Project 3

项目3

• 批准号: 9978141
• 负责人: AKIRA SAWA
• 金额: $ 26.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-12 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978141
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Anatomy; Animal Model; Autopsy; Behavior; Behavioral; Biological; Biological Markers; Brain; Brain region; Chronic; Clinical Research; Cognitive deficits; Data; Dendritic Spines; Development; Disease; Early Diagnosis; Early Intervention; Equilibrium; Future; Genes; Genetic; Genetic study; Human; Impaired cognition; Interneurons; Intervention; Lead; Link; Medial; Memory impairment; Mental disorders; Microtubule-Associated Proteins; Microtubules; Modeling; Molecular; Neurons; Onset of illness; Parvalbumins; Pathologic; Pathway interactions; Phenotype; Physiology; Pre-Clinical Model; Prefrontal Cortex; Psyche structure; Puberty; Schizophrenia; Short-Term Memory; Signal Transduction; Social isolation; Stress; Therapeutic; Time; base; cell type; critical period; experimental study; gene environment interaction; hippocampal pyramidal neuron; innovation; mouse model; neural circuit; neurodevelopment; psychosocial; relating to nervous system; stressor; tool; young adult

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.

摘要（项目3） 最近的临床研究，检查前驱受试者和最近发作的精神分裂症（SZ）表明， 与压力相关的通路在疾病发作之前和发作时被激活，与轻度相比， 在慢性阶段的路径的变化。此外，人类死后研究表明， 锥体神经元和小白蛋白（PV）阳性中间神经元树突棘的变化。这些是关键 前额叶皮层（PFC）神经元网络兴奋-抑制（E-I）失衡的神经基质 SZ的潜在认知缺陷。我们的初步数据显示，压力相关分子的变化， 小鼠模型中青春期和青年期的中间神经元显示出改变的成年行为 关于SZ这些模型携带微管相关分子的遗传扰动， 早期神经发育的缺陷。基于这一背景，我们提出以下两个目标：目标1将 确定和表征应力相关级联和E-I不平衡变化的关键时期， 几种遗传小鼠模型，在早期发育中具有由微管相关蛋白引起的轻度脑缺陷， 目标2将研究与神经回路相关的行为变化机制， 内侧PFC（mPFC）和眶额皮层（OFC），如工作记忆缺陷和行为 可靠性。我们还将调查青少年的社会孤立是否加剧了病理性的 签名.最后，我们将在分子、细胞类型和大脑区域特异性方面干预应激通路 在青春期试图挽救成人表型（生理，行为）的方式。我们认为， 这项研究是创新的，将导致早期诊断和干预的新工具的开发 与SZ相关的认知缺陷和相关精神障碍。