Identifying the neural ensembles mediating fear generalization during adolescence

识别青春期介导恐惧泛化的神经系统

• 批准号: 10648352
• 负责人: Christine Ann Denny
• 金额: $ 19.28万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648352
• 关键词: 4-Hydroxy-Tamoxifen; Adolescence; Adolescent; Adult; Age; Anatomy; Anesthetics; Antidepressive Agents; Anxiety Disorders; Applications Grants; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain imaging; Brain region; Cells; Childhood; Cytoskeletal Proteins; Data; Discrimination; Discrimination Learning; Dose; Environment; Euthanasia; Exposure to; Female; Female Adolescents; Freezing; Fright; Genetic; Goals; Hippocampus; Hour; Image; Immediate-Early Genes; Impairment; Individual; Ketamine; Label; Laboratories; Location; Longevity; Male Adolescents; Measures; Mediating; Memory; Mental disorders; Mouse Protein; Mus; NMDA receptor antagonist; National Institute of Mental Health; Neurons; Outcome Study; Pattern; Phenotype; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Proteins; Protocols documentation; Publications; Publishing; Reporting; Research Domain Criteria; Rest; Retrieval; Saline; Shock; Stimulus; Strategic Planning; Symptoms; System; Testing; Therapeutic; Time; Transgenic Mice; aged; brain tissue; conditioned fear; dentate gyrus; design; experimental study; improved; male; memory encoding; neural; neural circuit; neural correlate; neural network; novel; pharmacologic; response; sex

PROJECT SUMMARY / ABSTRACT A core symptom observed in anxiety disorders and post-traumatic stress disorder (PTSD) is increased fear generalization, as defined by the overgeneralization of fear from a conditioned, fear-inducing stimulus to neutral stimuli. Fear generalization can lead to maladaptive responses in a safe environment. Our laboratory uses a behavioral assay called contextual fear discrimination (CFD) to assess fear generalization in mice. We shock a mouse in one context (context A), and then we can measure whether they can discriminate between this aversive, shock-paired context and a similar, but safe context (context B) over approximately 10 days of discrimination learning. In our recent publications, we show that 1) adolescent male, but not adolescent female mice overgeneralize fear; 2) adult female, but not adult male mice overgeneralize fear; and 3) aged mice of both sexes overgeneralize fear and cannot discriminate between two contexts. Therefore, there is clearly an age- and sex-dependent influence on fear overgeneralization. However, the neural ensembles mediating fear generalization across the lifespan have yet to be identified. In this grant proposal, we will use this CFD paradigm, in combination with an activity-dependent tagging genetic mouse line to identify and pharmacologically manipulate the neural ensembles mediating fear generalization. In Aim 1, we will identify and quantify the neural ensembles mediating fear generalization in adolescent and adult mice by utilizing the ArcCreERT2 x EYFP mice. This mouse line allows for the indelible labeling of cells expressing the immediate early gene (IEG) Arc/Arg3.1 and allows for a comparison between the cells that are activated during the encoding of a memory and those that are activated during the retrieval of the corresponding memory, with the overlap between the two populations being defined as an engram or memory trace. Therefore, using our activity-dependent tagging mouse line, we can determine where and how sex and age impact fear generalization neural ensembles throughout the brain. In Aim 2, we will pharmacologically manipulate adolescent and adult mice with the goal of improving behavioral fear overgeneralization and the corresponding neural circuits. In the last two decades, (R,S)- ketamine has emerged as a rapid-acting antidepressant. Interestingly, we have reported that (R,S)-ketamine decreases fear generalization. Here, male and female adolescent and adult mice will be administered a single dose of saline or (R,S)-ketamine. CFD and ex vivo whole-brain imaging will be used in order to identify the underlying neural ensembles. The outcome of this study will provide direct evidence that altered neural ensembles result in fear overgeneralization, and that (R,S)-ketamine has the potential to decrease fear overgeneralization, a core system of anxiety disorders and PTSD.

项目摘要 /摘要 在焦虑症和创伤后应激障碍（PTSD）中观察到的核心症状是增加的恐惧 概括是由从条件的，恐惧刺激到恐惧过度笼统的定义 中性刺激。担心概括会导致在安全环境中导致不良适应的反应。我们的实验室 使用称为上下文恐惧歧视（CFD）的行为测定法来评估小鼠的恐惧概括。我们 在一个上下文（上下文a）中震惊鼠标，然后我们可以衡量它们是否可以区分 这种厌恶，震惊的配对背景以及大约10天的相似但安全的环境（上下文B） 歧视学习。在我们最近的出版物中，我们表明1）青春期男性但不是青春期的女性 小鼠过度笼罩恐惧； 2）成年女性，但不是成年男性小鼠过度笼罩恐惧； 3）老鼠的老鼠 两性性别都过分笼统，无法区分两种情况。因此，显然有一个 年龄和性别依赖性对恐惧过度笼统的影响。但是，神经合奏导致恐惧 整个生命周期的概括尚未确定。在此赠款建议中，我们将使用此CFD 范式，与活动依赖性的标记遗传小鼠线结合使用，以识别和 药理操纵神经合奏，介导恐惧概括。 在AIM 1中，我们将识别和量化介导青少年恐惧概括的神经集合 和成年小鼠，利用Arccreert2 X EYFP小鼠。该鼠标线允许不可磨灭的标签 表达直接早期基因（IEG）ARC/arg3.1的细胞，并可以在细胞之间进行比较 在记忆的编码过程中被激活，以及在检索期间被激活的 相应的内存，两个人群之间的重叠被定义为eNgram或内存 痕迹。因此，使用我们的活动依赖性标记鼠标线，我们可以确定性别和方式 年龄影响恐惧概括整个大脑的神经合奏。 在AIM 2中，我们将在药理学上操纵青少年和成年小鼠，以改善 行为恐惧过度笼统和相应的神经回路。在过去的二十年中，（R，S） - 氯胺酮已成为快速作用抗抑郁药。有趣的是，我们报告说（R，S） - 酮胺 减少恐惧的概括。在这里，将对男性和雌性青少年和成年小鼠进行一次管理 盐水或（R，S）酮胺的剂量。 CFD和EX VIVO全脑成像将用于确定 基础神经合奏。这项研究的结果将为改变神经的直接证据提供 合奏会导致恐惧过度笼过，（R，S） - 酮胺有可能减少恐惧 过度笼统，焦虑症和PTSD的核心系统。