Psychological stress susceptibility in juvenile female and male mice

幼年雌性和雄性小鼠的心理应激易感性

基本信息

批准号：
10412410
负责人：
Sergio Diaz Iniguez
金额：
$ 15.34万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412410
关键词：
Acute Address Adolescence Adolescent Adopted Adult Affect Affective Age Anhedonia Animal Model Animals Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavioral Biological Markers Biological Models Body Weight Brain Brain region C57BL/6 Mouse CREB1 gene Childhood Chronic Chronic stress Clinic Clinical Clinical Research Cocaine Corticosterone Data Depressive disorder Development Diagnosis Disease Drug abuse Epidemiology Evaluation Exhibits Exposure to FDA approved Female Female Adolescents Fluoxetine Functional disorder Goals Hippocampus (Brain)Impairment Incidence Ketamine Learned Helplessness Lifestyle-related condition Major Depressive Disorder Male Adolescents Mediating Memory Memory impairment Mental Depression Modeling Molecular Molecular Target Mood Disorders Moods Morbidity - disease rate Mus Neurobiology Outcome Study Performance Pharmaceutical Preparations Pharmacology Phenotype Phosphorylation Physiological Population Pre-Clinical Model Predisposition Principal Investigator Proteins Proto-Oncogene Proteins c-akt Psychological Stress Regulation Reporting Rewards Risk Factors Rodent Rodent Model Safety Sex Differences Shapes Signal Transduction Signaling Molecule Site Social Interaction Stimulus Stress Substance abuse problem Sucrose Symptoms Tail Suspension Validation Vulnerable Populations Woman abuse liability behavioral outcome behavioral pharmacology behavioral phenotyping bullying clinically relevant comorbidity depressive symptoms drug seeking behavior experience experimental study innovation insight male model design morris water maze mortality neurobiological mechanism neurochemistry neurotropic novel postnatal pre-clinical preference programs psychologic response sex social defeat social deficits spatial memory symptomatology

项目摘要

Program Director/Principal Investigator (Iñiguez, Sergio, Diaz): ABSTRACT Epidemiologic reports indicate that mood-related illnesses, like major depressive disorder (MDD), are among the leading cause of morbidity and mortality in the juvenile population. To make matters worse, women are twice as likely to be diagnosed with MDD, a sex difference that becomes apparent during the adolescent stage of development. These disparities highlight the critical need for the development of novel preclinical models to uncover the neurobiological factors that underlie MDD as a function of age and sex – particularly, because most animal models mainly incorporate adult male rodents. To address this issue, our group developed the vicarious defeat stress (VDS) paradigm wherein a mouse witnesses the defeat bout of a male conspecific from the safety of an adjacent compartment, leading to a behavioral outcome that resembles some of the core symptoms of MDD (deficits in sociability, decreased preference for reward-related stimuli and body weight, along with increased helplessness behavior and corticosterone). A major strength of this innovative approach is that it allows for the experimental inclusion of females and juveniles – vulnerable populations that are commonly excluded in preclinical/clinical studies. As such, the experiments described in this proposal will evaluate whether exposing juvenile female and male mice to VDS results in behavioral outcomes that recapitulate a depression-related phenotype. This will be accomplished within the framework of the following specific aims: [1] assess the behavioral consequences of VDS on sensitivity to reward (cocaine, sucrose), affect, and memory-performance in adolescent female and male mice (postnatal day 35). Also, [2] to evaluate if traditional (fluoxetine) and novel (ketamine) antidepressant medications can reverse the VDS-induced behavioral deficits observed. Lastly, [3] to evaluate the integrity of mood-related biological markers [brain derived neurotropic factor (BDNF)-related signaling] within the hippocampus. It is expected that juvenile VDS will mediate behavioral alterations associated with enhanced drug abuse potential (i.e., cocaine), anhedonia (decreased sucrose preference), maladaptive responses to subsequent inescapable stress (despair), and memory-related impairment. Furthermore, that clinically relevant medications (fluoxetine and ketamine) will reverse the VDS-induced social dysfunction, mimicking what is observed at the clinic in juvenile populations. Additionally, it is expected that site-specific neurochemical adaptations (BDNF fluctuations within the hippocampus) will be observed after VDS exposure in an age and sex specific manner. Collectively, the outcome of these studies will provide behavioral, pharmacological, and molecular evidence of VDS-induced dysfunction that may underlie the convergent (both sexes experiencing MDD) and divergent (age- and sex- specific) neurobiological underpinnings of MDD. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

计划总监/首席研究员（Iñiguez，塞尔吉奥，迪亚兹）：抽象的流行病学报告表明，与情绪相关的疾病（如主要抑郁症（MDD））是在少年人口中发病和死亡率的主要原因之一。更糟的是，女性被诊断为MDD的可能性是两倍，这种性别差异在青少年期间变得显而易见发展阶段。这些分布强调了开发新型临床前的关键需求发现MDD是年龄和性别的函数的神经生物学因素的模型，特别是因为大多数动物模型主要结合成年雄性啮齿动物。为了解决这个问题，我们的小组发展了替代的失败压力（VDS）范式，其中一只老鼠见证了一个男性的失败来自相邻隔间的安全性的同种，导致行为结果类似于某些 MDD的核心症状（社交能力缺陷，偏爱与奖励相关的刺激和身体的偏爱降低体重，无助行为和皮质酮增加）。这项创新的主要优势方法是，它允许实验女性和少年的实验 - 脆弱的人群通常在临床前/临床研究中排除。因此，本提案中描述的实验将评估将少年和雄性小鼠暴露于VDS是否会导致行为结果概括与抑郁症相关的表型。这将在以下框架内完成具体目的：[1]评估VD对奖励敏感性的行为后果（可卡因，蔗糖），青春期和雄性小鼠的影响和记忆绩效（产后第35天）。另外，[2]评估如果传统（氟西汀）和新颖（氯胺酮）抗抑郁药可以逆转VDS诱导的行为定义了观察到的。最后，[3]评估与情绪相关的生物标记的完整性[大脑海马内的衍生神经性因子（BDNF）相关信号传导。预计少年VD 将介导与增强药物滥用潜力相关的行为改变（即可卡因），Anhedonia （蔗糖偏爱减少），对随后不可避免的压力（绝望）的适应不良反应，以及与内存有关的障碍。此外，临床相关的药物（氟西汀和氯胺酮）将逆转VDS引起的社会功能障碍，模仿少年人群中诊所观察到的内容。此外，预计位点特异性的神经化学适应（BDNF的波动在VDS暴露后以年龄和性别方式暴露后，将观察到海马。集体，这些研究的结果将为VDS诱导的行为，药物和分子证据提供可能是融合（男女都会经历MDD）和分歧（年龄和性别）的功能障碍特定于MDD的神经生物学基础。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面