Psychological stress susceptibility in juvenile female and male mice

项目负责人/主要研究者（Iñiguez、Sergio、迪亚兹）： 摘要 流行病学报告表明，情绪相关疾病，如重度抑郁症（MDD）， 这是青少年发病和死亡的主要原因之一。更糟糕的是，女性 被诊断为MDD的可能性是男性的两倍，这种性别差异在青少年时期变得明显。 发展阶段。这些差异突出了开发新的临床前药物的迫切需要。 模型揭示了作为年龄和性别函数的MDD基础的神经生物学因素-特别是， 因为大多数动物模型主要包括成年雄性啮齿动物。为了解决这个问题，我们的团队 开发了替代性失败压力（VDS）范例，其中小鼠目睹了雄性的失败回合 与相邻隔间的安全性同种，导致类似于一些 MDD的核心症状（社交能力不足，对奖励相关刺激和身体的偏好降低） 体重，沿着无助行为和皮质酮的增加）。这一创新的主要优势 这种方法的一个重要特点是，它允许实验性地将女性和青少年-弱势群体-包括在内， 通常被排除在临床前/临床研究之外。因此，本提案中描述的实验将 评估将幼年雌性和雄性小鼠暴露于VDS是否会导致行为结果， 重现了抑郁症相关的表型。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， 情感和记忆表现（出生后第35天）。[2]评价 如果传统（氟西汀）和新型（氯胺酮）抗抑郁药物可以逆转VDS诱导的 观察到行为缺陷。最后，[3]评估与情绪相关的生物标志物[大脑]的完整性 衍生的神经营养因子（BDNF）相关的信号传导]。预计青少年VDS 将介导与增强的药物滥用潜力相关的行为改变（即，可卡因）、快感缺乏 （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 记忆力受损此外，临床相关药物（氟西汀和氯胺酮）将 逆转VDS诱导的社会功能障碍，模仿在青少年人群中的临床观察。 此外，预计位点特异性神经化学适应（脑源性神经营养因子在脑内的波动）， 海马）的变化。统称 这些研究的结果将提供行为，药理学和分子证据的VDS诱导 功能障碍可能是聚合（男女都经历MDD）和发散（年龄和性别）的基础， MDD的神经生物学基础。 OMB编号0925-0001/0002（修订版03/2020批准至02/28/2023）页码继续格式页码

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