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: 8339478
• 负责人: JOCELYNE H BACHEVALIER
• 金额: $ 42.38万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8339478
• 关键词: 6 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; 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; base; brain surgery; clinically relevant; conditioned fear; conditioning; design; emotional reaction; frontal lobe; infancy; male; mind control; neuropsychiatry; neuroregulation; neurotoxic; nonhuman primate; novel; pediatric traumatic brain injury; 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（由申请人提供）：许多焦虑症的核心症状之一，特别是创伤后应激障碍（PTSD），是在健康个体确实感到安全的情况下无法恐惧安全。因此，恐惧条件反射和恐惧抑制的动物模型提供了有用的工具，以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例，称为AX？，其中复合中的提示A和X表示厌恶事件，复合中的提示B和X表示无厌恶事件（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）导致恐惧反应降低。其他测试表明，这是真正的条件抑制，而不是由于外部抑制。我们现在已经发现这在人类和恒河猴中是真实的，我们在AB测试试验中看到了抑制的转移，与之前使用典型的条件抑制范式在人类中看到转移的失败相反。最重要的是，在三个独立的PTSD患者组中，我们看到AX和BX之间有一些区别，但在关键的AB测试试验中没有转移，因此检测到PTSD的核心症状。此应用程序的R21阶段是修改我们当前的AX？将这一新的范式转换为"工作记忆"测试，这将允许相同的猴子在这种新的范式中反复接受测试，使用一组图片作为刺激，而不是灯光和音调。然后，我们将在成年猴中评价持续性眶额区神经毒性病变14/25 vs.11/13 vs.12的安全信号学习和表达。作为阳性对照，我们还将测试这些猴子的反向学习，并加强贬值，这是已知的损害一个或多个这些病变。如果成功，R33阶段将开始评价从第1年到第3年的安全信号学习的发展，这是这些眶额区发生明显发育变化的时期。我们相信，这种安全信号学习措施的“工作记忆”版本，其中同一动物可以重复测试，将为研究精神疾病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。该项目具有临床相关性，因为：（1）人类中的许多情绪障碍，例如焦虑、恐惧症和创伤后应激障碍，其特征在于抵抗消除对致焦虑刺激或与这些致焦虑刺激相关的背景信息的习得情绪反应，（2）在婴儿早期习得的恐惧具有很强的抵抗力，不会在以后的生活中产生焦虑症;（3）焦虑症也被报道在几种发育性神经精神障碍中，例如自闭症和精神分裂症，以及在儿童创伤性脑损伤和早期生活压力之后。