Transdiagnostic and Disorder-Specific Effects of Immune and Metabolic Factors on Motivational Deficits Across Mood and Psychotic Disorders

免疫和代谢因素对情绪和精神障碍动机缺陷的跨诊断和疾病特异性影响

• 批准号: 9979349
• 负责人: Michael Tilghman Treadway
• 金额: $ 42.9万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979349
• 关键词: Affect; Anhedonia; Anterior; Anti-Inflammatory Agents; Behavioral; Biological; Bipolar Depression; Blood specimen; Brain; C-reactive protein; Cells; Chemosensitization; Clinical; Cognitive; Corpus striatum structure; Data; Decision Making; Diagnosis; Disease; Dopamine; Dorsal; Ecological momentary assessment; Exploratory/Developmental Grant; Expression Profiling; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Genetic Markers; Glycolysis; Goals; Human; Immune; Immunologic Markers; Immunotherapy; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Insula of Reil; Insulin; Laboratories; Laboratory Animals; Linear Models; Measures; Mediating; Mental Depression; Mental disorders; Metabolic; Metabolism; Mood Disorders; Moods; Motivation; NF-kappa B; Oxidative Phosphorylation; Pathology; Pathway interactions; Patients; Plasma; Prefrontal Cortex; Process; Protein Analysis; Proteins; Proto-Oncogene Proteins c-akt; Psychotic Disorders; Reporting; Research; Resources; Rewards; Role; Sampling; Schizoaffective Disorders; Schizophrenia; Statistical Models; Study models; Symptoms; Testing; Theoretical model; Time; Transcript; Unipolar Depression; Universities; Ventral Striatum; Washington; Work; aerobic glycolysis; attenuation; base; cytokine; discounting; immune activation; inflammatory marker; monocyte; motivated behavior; neuroimaging; neuroimaging marker; peripheral blood; pre-clinical; predictive marker; predictive modeling; protein biomarkers; recruit; relating to nervous system; response; reward processing; sex; translational model; willingness

PROJECT SUMMARY Symptoms related to low motivation are common to many psychiatric disorders, particularly mood and schizophrenia spectrum disorders. These motivational deficits have been associated with elevated inflammatory markers across these disorders. Significant clinical and preclinical data indicate that effects of inflammatory mediators on dopamine (DA) in the ventral striatum may mediate the association between inflammation and decreased motivated behavior. In a related fashion, increased inflammation is associated with a shift in immunometabolism away from the more energy efficient oxidative phosphorylation to the relatively inefficient aerobic glycolysis. This shift in metabolism significantly depletes available energy resources that may be communicated to the brain through effects of inflammatory mediators on striatal DA in order to constrain motivation and conserve energy resources during periods of heightened immune activation. To date, however, it remains unknown whether these striatal DA-immune interactions represent a transdiagnostic mechanism for motivational deficits across different disorders. The focus of this proposal is to determine whether elevations in inflammation and related immunometabolic changes represent a common mechanism for impairments in motivation across disorders of psychosis and mood. Given that recruitment of a well-powered transdiagnostic sample would not be possible under an R21 mechanism, this proposal is uniquely poised to leverage data collected by R01MH066031 (PI: Barch) at Washington University. R01MH066031 is recruiting a transdiagnostic sample to assess behavioral and neuroimaging measures of motivation, including effort-based decision-making (EBDM) paradigms and ecological momentary assessment (EMA). The focus of the current proposal is to expand this project through the analysis of protein and genetic markers of immune activity and immunometabolism from this sample. Specifically, using blood samples collected from patients with unipolar depression, bipolar depression, schizophrenia, and schizoaffective disorder (n = 50 per group) as well as 75 healthy controls, elevations in inflammatory markers and their relationship to EBDM and EMA measures of motivation will be compared across groups (Aim 1). In Aim 2, we will assess different levels of gene expression within pathways of inflammation and immunometabolism and will relate changes to specific immune cell subsets using transcript-of-origin analyses. In particular, we will test whether enriched expression of genes in inflammatory pathways (e.g. NF-kB) and pathways related to glycolysis (e.g., insulin, MTOR, AKT, PI3K) localized within specific immune cells (e.g. monocytes) predicts reduced effort during EBDM and EMA measures. These data will help determine the extent to which potential immunotherapies, including anti-inflammatories and/or regulators of immunometabolism can confer disorder- specific or transdiagnostic benefits to patients with mood or schizophrenia spectrum disorders.

项目摘要 与动力低相关的症状对于许多精神疾病，尤其是情绪和 精神分裂症谱系障碍。这些动机赤字与升高有关 这些疾病的炎症标记。大量的临床和临床前数据表明 腹侧纹状体的多巴胺（DA）上的炎症介质可以介导 炎症和动机行为减少。以相关的方式，炎症增加与 免疫代谢的转变从更有效的氧化磷酸化转移到 相对低效的有氧糖酵解。新陈代谢的这种转变可显着耗尽可用的能量 通过炎症介体对纹状体DA的影响，可以传达给大脑的资源 为了限制动机并节省免疫激活期间的能源。 然而，迄今为止，这些纹状体DA-免疫相互作用是否代表 跨不同疾病的动机缺陷的转诊机制。该提议的重点是 确定炎症和相关免疫代谢变化的高程是否代表常见 跨精神病和情绪障碍动机损害的机制。鉴于招募 在R21机制下，不可能实现良好的转诊样本，该建议是 独特的准备利用华盛顿大学R01MH066031（PI：Barch）收集的数据。 R01MH066031正在招募转诊样本，以评估行为和神经影像学指标 动机，包括基于努力的决策（EBDM）范式和生态瞬时评估 （EMA）。当前建议的重点是通过分析蛋白质和遗传来扩展该项目 来自该样品的免疫活性和免疫代谢的标记。具体而言，使用血液样本 从单极抑郁症，躁郁症抑郁症，精神分裂症和精神分裂症患者中收集 疾病（每组n = 50）以及75种健康对照，炎症标记的升高及其 将在各组之间比较与EBDM和EMA动机衡量标准的关系（AIM 1）。在AIM 2中，我们 将评估炎症和免疫代谢途径中不同水平的基因表达以及 将使用原始分析的转录本将变化与特定的免疫细胞亚群有关。特别是，我们将测试 炎症途径（例如NF-KB）中基因表达的富集和与 糖酵解（例如胰岛素，mTOR，AKT，PI3K）局部局部在特定的免疫细胞内（例如单核细胞）预测 在EBDM和EMA措施中减少了努力。这些数据将有助于确定潜力的程度 免疫疗法，包括免疫代谢的抗炎和/或调节剂可以赋予疾病 - 对情绪或精神分裂症谱系障碍患者的特定或经诊断益处。