Safety signal learning in Rhesus monkeys following early life stressChallenge Ar

恒河猴在早期生活压力后学习安全信号挑战 Ar

• 批准号: 7937001
• 负责人: MAR M SANCHEZ
• 金额: $ 40.41万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937001
• 关键词: Acoustics; Address; Affect; Air; Animals; Anxiety; Area; Back; Behavior; Behavioral; Behavioral Paradigm; Biological Markers; Brain; Brain imaging; Clinical; Comorbidity; Cues; DNA Library; Data; Discrimination; Disease; Event; Female; Fright; Funding; Future; Genetic; Genotype; Grant; Home environment; Human; Human Resources; Individual; Infant; Lead; Learning; Life; Life Stress; Light; Macaca mulatta; Major Depressive Disorder; Measures; Mental Depression; Mental disorders; Modeling; Monkeys; Mothers; National Institute of Mental Health; Patients; Post-Traumatic Stress Disorders; Prevention; Primates; Rattus; Reaction; Recovery; Reflex action; Resources; Safety; Sampling; Signal Transduction; Smell Perception; Stimulus; Sulfur; Symptoms; System; Techniques; Testing; Time; Veterans; Vietnam; Work; behavior measurement; cohort; combat; experience; genetic variant; male; neuroimaging; nonhuman primate; novel; programs; public health relevance; relating to nervous system; resilience; response; social; sound; wasting; young adult

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.

描述（由申请人提供）：此申请解决了广泛的挑战领域（01）行为，行为改变以及预防和特定挑战主题03-MH-101*精神障碍生物标志物。主要假设是创伤后应激障碍（PTSD）导致对安全信号的响应能力降低。例如，PTSD临床问题的核心是在患有早期生活压力的患者中与重度抑郁症的合并症约为90％，这是这些患者无法抑制他们恐惧的刺激，即使在安全条件。实际上，我们现在有证据表明无法抑制恐惧可能是PTSD的独特生物标志物。因此，即使在自己家的安全中，汽车向后射击或硫磺味的声音也会导致越南退伍军人的恐惧反应。尽管有大量的轶事证据支持这一假设，但使用良好控制的行为范式的人类或动物的直接测试仍受到限制。现在，我们在大鼠，恒河猴和人类中发展了使用相同的范式和所有物种中的声学惊吓反射的安全信号学习和表达的客观衡量。三个提示用于AX+/BX-的形式，其中Cues A和X中的A和X在化合物中（例如，来自安静风扇的轻吹气）与厌恶事件（+）配对，而新的提示B（例如，音调）和相同的提示x信号无反感事件（ - ）。当受试者得知A和X呈现在一起预测美国时，提示A变得兴奋。提示B成为抑制性，因为B呈现X呈现了美国的“安全性”。在随后的关键转移测试试验中，与A的反应相比，A和B一起呈现A和B在一起会导致恐惧反应降低。但是，在所有三项研究中，PTSD患者均未抑制AB测试试验的恐惧。由于PTSD与早期生活压力和重大抑郁症具有很高的合并症，我们小组的其他研究表明，只有早期压力或重度抑郁症的患者仅具有正常的安全信号学习，并且只有PTSD或患有抑郁症的PTSD患者显示出显示安全信号学习或表达。因此，我们认为我们有一种客观的方法来衡量PTSD的主要生物标志物。在先前的赠款中，我们测试了6只年轻的恒河猴，3个具有典型的社交和母亲相互作用（对照）（对照组），每天与母亲分开，每天都与母亲分开（母亲分离）。 3对照和1个母体分离显示了成功的AX+，BX-歧视，并且在AB存在的情况下，所有这些都少了。因为他们继续担心A和B（即，在生命早期压力之后没有安全信号学习）。一只母亲分离的猴子学到了很好的猴子表明，这种动物对早期生活压力的韧性。目前，我们正在测试第二个猴子的第二个队列，应在接下来的两个月内完成，以便我们将有12只猴子，6个对照和6个孕妇分离。作为Yerkes国家灵长类动物中心一项漫长的持续计划的一部分，研究了早期生活压力在恒河猴中的影响，除了还将测试的12种动物外，还进行了大量有关另外36只动物的数据。这包括神经内分泌，行为，自主神经，神经影像学和遗传数据，以及可用于进一步基因分型的所有动物的库存DNA。我们认为，这是不应浪费的巨大资源。如果我们不能对这些动物支付每日债券，则必须释放它们，我们将不再可以访问它们。因此，我们建议完成这36个额外的猴子测试，以便我们的最终样本将是48位猴子。这将允许对早期生活压力如何影响安全信号学习，自主神经，神经影像和神经内分泌功能以及其中一些影响是否与各种遗传变异有关。它还可以检测到对早期生活压力有弹性的猴子，因此已经收集到的措施可以与这种弹性的行为度量相关。这是一个“铲子就绪”项目。通过雇用两名全职全职技术人员，完全专门针对该项目，我们可以在两年内完成这项工作，并认为NIMH花费了很多钱。 公共卫生相关性：主要的假设是创伤后应激障碍（PTSD）导致对安全信号的响应能力降低。我们有对人类的恐惧抑制作用的证据。在这笔赠款中，我们要评估恒河猴早期的生命压力是否会使用我们在猴子中发展的相同客观的恐惧抑制作用衡量。如果是这样，将提供恒河猴中的PTSD的第一个模型。