UC Davis Conte Center: Neuroimmune Mechanisms of Psychiatric Disorders

项目总结--总体 精神疾病，包括精神分裂症，影响着相当大比例的人口，但目前 治疗对许多人来说只是部分有效的，对于SZ来说，对解决残疾问题几乎没有作用 认知和阴性症状。因此，迫切需要开发生物标记物来识别风险 早期干预的个体和新的分子途径，以开发新的治疗方法为目标。一个 与SZ相关的日益引人注目的途径是免疫失调。这项建议的续期 加州大学戴维斯分校孔蒂中心以独特的组合和广泛的 补充专业知识，以解决与免疫之间潜在联系相关的知识的严重差距 调节失调和精神疾病。在上一个资助期内，我们采取了多管齐下的方法 验证我们的中心假设，即母体免疫系统的早期激活会改变大脑发育 在子代中导致连接的结构和功能变化，这与 青春期和青春期出现的精神病理学。出现了四个重要的发现 来自那些作为续签申请的前提的研究。首先，我们发现了两个因素 预测后代对MIA易感性和弹性的小鼠模型，使我们能够研究MIA引起的原因 只有一小部分怀孕的异常结局，以及它如何导致后代的不同表型。 其次，我们早在6岁时就在我们的男性MIA NHP后代中发现了大脑发育异常的迹象 出生几个月，表明出生后早期对于了解MIA对大脑的影响至关重要 发展。第三，来自NHP和小鼠模型的综合结果表明，皮质-纹状体回路是中枢 对MIA后代的行为结果的影响。最后，MIA NHP成像结果与最近的 发病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最初的 跨物种中心假说(小鼠和NHP MIA模型以及患有SZ的人类)，通过三个特定的 目标：(I)确定孕前和孕期女性的免疫信号通路，使其具有易感性 或对MIA诱导的行为表型的不同亚型的适应能力，(Ii)确定 皮质纹状体环路在MIA小鼠易感性、恢复力和表型异质性中的作用 和NHP后代以及患有SZ的个人，以及(Iii)确定性行为如何有助于易感性， MIA子代和SZ患者个体的韧性和表型异质性。成功完成 这些目标只有在提议的高度集成的跨学科中心才能实现，将 识别特定神经回路中的因果分子通路，这对指导疾病的发展至关重要 针对MIA后高危子女的发育年龄和性别进行优化的干预措施。他们还将 揭示新的免疫信号通路，可作为开发生物标记物的靶点，以识别- 风险怀孕，以及一种新的急需的治疗干预措施，以预防SZ和其他NDDS。

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.