UC Davis Conte Center: Neuroimmune Mechanisms of Psychiatric Disorders

加州大学戴维斯分校康特中心：精神疾病的神经免疫机制

• 批准号: 10378728
• 负责人: Cameron S. Carter
• 金额: $ 312.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378728
• 关键词: Address; Adolescence; Affect; Age; Age-Months; Behavioral; Biological Markers; Brain; COVID-19 pandemic; Cells; Cognitive; Computer Models; Corpus striatum structure; Coupled; Development; Diffusion Magnetic Resonance Imaging; Disease; Dopamine; Early Intervention; Female; Functional Magnetic Resonance Imaging; Funding; Gene Expression; Genomics; Heterogeneity; Human; Image; Immune; Immune response; Immune signaling; Immune system; Incidence; Individual; Infection; Intervention; Knowledge; Lead; Link; Magnetic Resonance Spectroscopy; Maternally-Acquired Immunity; Measures; Mediating; Mental disorders; Modeling; Molecular; Mothers; Motivation; Mus; Neurodevelopmental Disorder; Neuroimmune; Neuroimmunomodulation; Outcome; Pathway interactions; Patients; Phenotype; Poly I-C; Population; Predisposition; Pregnancy; Psychopathology; Research; Research Personnel; Risk; Risk Factors; Rodent Model; Schizophrenia; Sex Differences; Signal Pathway; Symptoms; Testing; Therapeutic Intervention; Time; at-risk pregnancies; base; behavioral outcome; behavioral phenotyping; biological sex; biomarker development; brain abnormalities; clinically relevant; cognitive control; immune activation; immunoreactivity; in vivo; male; mouse model; neural circuit; neuroimaging; neuromelanin; neuropsychiatric disorder; non-genetic; nonhuman primate; novel therapeutics; offspring; optogenetics; outcome prediction; postnatal period; predictive modeling; prevent; relating to nervous system; resilience; response; schizophrenia risk; sex; therapy development; transcriptomics; young adult

PROJECT SUMMARY - OVERALL Psychiatric illnesses, including schizophrenia, affect a significant proportion of the population, yet current treatments are only partially effective for many individuals and, in the case of SZ, do little to address disabling cognitive and negative symptoms. Thus, there is a pressing need to develop biomarkers to identify at-risk individuals for early intervention and new molecular pathways to target for development of novel therapies. An increasingly compelling pathway associated with SZ is immune dysregulation. This proposed renewal of the UC Davis Conte Center brings together investigators with a unique combination and wide range of complementary expertise to address a critical gap in knowledge related to the potential links between immune dysregulation and psychiatric illness. During the previous funding period, we took a multi-pronged approach to test our Center hypothesis that early activation of the maternal immune system alters brain development in offspring leading to structural and functional changes in connectivity that are associated with the emergence of psychopathology in adolescence and young adulthood. Four important findings emerged from those studies that serve as the premise for this renewal application. First, we discovered two factors in the mouse model that predict susceptibility and resilience of offspring to MIA, allowing us to study why MIA causes aberrant outcomes in only a subset of pregnancies and how it can lead to diverse phenotypes in offspring. Second, we found signatures of abnormal brain development in our male MIA NHP offspring as early as 6 months of age, indicating that the early postnatal period is critical for understanding the impact of MIA on brain development. Third, combined results from NHP and mouse models point to cortico-striatal circuitry as central to behavioral outcomes in MIA offspring. Finally, convergence between MIA NHP imaging findings and recent onset SZ support the clinical relevance of the MIA models. In this renewal, we will continue to test our original Center hypothesis across species (mouse and NHP MIA models and humans with SZ), through three specific aims: (i) Identify immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced behavioral phenotypes in offspring, (ii) Determine the contribution of cortico-striatal circuits to susceptibility, resilience and phenotypic heterogeneity in MIA mouse and NHP offspring and in individuals with SZ, and (iii) Determine how sex contributes to susceptibility, resilience and phenotypic heterogeneity in MIA offspring and individuals with SZ. Successful completion of these Aims, which could only be accomplished in a highly integrated interdisciplinary Center as proposed, will identify causal molecular pathways in specific neural circuits critical for guiding the development of interventions optimized for the developmental age and sex of at-risk offspring following MIA. They will also reveal new immune signaling pathways that can be targeted for the development of biomarkers to identify at- risk pregnancies, and a new class of much-needed therapeutic interventions to prevent SZ and other NDDs.

项目摘要 - 总体 包括精神分裂症在内的精神病疾病会影响大部分人群，但目前 治疗仅对许多人有部分有效，而对于SZ，治疗无济于事 认知和负面症状。因此，迫切需要开发生物标志物以识别高危 早期干预的个体和新的分子途径，以靶向开发新疗法。一个 与SZ相关的越来越引人注目的途径是免疫失调。这个提议的续约 UC Davis Conte中心将调查员汇集在一起 补充专业知识，以解决与免疫之间潜在联系有关的知识的关键差距 失调和精神病。在上一个资金期间，我们采取了多管齐下的方法 测试我们的中心假设，即产妇免疫系统的早期激活改变了大脑的发展 在后代导致连通性的结构和功能变化，这与 青春期和成年期心理病理学的出现。出现了四个重要发现 从那些作为此续签应用的前提的研究。首先，我们在 预测后代对MIA的敏感性和弹性的鼠标模型，使我们能够研究为什么MIA原因 仅在一部分妊娠中及其如何导致后代各种表型的异常结果。 其次，我们发现雄性MIA NHP后代的脑发育异常的特征早在6 几个月大，表明产后早期对于理解MIA对大脑的影响至关重要 发展。第三，NHP和小鼠模型的总结果指向皮质 - 纹状体电路作为中心 在MIA后代的行为结果。最后，MIA NHP成像发现与最近的收敛 发作SZ支持MIA模型的临床相关性。在此续约中，我们将继续测试我们的原始 跨物种（小鼠和NHP MIA模型和SZ的人类）的中心假设，通过三个特定 目的：（i）确定怀孕前后女性的免疫信号通路，以赋予易感性 或对后代中MIA诱导的行为表型的不同子集的韧性，（ii）确定 皮质 - 纹状体电路对MIA小鼠的敏感性，弹性和表型异质性的贡献 和NHP后代以及患有SZ的个体，以及（iii）确定性别如何促进易感性， MIA后代和患有SZ的个体的弹性和表型异质性。成功完成 这些目标只能按照提议的高度整合的跨学科中心实现 确定特定神经回路中的因果分子途径对于指导发展至关重要 MIA之后，针对高危后代的发展年龄和性别进行了优化的干预措施。他们也会 揭示新的免疫信号通路，可以针对生物标志物的开发来识别AT- 风险怀孕，以及一类急需的治疗干预措施，以防止SZ和其他NDD。