Safety Signal Learning in Monkeys: Cortical Regulation and its Development

猴子的安全信号学习：皮质调节及其发展

• 批准号: 7906061
• 负责人: JOCELYNE H BACHEVALIER
• 金额: $ 40.6万
• 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: 2009-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906061
• 关键词: 6 year old; 9 year old; Acoustics; Adolescent; Adult; Age; Age-Months; Anatomy; Animal Model; Animals; Anxiety; Anxiety Disorders; Area; Autistic Disorder; Behavioral inhibition; Boxing; Brain imaging; Brain region; Characteristics; Childhood; Color; Computers; Cues; Data; Development; Discrimination; Disease; Dorsal; Emotional disorder; Emotions; Environmental Risk Factor; Event; Extinction (Psychology); Failure; Female; Fright; Functional disorder; Goals; Human; Individual; Lateral; Lead; Learning; Lesion; Life; Life Stress; Literature; Longitudinal Studies; Macaca mulatta; Mammals; Maps; Measures; Mediating; Mental disorders; Methods; Modeling; Modification; Molecular; Monkeys; Neurotransmitters; Operative Surgical Procedures; Output; Panic Disorder; Pathway interactions; Patients; Phase; Phobic anxiety disorder; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Price; Primates; Procedures; Process; Rattus; Recovery; Regulation; Reporting; Research; Resistance; Reversal Learning; Rodent; Role; Safety; Schizophrenia; Series; Short-Term Memory; Signal Transduction; Stimulus; Symptoms; Testing; Time; Training; Translating; Traumatic Brain Injury; base; clinically relevant; conditioned fear; conditioning; design; emotional reaction; frontal lobe; infancy; male; mind control; neuropsychiatry; neuroregulation; neurotoxic; nonhuman primate; novel; prevent; relating to nervous system; research study; response; safety study; sex; showing emotion; social; tool; translational approach; visual stimulus; young adult

DESCRIPTION (provided by applicant): One of the core symptoms of many anxiety disorders, especially Post-Traumatic Stress Disorder (PTSD), is an inability for fear safe in situations where healthy individuals do feel safe. Thus, animal models of fear conditioning and fear inhibition offer useful tools to determine how these learned fears are diminished or inhibited. We have developed a new paradigm in rodents referred to as AX?, where cues A and X in compound signal an aversive event and cues B and X in compound signal no aversive event (safety). 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. Other tests have shown this is bona fide conditioning inhibition and not due to external inhibition. We have now found this to be true in humans and rhesus monkeys where we see transfer of inhibition on AB test trials, in contrast to prior failures to see transfer in humans using the typical conditioned inhibition paradigm. Most importantly, in three independent groups of patients with PTSD we see some discrimination between AX and BX but no transfer on the critical AB test trial, thus detecting a core symptom in PTSD. The R21 phase of this application is to modify our current AX? paradigm into a "working memory" test, which will allow the same monkeys to be tested repeatedly in this new paradigm using sets of pictures as stimuli instead of lights and tones. We will then evaluate in adult monkeys that have sustained neurotoxic lesions of orbital frontal areas 14/25 vs.11/13 vs. 12 in safety signal learning and expression. As a positive control, we will also test these monkeys in reversal learning and reinforce devaluation that is known to be compromised by damage to one or more of these lesions. If successful, the R33 phase will begin to evaluate the development of safety signal learning from year 1 to year 3, a time period when pronounced developmental changes occur in these orbital frontal areas. We believe a "working memory" version of this measure of safety signal learning in which the same animal can be tested repeatedly will provide a major new paradigm to study safety signal learning in psychiatric disorders and to eventually lead to new and better treatments for people with anxiety disorders. This project is clinically relevant because: (1) many emotional disorders in humans, such as anxiety, phobias and post-traumatic stress disorders, are characterized by a resistance to extinguish learned emotional reactions to anxiogenic stimuli or contextual information associated with these anxiogenic stimuli, (2) learned fear in early infancy has strong resistance to extinction that yield anxiety disorders later in life and (3) anxiety disorders have also been reported in several developmental neuropsychiatric disorders, such as autism and schizophrenia, as well as following pediatric traumatic brain injury and early life stress.

描述(申请人提供)：许多焦虑症的核心症状之一，特别是创伤后应激障碍(PTSD)，是在健康人确实感到安全的情况下，由于害怕而无法安全。因此，恐惧条件作用和恐惧抑制的动物模型提供了有用的工具来确定这些习得的恐惧是如何减少或抑制的。我们在啮齿类动物中开发了一种新的范式，称为AX？，其中复合体中的线索A和X表示厌恶事件，复合体中的线索B和X表示没有厌恶事件(安全)。在随后的关键转移测验中，与对A的反应相比，呈现A和B一起(AB)会导致恐惧反应减少。其他测试表明，这是真正的条件性抑制，而不是由于外部抑制。我们现在已经在人类和恒河猴身上发现了这一点，我们在AB测试试验中看到了抑制转移，而以前使用典型的条件抑制范式在人类中未能看到抑制转移。最重要的是，在三组独立的PTSD患者中，我们看到了AX和BX之间的一些区别，但在关键的AB测试试验中没有转移，因此检测到了PTSD的核心症状。这个应用程序的R21阶段是修改我们当前的AX？这项研究将这一实验模式转变为一种“工作记忆”测试，这将允许在这一新的测试模式中重复测试相同的猴子，使用一组图片作为刺激，而不是使用灯光和音调。然后，我们将评估成年猴子在安全信号学习和表达方面的安全性，这些成年猴子的眼眶额区神经毒性损伤分别为14/25、11/13和12。作为积极的对照，我们还将测试这些猴子的逆转学习能力，并加强已知受到这些损伤中的一个或多个损害的贬值。如果成功，R33阶段将开始评估从第1年到第3年安全信号学习的发展情况，这是这些眼眶额区发生显著发育变化的时期。我们相信，这种安全信号学习方法的工作记忆版本，即同一动物可以重复测试，将为研究精神障碍中的安全信号学习提供一个重要的新范式，并最终为焦虑症患者带来新的更好的治疗方法。这个项目具有临床意义，因为：(1)人类的许多情绪障碍，如焦虑、恐惧症和创伤后应激障碍，其特点是对焦虑刺激或与这些焦虑刺激相关的背景信息产生的获得性情绪反应难以消除，(2)婴儿期习得的恐惧对消退具有很强的抵抗力，从而在以后的生活中产生焦虑症，(3)据报道，焦虑症也出现在几种发育性神经精神障碍中，如自闭症和精神分裂症，以及儿童创伤性脑损伤和早期生活应激。