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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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恐惧增加泛化，定义为由于条件性的、引起恐惧的刺激而过度概括恐惧中性刺激。恐惧泛化可能会导致安全环境中的适应不良反应。我们的实验室使用一种称为情境恐惧歧视（CFD）的行为分析来评估小鼠的恐惧泛化。我们在一个上下文（上下文 A）中电击一只老鼠，然后我们可以测量它们是否能够区分在大约 10 天的时间里，这种令人厌恶的、震惊的情境和类似但安全的情境（情境 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，但不是青春期女性老鼠过度概括了恐惧； 2）成年雌性小鼠而非成年雄性小鼠会过度概括恐惧； 3）老年小鼠男女都会过度概括恐惧，并且无法区分两种情况。因此，显然有一个年龄和性别对恐惧过度概括的影响。然而，调节恐惧的神经系统整个生命周期的普遍性尚未确定。在此拨款提案中，我们将使用此 CFD 范例，结合活动依赖性标记遗传小鼠系来识别和从药理学上操纵介导恐惧泛化的神经系统。在目标 1 中，我们将识别并量化调节青少年恐惧泛化的神经群和使用 ArcCreERT2 x EYFP 小鼠的成年小鼠。该小鼠系可以对以下物质进行不可磨灭的标记表达立即早期基因 (IEG) Arc/Arg3.1 的细胞，并允许对表达立即早期基因 (IEG) Arc/Arg3.1 的细胞进行比较在记忆编码过程中被激活，在记忆检索过程中被激活相应的记忆，两个群体之间的重叠被定义为印迹或记忆痕迹。因此，使用我们的活动依赖性标记小鼠系，我们可以确定性别和性行为的地点和方式。年龄影响整个大脑的恐惧泛化神经元。在目标 2 中，我们将对青少年和成年小鼠进行药理学操作，目的是改善行为恐惧过度概括和相应的神经回路。在过去的二十年里，(R,S)- 氯胺酮已成为一种速效抗抑郁药。有趣的是，我们报道了 (R,S)-氯胺酮减少恐惧泛化。在这里，雄性和雌性青少年和成年小鼠将被施用单次剂量的盐水或(R,S)-氯胺酮。将使用 CFD 和离体全脑成像来识别底层神经元集合。这项研究的结果将提供改变神经元的直接证据整体会导致恐惧过度概括，而（R，S）-氯胺酮有可能减少恐惧过度概括，焦虑症和创伤后应激障碍的核心系统。