Sexually dimorphic development of cognitive inflexibility following early life stress: the role of parvalbumin and the orbitofrontal cortex

项目总结 儿童时期的创伤和忽视会影响情绪发展，增加罹患 情感病理学。女性对早期生活压力(ELS)的影响更容易受到影响，并且 患抑郁症等与压力相关的疾病的可能性是男性的两倍。抑郁的病理是 高度并存的认知障碍和僵硬，主要由额叶引起 功能障碍。然而，ELS如何影响男性与女性的认知功能在很大程度上是未知的，如果 压力导致的认知缺陷在细胞水平上得到了支持。在拟议的研究中，结合了 尖端的行为、分子和光遗传技术将开始测试可能的 女性易患ELS和应激性认知功能障碍的机制。GABA能中间神经元 含有钙结合蛋白的小白蛋白(PV)被认为有助于PFC的认知功能 受压力的影响很大。因此，我提出了一种策略来确定光伏电池在 与压力相关的认知缺陷的性二态发展。我的目标是1)测试ELS的影响 注意定势转移任务中成年雄性和雌性小鼠认知灵活性的研究 ELS对眶前叶皮质PV中间神经元成熟度和密度的影响 确定眶前额叶PV中间神经元对认知的不同方面的功能贡献 灵活性，包括集合移位和反转学习。根据初步数据，我推测 在规则逆转阶段，暴露于ELS的雌性小鼠将比雄性小鼠受到更严重的损害 认知灵活性任务，这些损伤将与PV表达的改变相关。 眶前叶皮质中的中间神经元。评价男性和女性OFC中PV细胞的成熟度和密度 暴露于ELS的小鼠，我将使用免疫组织化学方法检测PV细胞计数，RT qPCR检测PV和GAD67 MRNA分析。此外，我认为OFC内的PV中间神经元特异性地介导了规则逆转学习， 而不是认知灵活性的其他方面，包括集合转移或初始规则学习。在清醒的时候，行为举止 动物I将在规则逆转或规则转变阶段使用光遗传学来抑制OFC中的PV细胞 注意定势转移任务。根据初步数据，我假设这一操纵将 导致规则反转学习中的选择性障碍，但不会导致规则转移、表观复制障碍 在暴露于ELS的雌性中观察到。这项工作将解决存在于 情感病理学的发展，这是一个相关的、在很大程度上被忽视的公共卫生问题。 这将为预测性行为的风险因素和生物标记物奠定基础。 易受压力影响的差异以及与抑郁相关的认知障碍。

PROJECT SUMMARY Childhood trauma and neglect influence emotional development and increase the risk for and severity of affective pathology. Women have a heightened susceptibility to the effects of early life stress (ELS) and are twice as likely than men to develop stress-associated pathology, such as depression. Depressive pathology is highly comorbid with cognitive impairments and inflexibility, resulting predominantly from frontal lobe dysfunction. However, it is largely unknown how ELS affects cognitive function in males versus females, and if stress-induced cognitive deficits are supported at a cellular level. In the proposed study, a combination of cutting-edge behavioral, molecular and optogenetic techniques will be used to begin to test a possible mechanism of female vulnerability to ELS and stress-induced cognitive dysfunction. GABAergic interneurons containing the calcium binding protein parvalbumin (PV) are thought to facilitate cognitive function in the PFC and are significantly affected by stress. Thus, I propose a strategy to determine the role of PV cells in the sexually dimorphic development of stress-associated cognitive deficits. I aim to 1) test the influence of ELS on cognitive flexibility in adult male and female mice in an attentional set-shifting task; 2) test the effects of ELS on PV interneuron maturity and density in the orbitofrontal cortex (OFC); and, 3) determine the functional contribution of orbitofrontal PV interneurons to different facets of cognitive flexibility, including set shifting and reversal learning. Based on preliminary data, I hypothesize that female mice exposed to ELS will be more severely impaired than males in the rule-reversal phase of a cognitive flexibility task, and that these impairments will be correlated with altered expression of PV- interneurons in the orbitofrontal cortex. To assess PV cell maturity and density in the OFC of male and female mice exposed to ELS, I will use immunohistochemistry for PV cell counts and RT qPCR for PV and GAD67 mRNA analysis. Further, I propose that PV-interneurons in the OFC specifically mediate rule-reversal learning, and not other aspects of cognitive flexibility, including set shifting or initial rule learning. In awake, behaving animals I will use optogenetics to inhibit PV cells in the OFC throughout the rule reversal or rule shift phases of the attentional set-shifting task. In accordance with preliminary data, I hypothesize that this manipulation will lead to selective impairments in rule-reversal learning but not rule shifting, phenocopying impairments observed in ELS-exposed females. This work will address sexual dimorphism that exists in the development of affective pathology, which is a relevant and largely overlooked public health concern. It will lay the foundation for predictions regarding risk factors and biomarkers that underlie sex differences in vulnerability to stress and associated cognitive impairments linked with depression.