Fear generalization after traumatic experience in the dentate gyrus

齿状回创伤经历后的恐惧泛化

• 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
• 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

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.

摘要 焦虑症的标志性症状之一是恐惧泛化。被诊断患有疾病的患者 这些人的特点是不仅害怕刺激和危险或类似的情况， 在最初的创伤发生的背景下，但也害怕客观上的刺激和情况， 安全或只是隐约类似于最初的创伤背景。海马作为边缘系统的一部分， 并整合空间和上下文信息以及内部状态。此外，海马体的一部分， 特别是齿状回（DG）是抗抑郁药作用的主要靶点之一， 抗焦虑药，也发挥了作用，在编码信息的环境，区分类似 这是一个叫做模式分离的过程。这种计算被认为主要是由颗粒执行的 然而，最近的实验结果表明，苔藓细胞（MC）的第二大主要细胞类型， 总干事也可参与这一进程。因此，我们假设压力下的恐惧泛化 诱导性恐惧学习小鼠模型反映为MC的背景辨别功能受损。我们将 通过在头部固定模式期间记录应激小鼠体内MC的钙活性来检验这一假设 分离范式 SSRI治疗，作为一线药物治疗被诊断为焦虑症的患者被认为是恢复 DG中5-羟色胺（5-HT）水平较低。尽管有这个概念，但对实际活动的了解要少得多。 在正常或病理条件下的5-HT轴突的模式，绝对没有数据， 主细胞和5-HT轴突的相关活性。MC表达兴奋性5-HT 2A受体， 表明MCs的活性可能受到5-HT的控制，事实上，已经显示长期SSRI治疗 以增强MC的活性。因此，我们推测，在应激状态下，5-HT轴突活性的降低可能与应激状态有关。 小鼠导致DG中5-HT水平降低，最终导致MC活性受到抑制， 图案分离中断。为了验证这一假设，我们首先将通过以下方法证实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，然后我们将记录钙离子浓度。 双色双光子显像对应激性恐惧后5-HT轴突和MC活性的同步观察 学习总而言之，这项建议旨在更好地了解MC的作用，MC是一种仍然“神秘”的细胞类型， DG在恐惧泛化中的作用，为5-HT系统在恐惧泛化中的作用提供直接证据。 焦虑症此外，我们的实验将为进一步的研究奠定基础， 了解微电路水平的神经调节机制。