在急性压力暴露上。然而，它是慢性压力，是最经常牵连作为一个病因因素的发展，广泛的精神和躯体疾病。事实上，还没有研究经验的因素和机制，可能是重要的，在产生抵抗慢性压力的行为和神经化学的影响，目前的建议是解决这些问题。该研究确定a）对急性应激源的控制经验是否会预防和/或逆转慢性社会应激源的影响，成年人的社会孤立，以及B）vmPFC是这些保护作用的关键介导者。慢性压力是许多疾病发展的病因。并非所有暴露于慢性压力的人都会受到严重影响，对使个人具有弹性的因素的理解可能会导致新的治疗方法。拟议的研究将确定a）在暴露于不同的慢性应激源之前对有效急性应激源的行为控制的体验是否会预防慢性应激源的行为和神经化学效应，和/或在慢性应激源逆转后的控制体验是否会预防慢性应激源的行为和神经化学效应，以及B）通过控制激活内侧前额叶皮层来介导保护。

DESCRIPTION (provided by applicant): This application addresses Challenge Area 15 (Translational Science). Specific Challenge Topic 15-MH-109 Prefrontal cortex regulation of higher brain functions and complex behavior. There is growing emphasis on understanding what might produce resilience to the behavioral and neural impact of stress, and coping factors are thought to play a pivotal role. Behavioral control over the stressor is a key aspect of coping, and the presence of control not only blunts the effects of the stressor being controlled (Maier et al., 2006), but also reduces and even eliminates the behavioral and neurochemical changes produced by subsequent stressors, even if the subsequent stressor is not behaviorally controllable (Amat et al.,2006). That is, the experience of controlling a potent acute stressor appears to "immunize" the organism against the effects of later (acute) stress. Importantly, the ventral medial prefrontal cortex (vmPFC) has been shown to mediate both the immediate and proactive protective effects of behavioral control. The presence of control has been shown to activate top-down vmPFC inhibitory control over stress-responsive brainstem and limbic structures, thereby reducing the neurochemical impact of the stressor, as well as the behavioral sequelae of the activation of these structures (Amat et al.,2005). Furthermore, the experience of control over a potent stressor alters the vmPFC in such a way that subsequent stressors that are uncontrollable now activate vmPFC inhibitory control, thereby leading to protection against subsequent stressor exposure (Amat et al., 2006; Baratta et al, 2008). The research that has explored the resilience-inducing properties of control, as well as the role of the vmPFC in stress-resilience, has focused entirely on acute stress exposure. However, it is chronic stress that is most often implicated as an etiological factor in the development of a broad spectrum of psychiatric and somatic disorders. There has been virtually no study of experiential factors and mechanisms that might be important in producing resistance to the behavioral and neurochemical impact of chronic stress, and the present proposal is addressed at these issues. The research determines whether a) an experience with control over an acute stressor will prevent and/or reverse the impact of a chronic social stressor, adult social isolation, and b) the vmPFC is a critical mediator of these protective effects. Chronic stress is an etiological factor in the development of numerous disorders. Not all individuals exposed to chronic stress are severely impacted, and an understanding of factors that make individuals resilient are likely to lead to new treatments. The proposed research will determine whether a) the experience of behavioral control over a potent acute stressor before exposure to a different chronic stressor will prevent, and/or the experience of control after a chronic stressor reverse, the behavioral and neurochemical effects of the chronic stressor, and b) the protection is mediated by activation of the medial prefrontal cortex by control.