Neurodevelopment of Mesolimbic Afferents in Healthy Adolescents and First-Episode Psychosis

健康青少年和首发精神病中脑边缘传入神经发育

• 批准号: 10002289
• 负责人: Vishnu Pradeep Murty
• 金额: $ 16.57万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002289
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Age; Age-Years; Animal Model; Antipsychotic Agents; Award; Behavior; Biological Assay; Caregivers; Chronic; Clinical; Communities; Data Analyses; Deterioration; Development; Diffusion; Disease; Dopamine; Economics; Emotional; Etiology; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Grant; Hippocampus (Brain); Human; Individual; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Learning; Measures; Medial; Mediating; Mentors; Modeling; Nature; Participant; Pathology; Pathway Analysis; Patients; Pharmaceutical Preparations; Phase; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Psychopathology; Psychotic Disorders; Regulation; Research; Research Domain Criteria; Research Training; Rest; Rewards; Risk; Role; Sampling; Schizophrenia; Signal Transduction; Structure; Substantia nigra structure; System; Systems Development; Techniques; Testing; Time; Training; Translating; Translations; Universities; Ventral Tegmental Area; Visit; Work; base; clinical predictors; cognitive neuroscience; data archive; dopamine system; dopaminergic neuron; emerging adult; first episode psychosis; follow-up; insight; lens; mesolimbic system; multimodality; neurodevelopment; neuroimaging; neuroimaging marker; neuroregulation; novel; phenomenological models; programs; recruit; relating to nervous system; remediation; social; spectrograph; translational neuroscience; white matter; young adult

Project Summary/Abstract The objective of this Career Development Award is to support new mentored training in cognitive neuroscience studies of dopamine-related function in healthy adolescents and first-episode psychosis, as the candidate begins an independent research program. Psychosis is a devastating illness that afflicts ~3% of the world’s population, and has sever economic and social/emotional consequences for both patients and their caregivers. Prior research has implicated deficits in dopamine systems in both the etiology and pathology of the disorder, and thus remediation of this system has been a prominent target for intervention. Although these deficits have been well documented, open questions remains as to how and why these deficits emerge. Prominent models of psychosis have implicated aberrant development of neural systems regulating the activation of dopamine systems. However, very little research has investigated how these regulatory systems develop in normative populations; let alone how deviations from normative development may be implicated in psychosis. Thus, a full understanding of psychosis necessitates a characterization of dopamine-related networks in healthy adolescence and deviations from these trajectories in psychosis. These findings will provide insight into determinants of risk for conversion from a developmental perspective and in turn the timing of interventions. The proposed award will build upon the candidate’s prior training in cognitive neuroscience, to extend this knowledge into the domain of normative development in adolescents and aberrant development in psychosis within dopamine-related networks. Aim 1 will investigate the normative development of neural systems regulating engagement of the ventral tegmental area and substantia nigra, the core of the mesolimbic dopamine system, using multimodal neuroimaging. These developmental neuroimaging markers will then be associated with direct and indirect measures of dopamine to assess how they relate to dopaminergic function. Aim 2 will evaluate how individuals with first-episode psychosis deviate from the normative trajectories characterized in Aim 1, and further probe how these deviations relate to anti-psychotic medication status. Finally, Aim 3 will have first-episode patients return for a 2-year follow-up to characterize how the clinical course of psychosis relates to early markers of dopamine-related dysfunction. Mentored training will compliment the candidate’s expertise in neuroimaging of dopamine-related circuits in healthy adults. Paralleling the proposed research, training will focus on the candidate gaining expertise in conducting neuroimaging studies in adolescent (Aim 1) and psychosis populations (Aim 2,3). Further, the candidate will gain expertise in the translation of animal models of behavior in adolescent and psychosis population, with a focus on understanding the nature of homology across multiple species (Aims 1-3). Finally, the candidate will gain expertise in experimental techniques associated with studying neurodevelopment (e.g., longitudinal data analysis; Aims 1-3), psychosis (e.g., adjustment for antipsychotic medication, characterizing clinical phenomenology; Aims 2-3), and translational neuroscience (e.g., integration of direct/indirect measures of dopamine; Aim 3). The candidate has recruited a mentoring team with expertise in all of the above domains led by mentor Dr. Bea Luna, an expert in adolescent development, and co-mentor Deanna Barch, an expert in neuroimaging in psychosis populations. Further, the candidate will take advantage of the known strengths of the schizophrenia and adolescent research communities, as well as the emphasis on cross-species translation at the University of Pittsburgh. The proposed research will offer novel insight into dopamine dysfunction in psychosis through the lens of adolescent neurodevelopment. Further, the training will lay the foundation for an independent research program assaying the neurodevelopmental of neuromodulatory systems in psychosis. !

项目概要/摘要 该职业发展奖的目的是支持认知神经科学领域新的指导培训 健康青少年和首发精神病中多巴胺相关功能的研究，作为候选者 开始一项独立的研究计划。精神病是一种毁灭性的疾病，困扰着世界上约 3% 的人 人口，并对患者及其护理人员产生严重的经济和社会/情感后果。 先前的研究表明，该疾病的病因学和病理学均存在多巴胺系统缺陷， 因此，对该系统的修复一直是干预的一个突出目标。尽管这些赤字 尽管这些赤字是如何以及为何出现的，但仍有待解决的问题。杰出模特 精神病的发生与调节多巴胺激活的神经系统的异常发育有关 系统。然而，很少有研究调查这些监管体系如何在规范中发展。 人口；更不用说偏离规范发展如何可能与精神病有关。这样，一个完整的 对精神病的理解需要对健康人群中多巴胺相关网络进行表征 青春期以及精神病中偏离这些轨迹的情况。这些发现将提供深入了解 从发展的角度来看，转化风险的决定因素以及干预的时机。 拟议的奖项将建立在候选人之前的认知神经科学培训的基础上，以扩展 这些知识涉及青少年的规范发展和青少年的异常发展领域 多巴胺相关网络中的精神病。目标 1 将研究神经元的规范发展 调节腹侧被盖区和黑质（中脑边缘的核心）接合的系统 多巴胺系统，使用多模式神经影像。这些发育神经影像标记将被 与多巴胺的直接和间接测量相关，以评估它们与多巴胺能功能的关系。 目标 2 将评估首发精神病患者如何偏离正常轨迹 目标 1 中的特征，并进一步探讨这些偏差与抗精神病药物状态的关系。 最后，目标 3 将让首发患者返回进行为期 2 年的随访，以了解临床表现如何 精神病的病程与多巴胺相关功能障碍的早期标志物有关。辅导培训将 赞扬候选人在健康成人多巴胺相关回路的神经影像学方面的专业知识。 与拟议的研究并行，培训将侧重于候选人获得进行 青少年（目标 1）和精神病人群（目标 2,3）的神经影像学研究。此外，候选人将 获得青少年和精神病人群动物行为模型转化方面的专业知识， 重点了解多个物种之间同源性的本质（目标 1-3）。最后，候选人将 获得与研究神经发育相关的实验技术的专业知识（例如，纵向数据 分析;目标 1-3)、精神病（例如，调整抗精神病药物、描述临床特征） 现象学；目标 2-3）和转化神经科学（例如，整合直接/间接测量 多巴胺；目标3）。候选人已招募了一支在上述所有领域具有专业知识的指导团队 由导师 Bea Luna 博士（青少年发展专家）和联合导师 Deanna Barch（青少年发展专家）共同指导 精神病人群的神经影像学。此外，候选人将利用已知的优势 精神分裂症和青少年研究界，以及对跨物种翻译的重视 在匹兹堡大学。拟议的研究将为多巴胺功能障碍提供新的见解 从青少年神经发育的角度来看精神病。此外，培训将为 分析精神病中神经调节系统的神经发育的独立研究计划。 ！