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(申请人提供)：焦虑症，如创伤后应激障碍(PTSD)，在暴露于危及生命的创伤经历后，涉及对恐惧的不适当抑制控制，表现出更强的恐惧泛化和无法消除后天恐惧。目前可用的治疗创伤后应激障碍的药物只能起到有限的缓解作用，因此需要开发更有效的治疗方法。了解参与恐惧调节的神经回路有助于开发出更有效的治疗这种疾病的方法。杏仁核及其分支包括基底外侧核(BLA)和中央核(CEA)，是恐惧回路的关键部分。虽然已知BLA对FER的获得和CEA的恐惧表达具有重要作用，但BLA调节CEA功能的确切机制尚不清楚。GPCR信号通路、垂体腺苷环化酶激活肽(PACAP)及其受体PAC1可调节恐惧，表达于恐惧的神经回路，也与创伤后应激障碍的诊断和症状严重程度有关。我们的发现表明，BLA中的PACAP神经元支配着位于BLA和CEA交界处的一群被称为插层细胞(ICCs)的细胞，CEA是一种新的微电路，可能对调节恐惧很重要。ICCs接受BLA的兴奋性投射，向CEA发送抑制性投射，表达PAC1受体，并已被证明对消除恐惧行为具有重要作用。鉴于PACAP/PAC1系统和ICC在恐惧回路中的假定作用以及它们在调节恐惧中的作用，本研究试图阐明PACAP在BLA中的作用，该作用是通过ICCs中含有PAC1的神经元进而投射到CEA来调节恐惧的表达、概括和消亡。这项提议将通过使用压力增强恐惧学习(SEFL)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说，SEFL是我们实验室设计的一个模型，旨在使用恐惧条件化程序专门测试创伤经历对恐惧行为的影响。这些研究将测试1)ICCs中PAC1受体功能的丧失，以及2)ICCs中兴奋的抑制信号如何改变SEF1的表达、概括和消亡。这项研究的发现可能揭开关于BLA-ICCS-CEA微回路的新信息，因为这些涉及PACAP/PAC1系统的通路在恐惧相关行为中还没有被研究过。重要的是，这些结果可能与临床相关，因为该回路任何部分的异常都可能导致创伤后应激障碍等疾病的病理变化，从而允许开发靶向治疗。