Safety signal learning in Rhesus monkeys following early life stressChallenge Ar

描述（由申请人提供）：本申请涉及广泛的挑战领域（01）行为，行为改变和预防以及特定的挑战主题03-MH-101*精神障碍中的生物标志物。主要的假设是，创伤后应激障碍（PTSD）导致对安全信号的反应能力下降。例如，创伤后应激障碍的临床问题的核心是，即使在安全的条件下，这些患者也无法抑制对创伤经历刺激的恐惧，在早期生活压力的患者中，PTSD与重度抑郁症共病率约为90%。事实上，我们现在有证据表明，无法抑制恐惧可能是创伤后应激障碍的一个独特的生物标志物。因此，一辆汽车向后开火的声音或硫磺的气味会导致越战老兵在战斗多年后产生强烈的恐惧反应，即使是在他们自己安全的家中。尽管有大量轶事证据支持这一假设，但使用控制良好的行为范式对人类或动物进行的直接试验有限。我们现在已经在大鼠、恒河猴和人类身上开发了一种安全信号学习和表达的客观测量方法，使用相同的范式和所有物种的声惊吓反射。三个线索以AX+/BX-的形式使用，其中线索A和X复合（例如，从安静的风扇吹出的光和空气）与厌恶事件（+）配对，而新的线索B（例如，音调）和相同的线索X信号没有厌恶事件（-）。当被试得知A和X一起呈现预示着美国时，提示A变得兴奋起来。提示B变得具有抑制性，因为提示B呈现X预示着来自美国的“安全”。在一项关键的后续转移试验中，与对a的反应相比，同时呈现a和B （AB）导致恐惧反应减少。在三项独立研究中，PTSD患者有时可以区分AX和BX，而其他人则不能。然而，在所有三项研究中，PTSD患者在AB测试试验中并没有抑制对A的恐惧。因为创伤后应激障碍与早期生活压力和重度抑郁症有很高的共病性我们小组的其他研究现在已经表明只有早期生活压力或重度抑郁症的患者只有正常的安全信号学习只有PTSD或PTSD合并抑郁症的患者没有安全信号学习或表达。因此，我们相信我们有一种客观的方法来测量创伤后应激障碍的主要生物标志物。在之前的一项研究中，我们测试了6只年轻的成年恒河猴，其中3只具有典型的社交和母婴互动（对照组），另外3只在婴儿时期每天与母亲分开不同的时间（母亲分开）。3只对照组和1只母亲分离的猴子表现出成功的AX+， BX-辨别能力，它们在AB和A存在时的惊吓程度都较低。另外两只母亲分离的猴子从未能够区分A+和B-，因为它们仍然害怕A和B（即在早期生活压力后没有安全信号学习）。与母亲分离的猴子学习得很好，这表明这种动物对早期生活压力的适应能力很强。目前，我们正在测试第二批6只猴子，这将在未来2个月内完成，因此我们总共将有12只猴子，6只对照组和6只母猴分离。作为Yerkes国家灵长类动物中心长期进行的项目的一部分，研究猕猴早期生活压力的影响，除了我们将要测试的12只动物之外，还对另外36只动物进行了大量的数据研究。这包括神经内分泌、行为、自主神经、神经成像和遗传数据，以及所有动物的DNA库，可用于进一步的基因分型。我们认为，这是一项不应浪费的巨大资源。如果我们不能支付这些动物的日常费用，它们将不得不被释放，我们将再也无法接触到它们。因此，我们建议完成这36只猴子的额外测试，这样我们的最终样本将是48只猴子。这将有助于全面分析早期生活压力如何影响安全信号学习、自主神经、神经成像和神经内分泌功能，以及这些影响是否与各种遗传变异有关。它还可以检测出对早期生活压力有弹性的猴子，因此已经收集到的关于它们的测量可以与这种弹性的行为测量相关联。这是一个“准备就绪”的项目。通过雇用两名新的全职技术人员完全投入到这个项目中，我们可以在两年内完成这项工作，我相信NIMH花的钱是物有所值的。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic 03-MH-101* Biomarkers in mental disorders. The major hypothesis is that post-traumatic stress disorder (PTSD) leads to a reduction in the ability to respond to safety signals. For example, central to the clinical problem of PTSD, which has a ~90% comorbidity with major depressive disorder in patients who had early life stress, is the inability of these patients to inhibit their fear to stimuli reminiscent of their traumatic experience, even in safe conditions. In fact, we now have evidence that the inability to inhibit fear may be a unique biomarker of PTSD. Thus the sound of a car back firing or the smell of sulfur can lead to an intense fear reaction in Viet Nam veterans many years after combat, even in the safety of their own home. Despite substantial anecdotal evidence in support of this hypothesis, direct tests in humans or animals, using well-controlled behavioral paradigms, have been limited. We have now developed in rats, rhesus monkeys and humans an objective measure of safety signal learning and expression using identical paradigms and the acoustic startle reflex in all species. Three cues are used in the form AX+/BX-, where cues A and X in compound (e.g. a light and air blowing from a quiet fan) are paired with an aversive event (+), and a new cue B (e.g. a tone) and the same cue X signal no aversive event (-). Cue A becomes excitatory as the subject learns that A and X presented together predict the US. Cue B becomes inhibitory because B presented with X predicts "safety" from the US. In a critical subsequent transfer test trial, presentation of A and B together (AB) results in a reduced fear response compared with the response to A. In three independent studies PTSD patients sometimes could discriminate AX from BX while others could not. However, in all three studies PTSD patients did not inhibit fear to A on AB test trials. Because PTSD has high comorbidity with early life stress and major depression other studies in our group have now shown that patients with early life stress only or major depression only have normal safety signal learning and only patients with PTSD or PTSD with depression fail in show safety signal learning or expression. Thus, we believe we have an objective way to measure a major biomarker of PTSD. In a prior grant we tested 6 young adult rhesus monkeys, 3 with typical social and mother-infant interactions (controls) and 3 separated from their mothers for variable periods of time each day when they were infants (maternally-separated). 3 control and 1 maternally-separated showed successful AX+, BX- discrimination and all of them had less startle in the presence of AB, vs. A. The other two monkeys, both maternally separated, were never able to discriminate between A+ and B- because they continued to be fearful of both A and B (i.e. no safety signal learning following early life stress). The one maternally separated monkey that learned very well suggests resilience to early life stress in this animal. Currently we are testing the second cohort of 6 monkeys which should be completed in the next 2 months so we will have 12 monkeys in total, 6 control and 6 maternally-separated. As part of a long standing ongoing program at the Yerkes National Primate Center studying the effects of early life stress in rhesus monkeys, a great deal of data on another 36 animals in addition to the 12 we will have tested has been carried out. This includes neuroendrocrine, behavioral, autonomic, neuroimaging and genetic data, as well as banked DNA from all the animals available for further genotyping. We believe this is a tremendous resource that should not be wasted. If we cannot pay the per diems on these animals they will have to be released and we will no longer have access to them. Hence, we propose to finish testing these 36 additional monkeys so that our final sample will be 48 monkeys. This will allow a thorough analysis of how early life stress affects safety signal learning, autonomic, neuroimaging and neuroendrocrine functioning and whether some of these effects can be associated with various genetic variants. It may also detect monkeys that are resilient to early life stress so the measures already collected on them can be correlated with this behavioral measure of resilience. This is a "shovel ready" project. By hiring two new, full time technicians devoted entirely to this project we can get this work done in 2 years and believe it will be money well spent by NIMH. PUBLIC HEALTH RELEVANCE: The major hypothesis is that post-traumatic stress disorder (PTSD) leads to a reduction in the ability to respond to safety signals. We have evidence for this in humans using an objective test of fear inhibition. In this grant we want to evaluate whether early life stress in rhesus monkeys will associated with this deficit using the same objective measure of fear inhibition we also have developed in monkeys. If so would provide the first model of PTSD in rhesus monkeys.