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

围产期有机磷阻燃剂暴露与成人慢性应激对认知加工的相互作用

• 批准号: 10449738
• 负责人: Kimberly Robyn Wiersielis
• 金额: $ 12.08万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-02 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449738
• 关键词: Acetylcholine; Adolescent; Adult; Adult Children; Animal Model; Animals; Award; Beds; Behavioral; Brain; Brain Diseases; Brain region; CRH gene; Chemical Exposure; Chronic; Chronic stress; Cognition; Cognitive; Corticotropin-Releasing Hormone; Decision Making; Dendritic Spines; Development; Disease; Dopamine; Electrophysiology (science); Endocrine Disruptors; Estrogen Receptors; Exposure to; Faculty; Female; Flame Retardants; Gene Expression; Genes; Goals; Golgi Apparatus; High Pressure Liquid Chromatography; Hippocampus; Human; Hypothalamic structure; Immunohistochemistry; Impaired cognition; Impairment; Individual; Institution; Interneurons; Knowledge; Learning; Life; Link; Literature; Long-Term Potentiation; Major Depressive Disorder; Maternal Exposure; Measurement; Measures; Memory; Mental Depression; Mental disorders; Modeling; Moods; Morphology; Motor Activity; Mus; Muscarinics; Neonatal; Neurologic; Neurons; Neurotransmitters; Norepinephrine; Nuclear; Nuclear Receptors; Organophosphates; Pathology; Perinatal; Perinatal Exposure; Phase; Positioning Attribute; Prefrontal Cortex; Pregnancy; Receptor Signaling; Research; Rodent; Role; Schizophrenia; Secure; Signal Transduction; Steroid Receptors; Stress; Stressful Event; Symptoms; Synaptic Transmission; Testing; Toxic effect; Training; Training Programs; Vertebral column; Work; avoidance behavior; behavior measurement; behavior test; behavioral response; cognitive testing; density; environmental chemical; hormonal signals; human model; male; memory process; mouse development; neural circuit; novel; object recognition; offspring; optogenetics; postnatal; programs; sound; stressor; toxicant

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.

项目摘要 精神障碍，包括重度抑郁症、精神分裂症和其他精神障碍，都有一个共同的中心特征- 认知障碍，导致个体在记忆、注意力集中和 决策的新出现的证据指出了两个导致认知能力下降的关键因素， 潜在疾病病理学-接触1）环境化学品，如内分泌干扰物 2）发育过程中的内分泌干扰物（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;但一起可能会加剧认知障碍。首先，EDCs发挥其 在敏感的大脑发育时期破坏核受体信号传导而产生毒性。许多EDC 研究已经发现人类和动物的认知障碍。一组研究不足的内分泌干扰物是 有机磷阻燃剂（OPFR）作用于与认知相关的核和类固醇受体。的 围产期OPFR暴露和认知加工之间的关联尚未被探索。我们之前 发现围产期OPFR暴露与新生儿和青少年下丘脑基因相关 表达和成年运动活动和接近/回避行为。第二，精神障碍患者 共同功能：暴露于压力下，通过加重症状而导致认知功能障碍。一 概括啮齿动物慢性应激源的常见范例是施加轻度应激6周，称为 慢性可变轻度应激（CVMS）。使用CVMS，神经回路潜在的适应不良的影响， 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 (ACh)和多巴胺（DA），它们控制着大脑的关键区域（海马体，前额叶皮层）， 在认知和情绪上。基于我们以前的工作和文献，我假设围产期OPFR暴露 单独或与成人慢性压力暴露相结合时，会破坏认知。我的核心假设是 内分泌干扰物，如OPFRs，可能会影响发育中的认知和应激神经回路， 在认知过程中引起长期的功能缺陷，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OPFR暴露是否会破坏成人 认知的行为水平上，并通过改变乙酰胆碱突触传递使用电生理学。 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 和相关基因在成人中的表达，以及海马CRF神经元使用光遗传学的作用。最后， 在目标3（R 00）中，我将联合收割机结合我先前在脊柱密度分析和免疫组织化学方面专长， 电生理学、高效液相色谱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 计划将确定围产期EDC暴露和成人慢性应激源对认知功能的相互作用。 通过影响CRF和整个大脑的神经递质信号来处理。