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

项目总监/首席研究员（Iñiguez、Sergio、Diaz）：抽象的流行病学报告表明，与情绪相关的疾病，如重度抑郁症 (MDD)，更糟糕的是，女性是青少年发病和死亡的主要原因之一。被诊断患有 MDD 的可能性是其两倍，这种性别差异在青少年时期变得明显这些差异凸显了开发新型临床前药物的迫切需要。模型揭示 MDD 背后的神经生物学因素作为年龄和性别的函数 - 特别是，因为大多数动物模型主要包含成年雄性啮齿动物，为了解决这个问题，我们的小组。开发了替代失败压力（VDS）范式，即小鼠目睹雄性的失败回合与相邻隔间的安全性相同，导致类似于某些行为的结果 MDD 的核心症状（社交能力缺陷、对奖励相关刺激的偏好降低以及身体体重，以及增加的无助行为和皮质酮）是这一创新的主要优势。方法是允许试验性地将女性和青少年纳入其中——这些弱势群体通常被排除在临床前/临床研究中，因此，本提案中描述的实验将被排除。评估将幼年雌性和雄性小鼠暴露于 VDS 是否会导致以下行为结果：概括一下与抑郁症相关的表型。这将在以下框架内完成。具体目标：[1] 评估 VDS 对奖励（可卡因、蔗糖）敏感性的行为后果，青春期雌性和雄性小鼠（出生后第 35 天）的影响和记忆表现此外，[2] 进行评估。传统（氟西汀）和新型（氯胺酮）抗抑郁药物是否可以逆转 VDS 引起的抑郁症最后，[3]评估情绪相关生物标记物[大脑]的完整性。海马内的衍生神经营养因子（BDNF）相关信号传导]预计幼年VDS。将介导与药物滥用潜力（即可卡因）、快感缺失增强相关的行为改变（蔗糖偏好降低），对随后不可避免的压力（绝望）的适应不良反应，以及此外，临床相关药物（氟西汀和氯胺酮）会导致记忆相关障碍。逆转 VDS 引起的社会功能障碍，模仿在青少年人群中观察到的情况。此外，预计位点特异性神经化学适应（BDNF 内的波动）海马体）将在 VDS 暴露后以年龄和性别特定的方式进行观察。这些研究的结果将提供 VDS 诱导的行为、药理学和分子证据可能是趋同性（男女都经历 MDD）和趋异性（年龄和性别）的功能障碍 MDD 的具体）神经生物学基础。 OMB 编号 0925-0001/0002（修订版 03/2020 已批准至 02/28/2023）页面延续格式页面