The interaction of perinatal organophosphate flame retardant exposure and adult chronic stress on cognitive processing

项目摘要摘要 精神障碍，包括严重的抑郁障碍，精神分裂症和其他，都有一个中心特征- 认知障碍，导致个人面临记忆、注意力和精神障碍。 决策。新出现的证据指出了导致认知能力下降的两个关键因素 基础疾病病理学-暴露在环境化学物质中，如内分泌干扰 发育期间的化合物(EDCs)和2)成年期的慢性应激。化学物质的相互作用 暴露和压力是未知的，但两者一起可能会加剧认知障碍。首先，EDC发挥了他们的 在大脑发育敏感期干扰核受体信号的毒性。众多EDC 研究发现，人类和动物都存在认知障碍。一组未被研究的EDC是 作用于核受体和类固醇受体的有机磷阻燃剂(OPFR)与认知有关。这个 围产期OPFR暴露和认知过程之间的联系尚未被探索。我们之前 确认围产期OPFR暴露对新生儿和青少年下丘脑基因的影响 表情和成人的运动活动和接近/回避行为。第二，精神障碍与 共同特征：暴露在压力下，这会加剧症状，从而导致认知功能障碍。一个 概括啮齿动物慢性应激源的常见范例是施加6周的温和应激，称为 慢性可变轻度应激(CVMS)。使用CVMS，应激适应不良效应背后的神经回路 包括促肾上腺皮质激素释放因子(CRF)神经元。CRF与去甲肾上腺素(NE)、乙酰胆碱共同释放 (ACh)和多巴胺(DA)，它们控制着大脑的关键区域(海马体、前额叶皮质)，所有这些都参与其中 在认知和情绪上。根据我们之前的工作和文献，我假设围产期接触OPFR 可能会单独或与成人慢性应激暴露相结合时扰乱认知。我的中心假设是 像OPFR这样的内分泌细胞潜在地影响认知和应激神经回路的发育 导致认知过程中的长期功能缺陷，并使成年人对暴露于 小鼠的慢性应激。在目标1(K99阶段)中，我将首先确定围产期接触OPFR是否会干扰成人 通过电生理学对ACh突触传递的改变和对行为水平的认知。 在目标2(K99)中，我将研究OPFR暴露对NE、DA和CRF区域浓度的影响 以及相关基因在成人中的表达，以及利用光遗传学研究海马区CRF神经元的作用。最后， 在Aim 3(R00)中，我将结合我之前在脊柱密度分析和免疫组织化学方面的专业知识，以及新的 电生理学、高效液相色谱学和光遗传学方面的培训，以确定 围产期OPFR暴露和成人CVMS的组合改变认知。我研究的最终目标是 项目将确定围产期EDC暴露和成人慢性应激源对认知的交互作用 通过影响CRF和整个大脑的神经递质信号来进行处理。

Project Summary Abstract Mental disorders, including major depressive disorder, schizophrenia, and others, all share a central feature – cognitive impairment which results in individuals confronted with difficulty in memory, concentration, and decision-making. Emerging evidence points to two key factors contributing to cognitive decline beyond the underlying disease pathology - exposure to 1) environmental chemicals such as endocrine disrupting compounds (EDCs) during development and 2) chronic stress in adulthood. The interaction of chemical exposure and stress are unknown; but together may exacerbate cognitive impairment. First, EDCs exert their toxicity by disrupting nuclear receptor signaling during sensitive brain developmental periods. Numerous EDC studies have detected cognitive impairments in humans and animals. One group of understudied EDCs are organophosphate flame retardants (OPFRs) acting on nuclear and steroid receptors linked with cognition. The association between perinatal OPFR exposure and cognitive processing has not been explored. We previously identified an association between perinatal OPFR exposure on neonatal and juvenile hypothalamic gene expression and adult locomotor activity and approach/avoidance behaviors. Second, mental disorders share a common feature: exposure to stress, which contributes to cognitive dysfunction by exacerbating symptoms. A common paradigm to recapitulate chronic stressors in rodents is to apply mild stress for 6 weeks, known as chronic variable mild stress (CVMS). Using CVMS, the neural circuits underlying maladaptive effects of stress include corticotropin releasing factor (CRF) neurons. CRF is co-released with norepinephrine (NE), acetylcholine (ACh), and dopamine (DA), which control key brain regions (hippocampus, prefrontal cortex), and all are involved in cognition and mood. Based on our prior work and the literature, I hypothesize that perinatal OPFR exposure can disrupt cognition, alone or when combined with adult chronic stress exposure. My central hypothesis is that EDCs such as OPFRs influence the developing cognitive and stress neurocircuitry potentially inducing long-lasting functional deficits in cognitive processing and sensitize adults to exposure to chronic stress in mice. In Aim 1 (K99 phase), I will first determine if perinatal OPFR exposure disrupts adult cognition on the behavioral level and through alterations in ACh synaptic transmission using electrophysiology. In Aim 2 (K99), I will examine the effects of OPFR exposure on regional concentrations of NE and DA and CRF and associated gene expression in adults, and the role of hippocampal CRF neurons using optogenetics. Lastly, in Aim 3 (R00), I will combine my prior expertise in spine density analysis and immunohistochemistry, and new training in electrophysiology, high-performance liquid chromatography, and optogenetics to determine if the combination of perinatal OPFR exposure and adult CVMS alters cognition. The ultimate goal of my research program will be to determine the interactions of perinatal EDC exposure and adult chronic stressors on cognitive processing by influencing CRF and neurotransmitter signaling throughout the brain.