UC Davis Conte Center: Neuroimmune Mechanisms of Psychiatric Disorders

项目概要-总体 精神疾病，包括精神分裂症，影响了很大一部分人口，但目前 治疗对许多个体仅部分有效，在SZ的情况下，对解决残疾几乎没有作用。 认知和阴性症状。因此，迫切需要开发生物标志物来识别风险 个体的早期干预和新的分子途径，以靶向开发新的疗法。一个 与SZ相关的越来越引人注目的途径是免疫失调。这项提议的更新 加州大学戴维斯分校康特中心汇集了具有独特的组合和广泛的研究人员， 补充专门知识，以解决与免疫系统之间潜在联系有关的知识方面的关键差距 失调和精神疾病。在上一个资助期内，我们采取多管齐下的方法， 测试我们中心的假设，即母体免疫系统的早期激活会改变大脑发育 在后代中，导致连接性的结构和功能变化，这些变化与 精神病理学在青少年和青年期的出现。出现了四个重要的发现 从这些研究，作为前提，这一更新申请。首先，我们发现了两个因素， 预测后代对MIA的易感性和恢复力的小鼠模型，使我们能够研究MIA导致 仅在妊娠的一个子集中发生异常结果，以及它如何导致后代的不同表型。 第二，我们发现我们的雄性MIA NHP后代早在6岁时就有异常大脑发育的迹象。 表明出生后早期对于理解MIA对大脑的影响至关重要 发展第三，NHP和小鼠模型的综合结果表明，皮质-纹状体回路是中枢神经系统， 对MIA后代的行为影响。最后，MIA NHP成像结果与近期 起效SZ支持MIA模型的临床相关性。在这次更新中，我们将继续测试我们原来的 跨物种的中心假设（小鼠和NHP MIA模型以及SZ人类），通过三个特定的 目的：（i）确定女性在怀孕前和怀孕期间的免疫信号通路， 或对后代中MIA诱导的行为表型的不同子集的弹性，（ii）确定 皮质-纹状体回路对MIA小鼠易感性、恢复力和表型异质性的影响 和NHP后代和SZ个体，以及（iii）确定性别如何影响易感性， 恢复力和表型异质性的MIA后代和个人与SZ。成功完成 这些目标只能在所建议的高度综合的跨学科中心中实现， 确定特定神经回路中的因果分子通路，这些通路对于指导 针对MIA后有风险后代的发育年龄和性别优化干预措施。他们还将 揭示了新的免疫信号传导途径，可用于生物标志物的开发，以确定在 风险妊娠，以及一类新的急需的治疗干预措施，以防止SZ和其他NDD。

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.