Dissecting the role of the amygdala intercalated cells in expression, generalization and extinction of stress-enhanced fear learning

剖析杏仁核嵌入细胞在压力增强的恐惧学习的表达、泛化和消退中的作用

• 批准号: 9052054
• 负责人: Abha K Rajbhandari
• 金额: $ 5.42万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-16 至 2017-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052054
• 关键词: Affect; Alleles; Amygdaloid structure; Anxiety Disorders; Behavior; Brain; Brain region; Cell Nucleus; Cells; Chronic Disease; Designer Drugs; Development; Diagnosis; Disease; Dopamine D1 Receptor; Exposure to; Extinction (Psychology); Freezing; Fright; G Protein-Coupled Receptor Signaling; Genetic study; Injection of therapeutic agent; Intercalated Cell; Learning; Life; Link; Measures; Methods; Mus; National Research Service Awards; Neurons; Neuropeptides; PACAPR-1 protein; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Post-Traumatic Stress Disorders; Procedures; Regulation; Research; Research Project Grants; Role; Severities; Signal Transduction; Stress; Symptoms; System; Testing; Therapeutic; Transgenic Mice; Trauma; Virus; clinically relevant; conditioned fear; effective therapy; experience; fear memory; functional outcomes; learned behavior; loss of function; model design; neural circuit; novel; pituitary adenylate cyclase activating polypeptide; psychologic; public health relevance; receptor; recombinase; research study; response; targeted treatment

 DESCRIPTION (provided by applicant): Anxiety disorders such as post-traumatic stress disorder (PTSD) involve inappropriate inhibitory control over fear after exposure to life-threatening traumatic experiences showing enhanced fear generalization and inability to extinguish acquired fear. Currently available medications for PTSD provide limited relief and there is a need for developing more effective treatments for this disorder. Understanding the neural circuitry involved in fear regulation could help develop more effective treatments for this disorder. The amygdala, with its sub-divisions that include the basolateral (BLA) and central nuclei (CeA), is a crucial part of the fear circuitry. Although BLA is known to be important for fer acquisition and CeA for fear expression, the exact mechanisms through which BLA modulates CeA functions is unclear. A GPCR signaling cascade system, pituitary adenylate cyclase activating peptide (PACAP) and its receptor PAC1 have been shown to modulate fear and is expressed in the neural circuitry of fear and have also been related to PTSD diagnosis and symptom severity. Our findings demonstrate that PACAP neurons in the BLA innervate a cluster of cells known as the intercalated cells (ICCs) that lie at the interface of BLA and CeA, a novel microcircuit that could be important for modulation of fear. ICCs receive excitatory projections from the BLA, send inhibitory projections to the CeA, express PAC1 receptors, and have been shown to be important for extinguishing fear behaviors. Given the putative role of the PACAP/PAC1 system and the ICCs in the fear circuitry and their roles in regulating fear, this proposal seeks to elucidate the role of PACAP within the BLA acting via the PAC1-containing neurons in the ICCs that in turn project to CeA in modulation fear expression, generalization and extinction. This proposal will test this hypothesis by systematically manipulating several aspects of the microcircuit involving the BLA (PACAP)-ICCs (PAC1)-CeA using stress-enhanced fear learning (SEFL), a model designed in our lab to specifically test the effects of traumatic experiences on fear behaviors using fear conditioning procedures. The studies will test 1) how loss of function of PAC1 receptors from the ICCs, and 2) how exciting inhibitory signaling in the ICCs alters SEFL expression, generalization and extinction. The findings from the studies in this proposal could unravel novel information about BLA-ICCs-CeA microcircuit as these pathways involving the PACAP/PAC1 system has not been studied in fear-related behaviors. Importantly, these results may be clinically relevant as abnormalities in any part of this circuitry could contribute to the pathology observed in disorders like PTSD, allowing development of targeted therapies.

 描述（由适用提供）：诸如创伤后应激障碍（PTSD）之类的焦虑症涉及对恐惧的抑制作用不适当，暴露于危及生命的创伤经历后，表明恐惧的普遍性增强，无法消除获得的恐惧。当前用于PTSD的药物可提供有限的救济，并且需要为该疾病开发更有效的治疗方法。了解恐惧调节所涉及的神经回路可以帮助开发这种疾病的更有效的治疗方法。杏仁核及其细分包括基础设施（BLA）和中央核（CEA），是恐惧回路的关键部分。尽管众所周知，BLA对于FER获得和CE​​A对于恐惧表达很重要，但BLA调节CEA功能的确切机制尚不清楚。 GPCR信号级联系统，垂体腺苷酸环化酶激活肽（PACAP）及其接收器PAC1已显示可调节恐惧，并在恐惧的神经元回路中表达，也与PTSD诊断和症状严重程度有关。我们的发现表明，BLA中的PACAP神经元支配了一个被称为插入的细胞（ICC）的细胞簇，该细胞位于BLA和CEA界面上，这是一种新型的微电路，对于调节恐惧可能很重要。 ICC从BLA接收兴奋的项目，将抑制项目发送到CEA，表达PAC1接收器，并且已证明对消除恐惧行为很重要。鉴于PACAP/PAC1系统和ICC在恐惧电路中的推定作用及其在调节恐惧中的作用，该提案旨在阐明PACAP在ICC中通过含PAC1的神经元作用的PACAP在ICC中作用的作用，而ICC中的作用反过来又在调制恐惧表达，普遍的一般性，普遍性和扩展中向CEA进行了Project of Project。该提案将通过系统地操纵涉及BLA（PACAP）-ICCS（PAC1）-CEA的微电路的几个方面来检验这一假设，使用压力增强的恐惧学习（SEFL），这是我们实验室中设计的模型，该模型旨在专门测试创伤经历对使用恐惧条件进行恐惧行为的影响。研究将测试1）ICC中PAC1接收器的功能丧失以及2）ICC中令人兴奋的抑制信号如何改变SEFL表达，概括和扩展。该提案中研究的发现可以揭示有关BLA-ICCS-CEA微电路的新信息，因为这些涉及PACAP/PAC1系统的途径尚未研究与恐惧相关的行为。重要的是，这些结果可能在临床上相关，因为该电路的任何部分中的异常都可能导致在PTSD等疾病中观察到的病理，从而允许开发靶向疗法。