Project 3

摘要(项目3) 最近对先兆受试者和新近发病的精神分裂症(SZ)进行的临床研究表明 压力相关的通路在疾病之前和发病时被激活，这与病情较轻的情况相反 慢性期通路的变化。此外，人类尸检研究表明 锥体神经元和小白蛋白(PV)阳性中间神经元树突棘的变化。这些都是关键 前额叶皮质(PFC)神经元网络兴奋-抑制(E-I)失衡的神经基础 深圳潜在的认知缺陷。我们的初步数据显示压力相关分子和 表现出成年行为改变的小鼠模型中青春期和成年期的中间神经元 与深圳相关。这些模型携带着微管相关分子的遗传扰动，并显示出温和的 早期神经发育缺陷。基于这一背景，我们提出了以下两个目标：目标1将 确定和描述与应激相关的级联反应和E-I失衡变化的临界期 微管相关基因诱导的几种早期发育轻度脑缺陷小鼠遗传模型 基因；而Aim 2将研究基于神经回路的行为变化的机制 内侧前额叶(MPFC)和眶前叶皮质(OFC)，如工作记忆缺陷和行为 僵化。我们还将调查青少年的社会孤立是否会加剧 签名。最后，我们将干预分子、细胞类型和大脑区域特定的应激途径 在青春期试图挽救成人表型(生理、行为)的方式。我们相信建议的 这项研究是创新的，将导致开发用于早期诊断和干预的新工具 与SZ及相关精神障碍相关的认知缺陷。

Abstract (Project 3) Recent clinical studies that examine prodromal subjects and recent-onset schizophrenia (SZ) have indicated that stress-associated pathways are activated prior to and at the onset of the disease, in contrast to milder changes of the pathways in the chronic stages. In addition, human postmortem studies have demonstrated changes in dendritic spines of pyramidal neurons and parvalbumin (PV)-positive interneurons. These are key neural substrates for the excitatory-inhibitory (E-I) imbalance in prefrontal cortical (PFC) neuronal networks underlying cognitive deficits in SZ. Our preliminary data show changes in stress-associated molecules and interneurons in adolescence and young adulthood in mouse models that display altered adult behaviors relevant to SZ. These models carry genetic perturbations of microtubule-associated molecules and show mild deficits in early neurodevelopment. Based on this background, we propose the following two Aims: Aim 1 will determine and characterize the critical periods for changes in stress-associated cascades and E-I imbalance in several genetic mouse models with mild brain deficits in early development elicited by microtubule-associated genes; and Aim 2 will study the mechanisms of neurocircuitry-based behavioral changes associated with medial PFC (mPFC) and orbitofrontal cortex (OFC), such as working memory deficits and behavioral inflexibility. We will also investigate whether adolescent social isolation exacerbates the pathological signatures. Finally, we will intervene with the stress pathways in a molecule, cell type and brain region-specific manner during adolescence to try to rescue adult phenotypes (physiology, behavior). We believe the proposed study is innovative and will lead to the development of new tools for early diagnosis and intervention in cognitive deficits relevant to SZ and related mental disorders.