Impact of ambient PM2.5 concentrations on fear extinction recall, frontolimbic circuitry, and anxiety in adolescents

项目摘要/摘要 空气污染是一个主要的环境健康威胁，并与以下几个不利的健康后果有关 儿童和青少年包括哮喘、肥胖症和儿童期癌症。越来越多的证据表明，空气 污染物，包括颗粒物(PM)，也会对大脑发育产生负面影响，并增加患心脏病的风险 心理健康状况不佳。事实上，最近的研究表明，暴露在空气污染中，特别是PM2.5 (空气动力学直径&lt；2.5μm的PM)与焦虑的患病率和严重程度都有关 青年时期的精神障碍。此外，焦虑症通常始于青春期和早发性(与成人相比-- 发病)与较差的长期结果有关，包括更多的慢性病和较差的治疗 回应。然而，环境焦虑风险背后的神经发育机制是 未知。提议的F32将是第一个测试这一新假设的人，即青少年接触更高的 最近的PM2.5浓度将表现出较差的恐惧消退回忆，较低的额叶边缘激活，和较高的焦虑 症状。这个项目建立在先前研究的基础上，该研究表明，受损的恐惧消退和额叶边缘 功能障碍是焦虑症的神经发育标志，我们的最新和初步数据显示 恐惧调节和额叶边缘回路(即海马体、前额叶皮质)在 青春期早期，对环境侮辱(如创伤应激)敏感。此外，新兴市场 临床前和人类神经成像研究表明，与恐惧相关的学习和额叶边缘脑区 容易接触PM2.5，特别是在青春期，这是一个精神脆弱的时期。这个 拟议的研究将招募暴露在最近PM2.5浓度下的青少年，使用最先进的估计 由共同赞助商Brokamp开发的高分辨率(0.74平方公里)时空模型。参赛者将完成 一项为期两天的恐惧消退功能磁共振成像(FMRI)实验，由 赞助Marusak探索恐惧调节和前缘回路。该范例使用虚拟现实耦合 有心理生理记录和神经成像。这项团契研究提供了重要的第一步 确定精神病理学环境风险的潜在神经发育机制，并将 告知有针对性的早期干预措施，以遏制高危污染暴露青年焦虑的病因。带钥匙 关于环境对大脑发育的影响、心理生理学和功能磁共振成像的培训，以及 对于儿科焦虑症，这个项目非常适合F32机制。这个项目得到了一支 具有互补专业知识的导师，包括赞助商Marusak和共同赞助商Jovanovic，Ryan，Strawn， 还有布罗坎普。该培训项目将为Pi Zundel提供必要的关键数据和培训，以扩大 这项工作是纵向的，评估了暴露在污染中的年轻人的发展轨迹。它还将准备PI Zundel致力于揭示神经发育机制对环境的贡献 有患神经精神疾病的风险。

PROJECT SUMMARY/ABSTRACT Air pollution is a major environmental health threat and is associated with several adverse health outcomes in children and adolescents including asthma, obesity, and childhood cancer. Growing evidence indicates that air pollutants, including particulate matter (PM), can also negatively affect brain development and increase risk of poor mental health outcomes. Indeed, recent work has shown that exposure to air pollution, specifically PM2.5 (PM with an aerodynamic diameter < 2.5 μm) is associated with both the prevalence and severity of anxiety disorders in youth. Further, anxiety disorders commonly begin during adolescence and early-onset (vs. adult- onset) is associated with poor long-term outcomes, including more chronic disease and poorer treatment response. However, the neurodevelopmental mechanisms underlying environmental risk of anxiety are unknown. The proposed F32 will be the first to test the novel hypothesis that adolescents exposed to higher recent PM2.5 concentrations will exhibit poor fear extinction recall, lower frontolimbic activation, and higher anxiety symptoms. This project builds on prior research demonstrating that impaired fear extinction and frontolimbic dysfunction are neurodevelopmental markers of anxiety disorders, and our recent and preliminary data show that fear regulation and frontolimbic circuitry (i.e., hippocampus, ventromedial prefrontal cortex) develop during early adolescence and are sensitive to environmental insults (e.g., traumatic stress). Further, emerging preclinical and human neuroimaging studies suggest that fear-related learning and frontolimbic brain regions are susceptible to PM2.5 exposure, particularly during adolescence, a period of psychiatric vulnerability. The proposed study will recruit adolescents exposed to recent PM2.5 concentrations, estimated using state-of-the-art high resolution (0.74 km2) spatiotemporal models developed by Co-Sponsor Brokamp. Participants will complete a two-day fear extinction functional magnetic resonance imaging (fMRI) experiment developed and validated by Sponsor Marusak to probe fear regulation and frontolimbic circuitry. This paradigm uses virtual reality coupled with psychophysiological recordings and neuroimaging. This fellowship study provides an important first step towards identifying neurodevelopmental mechanisms underlying environmental risk of psychopathology, and will inform targeted early interventions to stem the etiology of anxiety in at-risk pollution-exposed youth. With key training in environmental impacts on brain development, psychophysiology and fMRI, and the neurobiology of pediatric anxiety, this project is ideally suited for the F32 mechanism. This project is supported by a team of mentors with complementary expertise, including Sponsor Marusak and Co-Sponsors Jovanovic, Ryan, Strawn, and Brokamp. This training project will provide PI Zundel with the critical data and training needed to expand on this work longitudinally, evaluating developmental trajectories in pollution-exposed youth. It will also prepare PI Zundel for a career committed to uncovering neurodevelopmental mechanisms contributing to environmental risk of neuropsychiatric disease.