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

早期生活压力后认知僵化的性别二态性发展：小白蛋白和眶额皮质的作用

• 批准号: 9326485
• 负责人: Haley L. Goodwill
• 金额: $ 4.4万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326485
• 关键词: Address; Adult; Affect; Affective; Animals; Attention; Behavior; Behavioral; Bilateral; Biological Markers; Brain; Brain region; Calcium-Binding Proteins; Caring; Cell Count; Cell Density; Cells; Cellular Morphology; Cognitive; Cognitive deficits; Comorbidity; Data; Depressed mood; Development; Dimensions; Emotional; Engineering; Enzymes; Failure; Female; Fiber Optics; Foundations; Frequencies; Functional disorder; Genetic; Goals; Halorhodopsins; Human; Human body; Immunohistochemistry; Impaired cognition; Impairment; Implant; Interneurons; Investigation; Knock-in Mouse; Laboratory Research; Lead; Learning; Legal patent; Lesion; Life Stress; Light; Link; Mediating; Mental Depression; Mental disorders; Messenger RNA; Metals; Molecular; Motor Cortex; Mus; Neurosciences; Parvalbumins; Pathology; Periodicity; Phase; Phenocopy; Phenotype; Predisposition; Primates; Public Health; Rattus; Reversal Learning; Risk; Risk Factors; Role; Severities; Sex Characteristics; Slice; Stress; Stress Tests; System; Techniques; Testing; Training; Woman; Work; awake; base; brain tissue; cognitive capacity; cognitive control; cognitive development; cognitive function; density; depression model; depressive symptoms; early experience; flexibility; frontal lobe; gamma-Aminobutyric Acid; interdisciplinary approach; mRNA Expression; male; men; mouse model; neglect; network models; optogenetics; pediatric trauma; relating to nervous system; sex; sexual dimorphism; stress reactivity

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.

项目摘要 童年创伤和忽视影响情感发展，增加了儿童精神分裂症的风险和严重性。 情感病理学女性对早期生活压力（ELS）的影响更敏感， 患上与压力有关的疾病（如抑郁症）的可能性是男性的两倍。抑郁症的病理是 与认知障碍和易失性高度共病，主要由额叶引起 功能障碍然而，在很大程度上还不清楚ELS如何影响男性与女性的认知功能， 压力引起的认知缺陷在细胞水平得到支持。在拟议的研究中， 尖端的行为、分子和光遗传学技术将用于开始测试一种可能的 女性易受ELS和应激诱导的认知功能障碍的机制。gaba能中间神经元 含有钙结合蛋白小清蛋白（PV）的药物被认为有助于PFC的认知功能 并且受到压力的显著影响。因此，我提出了一个战略，以确定光伏电池的作用， 压力相关认知缺陷的性二态发展。我的目标是1）测试ELS的影响力 对成年雄性和雌性小鼠在注意力转移任务中的认知灵活性的影响; 2）测试 ELS对眶额皮质（OFC）中PV中间神经元成熟度和密度的影响;以及3） 确定眶额PV中间神经元对认知功能的不同方面的功能贡献。 灵活性，包括设置转换和反转学习。根据初步数据，我假设 暴露于ELS的雌性小鼠在规则逆转阶段比雄性小鼠受到更严重的损害， 认知灵活性任务，这些障碍将与PV- 眶额皮质的中间神经元评估雄性和雌性眶额皮层PV细胞成熟度和密度 对于暴露于ELS的小鼠，我将使用免疫组织化学进行PV细胞计数，并使用RT qPCR进行PV和GAD 67 mRNA分析。此外，我认为，PV-中间神经元在眶额皮层专门介导规则逆转学习， 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，行为 动物，我将使用光遗传学在整个规则逆转或规则转换阶段抑制OFC中的PV细胞。 注意定势转移任务根据初步数据，我假设这种操纵将 导致规则颠倒学习中的选择性损伤，但不导致规则转换、表型复制损伤 在暴露于ELS的雌性中观察到。这项工作将解决性别二态性，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。 它将为预测性行为的风险因素和生物标志物奠定基础 对压力的脆弱性和与抑郁症相关的认知障碍的差异。