Safety Signal Learning in Monkeys: Cortical Regulation and its Development

描述（由申请人提供）：许多焦虑症的核心症状之一，尤其是创伤后应激障碍（PTSD），是在健康个体确实感到安全的情况下无法感到恐惧安全。因此，恐惧条件反射和恐惧抑制的动物模型为确定如何减少或抑制这些习得性恐惧提供了有用的工具。我们在啮齿类动物身上开发了一种新的范例叫做AX？，复合提示A和X表示厌恶事件，复合提示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）导致恐惧反应减少。其他试验表明，这是真正的条件反射抑制，而不是由于外部抑制。我们现在发现这在人类和恒河猴中是正确的我们在AB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不到转移的失败形成对比。最重要的是，在三个独立的PTSD患者组中，我们发现AX和BX之间存在一些区别，但在关键的AB测试试验中没有转移，从而发现了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？范式变成了“工作记忆”测试，这将允许同一只猴子在这个新范式中重复测试，使用一组图片作为刺激，而不是光和色调。然后，我们将在眼眶额区持续神经毒性病变的成年猴子中评估安全信号学习和表达的14/25、11/13和12。作为阳性对照，我们还将对这些猴子进行反向学习测试，并加强贬值，这种贬值已知会因一个或多个这些病变的损害而受到损害。如果成功，R33阶段将开始评估从1岁到3岁的安全信号学习的发展，这段时间内这些眶额区域发生了明显的发育变化。我们相信，这种安全信号学习测量的“工作记忆”版本，可以在同一只动物身上反复测试，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例，并最终为焦虑症患者带来新的更好的治疗方法。本项目具有临床意义，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，其特征是对焦虑性刺激或与这些焦虑性刺激相关的背景信息的习得性情绪反应的抵抗；(2)婴儿期的习得性恐惧对消退有很强的抵抗，这种抵抗会在以后的生活中产生焦虑症；(3)在一些发育性神经精神障碍中也有焦虑症的报道。比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压力。

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.