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.

抽象的 焦虑症的标志性症状之一是恐惧概括。诊断患有疾病的患者 该群体的形式不仅是害怕刺激和危险或非常相似的情况 在原始创伤发生的情况下，也害怕客观上的刺激和情况 安全或纯粹类似于原始创伤环境。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，海马的一部分， 具体而言，齿状回（DG）都是抗抑郁药和抗抑郁作用的主要目标之一 抗焦虑药，还通过区分相似的信息来编码有关环境的信息 上下文，一个称为模式分离的过程。该计算被认为主要由颗粒执行 但是细胞最近的实验结果表明苔藓细胞（MCS）是第二个主要主要细胞类型 DG的中断也可能参与此过程。因此，我们假设恐惧在压力下的概括 诱发的恐惧学习鼠标模型反映了MC的上下文歧视功能受损。我们将 通过在压力小鼠中记录MC在体内的钙活性在头部固定模式中测试该假设 分离范式。 SSRI治疗，作为诊断患有焦虑症的患者的第一道药物被认为可以恢复 DG中的低羟色胺（5-HT）水平。尽管有这样的概念，但对实际活动的了解很少 在正常或病理条件下的5-HT轴突的模式，并且绝对没有有关该轴突的数据 主要细胞和5-HT轴突的相关活性。 MCS表达兴奋性5-HT2A受体，该受体 表明MC的活性可以通过5-HT控制，实际上已经显示了慢性SSRI治疗 增强MC的活性。因此，我们假设在应力中减少了5-HT轴突的活性 小鼠在DG中导致低水平的5-HT水平，有时会导致MC的活动受到抑制和 破坏模式分离。为了检验这一假设，首先，我们将确认5-HT对MC的兴奋作用 将5-HT轴突的光学遗传操纵与两光子成像结合在一起，然后我们将记录钙 5-HT轴突和MC的活性，仅具有双色两光片成像后压力引起的恐惧 学习。总之，该提案旨在更好地了解MC的作用，MC是一种仍然“神秘的”细胞类型 DG在恐惧概括中，并为5-HT系统在发病机理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 了解微电路水平上神经调节的机制。