Fear generalization after traumatic experience in the dentate gyrus

齿状回创伤经历后的恐惧泛化

基本信息

批准号：
10265566
负责人：
Gergely Turi
金额：
$ 19.89万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265566
关键词：
Acetylcholine Amygdaloid structure Anatomy Anti-Anxiety Agents Anxiety Anxiety Disorders Area Attenuated Axon Brain Brain region Calcium Cell Communication Cells Chronic Code Color Cues Dangerousness Data Depression and Suicide Diagnosis Discrimination Disease Disease model Dopamine Drug usage Elements Environment Episodic memory Fluoxetine Foundations Fright Functional disorder Generalized Anxiety Disorder Genetic Hand Head Health Hippocampus (Brain)Human Hyperphagia Hypertension Hypothalamic structure Image Impairment Knowledge Learning Limbic System Link Literature Location Mediating Moods Mus Neuromodulator Neurons Norepinephrine Optics Pathogenesis Pathologic Pathological anxiety Patients Pattern Pharmaceutical Preparations Pharmacology Play Post-Traumatic Stress Disorders Prefrontal Cortex Probability Problem behavior Process Publishing Role Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Serotonin Receptor 5-HT2A Signal Pathway Source Stimulus Stress Symptoms Synapses Syncope System Techniques Testing Toxin Trauma Work antidepressant effect anxiety symptoms base cell type dentate gyrus emotion regulation essays experience experimental study granule cell in vivo in vivo calcium imaging in vivo two-photon imaging mossy fiber mouse model neurobiological mechanism neuronal patterning neuroregulation neurotransmission optogenetics place fields postsynaptic receptor serotonin receptor transmission process traumatic event two-photon way finding

项目摘要

Abstract One of the hallmark symptoms of anxiety disorders is fear generalization. Patients diagnosed with a disorder form this group are characterized by not only fearing stimuli and situations that are dangerous or closely resemble to the context in which the original trauma occurred but also fearing stimuli and situations that are objectively safe or just faintly resemble the original trauma context. Hippocampus as the part of the limbic system receives and integrates spatial and contextual information and internal states. Moreover, parts of the hippocampus, specifically the dentate gyrus (DG) are both one of the major targets of the effects of antidepressants and anxiolytics, and also play a role in encoding information about the environment by distinguishing between similar contexts, a process called pattern separation. This computation was thought to mostly performed by granule cells however recent experimental results suggest that mossy cells (MCs) the second major principal cell type of the DG may also participate in this process. Therefore, we hypothesized that fear generalization in a stress induced fear learning mouse model is reflected by impaired contextual discrimination function of MCs. We will test this hypothesis by recording the calcium activity of MCs in vivo in stressed mice during a head fixed pattern separation paradigm. SSRI treatment, as the first line of medication for patients diagnosed with anxiety disorders is thought to restore the low serotonin (5-HT) levels in the DG. Despite this notion there is much less known about the actual activity pattern of 5-HT axons under normal or pathological conditions and there is absolutely no data about the correlated activity of the principal cells and 5-HT axons. MCs express the excitatory 5-HT2A receptors which suggests that the activity of MCs may be controlled by 5-HT and indeed, chronic SSRI treatment has been shown to enhance the activity of MCs. Therefore, we hypothesized that decreased activity of 5-HT axons in stressed mice contributes to low levels of 5-HT in the DG which eventually leads to suppressed activity of MCs and disrupted patter separation. To test this hypothesis, first we will confirm the excitatory effect of 5-HT on MCs by combining optogenetical manipulation of 5-HT axons with two-photon imaging, then we will record the calcium activity of 5-HT axons and MCs simultaneously with dual color two-photon imaging following stress induced fear learning. Altogether, this proposal aims to better understand the role of MCs, a still “enigmatic” cell type in the DG in fear generalization and to provide direct evidence for the role of the 5-HT system in the pathogenesis of anxiety disorders. Furthermore, our experiments will lay the foundation for further studies aiming at understanding the mechanism of neuromodulation at the microcircuit level.

抽象的焦虑症的标志症状之一是被诊断患有这种疾病的患者的恐惧泛化。这个群体的特点是不仅害怕刺激和危险或非常相似的情况最初创伤发生的背景，但也害怕客观的刺激和情况作为边缘系统的一部分，海马体是安全的或只是微弱地类似于原始的创伤环境。并整合空间和上下文信息以及内部状态。特别是齿状回（DG）是抗抑郁药作用的主要目标之一，抗焦虑药，还通过区分相似的环境信息来编码环境信息上下文，一个称为模式分离的过程被认为主要由颗粒执行。然而最近的实验结果表明，苔藓细胞 (MC) 是第二大主要细胞类型总干事也可能参与这一过程，因此，我们在压力中追求恐惧泛化。诱导性恐惧学习小鼠模型反映了 MC 的情境辨别功能受损。通过记录头部固定模式期间应激小鼠体内 MC 的钙活性来检验这一假设分离范式。 SSRI 治疗作为诊断患有焦虑症的患者的一线药物被认为可以恢复 DG 中的血清素 (5-HT) 水平较低，尽管有这一观点，但对其实际活性知之甚少。正常或病理条件下 5-HT 轴突的模式，绝对没有关于 5-HT 轴突的数据主细胞和 5-HT 轴突的相关活性表达兴奋性 5-HT2A 受体。表明 MC 的活性可能受 5-HT 控制，事实上，慢性 SSRI 治疗已被证明因此，我们鼓励在压力下降低 5-HT 轴突的活性。小鼠 DG 中 5-HT 水平较低，最终导致 MC 活性受到抑制，为了验证这一假设，首先我们将通过以下方式确认 5-HT 对 MC 的兴奋作用。将 5-HT 轴突的光遗传学操作与双光子成像相结合，然后我们将记录钙压力引起的恐惧后 5-HT 轴突和 MC 的活动与双色双光子成像同时进行总而言之，该提案旨在更好地了解 MC 的作用，MC 是细胞中仍然“神秘”的细胞类型。 DG 在恐惧泛化中的作用，并为 5-HT 系统在恐惧泛化的发病机制中的作用提供直接证据此外，我们的实验将为进一步研究奠定基础。了解微电路水平的神经调节机制。