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

项目摘要 与低动机相关的症状在许多精神疾病中很常见，特别是情绪和 精神分裂症谱系障碍这些动机缺陷与 这些疾病的炎症标志物。重要的临床和临床前数据表明， 腹侧纹状体中多巴胺（DA）的炎症介质可能介导 炎症和动机行为减少。与此相关的是， 随着免疫代谢从能量效率更高的氧化磷酸化转变为 相对低效的有氧糖酵解。这种新陈代谢的转变大大消耗了可用的能量 可能通过炎症介质对纹状体DA的影响传达给大脑的资源， 以在免疫激活增强期间限制动机并保存能量资源。 然而，到目前为止，这些纹状体DA-免疫相互作用是否代表了一种免疫反应仍然是未知的。 跨不同障碍的动机缺陷的转诊断机制。本提案的重点是 确定炎症和相关免疫代谢变化的升高是否代表一种常见的 在精神病和情绪障碍的动机障碍的机制。鉴于招募一名 在R21机制下，不可能获得功效良好的跨诊断样本，因此， 独特地准备利用华盛顿大学的R 01 MH 066031（PI：Barch）收集的数据。 R 01 MH 066031正在招募一个跨诊断样本，以评估以下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）。目前建议的重点是通过分析蛋白质和遗传学来扩大这一项目。 免疫活性和免疫代谢的标志物。具体来说，使用血液样本 收集自单相抑郁症、双相抑郁症、精神分裂症和情感障碍患者 疾病（每组n = 50）以及75名健康对照，炎症标志物及其 与EBDM和EMA的关系将在各组之间进行比较（目标1）。在目标2中， 将评估炎症和免疫代谢途径中不同水平的基因表达， 将使用原始转录分析将变化与特定免疫细胞亚群联系起来。特别是，我们将测试 是否在炎症途径（例如NF-κ B）和与炎症相关的途径中富集基因表达， 糖酵解（例如，胰岛素、MTOR、AKT、PI 3 K）预测 减少EBDM和EMA措施期间的工作量。这些数据将有助于确定潜在的 免疫疗法，包括抗炎药和/或免疫代谢调节剂，可导致疾病- 对情绪或精神分裂症谱系障碍患者的特异性或跨诊断益处。

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.