Core C

核心C

• 批准号: 9978146
• 负责人: Michela Gallagher
• 金额: $ 12.28万
• 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/9978146
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Anatomy; Animal Model; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Behavioral Paradigm; Behavioral Research; Biological; Brain; Cognitive; Collaborations; Consult; DISC1 gene; Data; Data Analyses; Development; Dimensions; Disease; Dominant-Negative Mutation; Environment; Environmental Exposure; Evaluation; Expectancy; Experimental Models; Exposure to; Functional disorder; Genes; Genetic; Genetic Risk; Goals; Human; Investigation; Knockout Mice; Lead; Medial; Mediating; Mental disorders; Microtubules; Modeling; Molecular; Mus; Neurocognitive; Neurosciences; Outcome; Pathway interactions; Patients; Performance; Physiological; Pre-Clinical Model; Prefrontal Cortex; Primates; Process; Protocols documentation; Psychomotor Performance; Psychosocial Stress; Rat-1; Reaction Time; Research; Research Domain Criteria; Research Personnel; Reversal Learning; Rewards; Rodent; Role; Schizophrenia; Series; Short-Term Memory; Signal Transduction; Social isolation; Stress; Support System; System; Testing; Transgenic Mice; Work; base; behavior test; behavioral study; cognitive function; design; endophenotype; environmental stressor; experimental study; flexibility; functional status; gene environment interaction; genetic variant; in vivo; innovation; mouse model; neural circuit; neurobehavioral; neuroimaging; neuropsychiatry; novel therapeutics; pre-clinical; pre-clinical research; programs; relating to nervous system; response

Research under the current proposal is designed to determine behavioral alterations relevant to schizophrenia (SZ), which is elicited by activation of stress-associated cascades and the E-I imbalance in the prefrontal cortex in mouse models that carry microtubule-associated genetic variants. We will also study how adolescent social isolation exacerbates these changes at the molecular, circuitry, and behavioral levels in collaboration with three Projects. In addition to performing basic behavioral characterization of the mouse models, this Core will conduct behavioral assessments for neurocognitive domains that are mediated by medial prefrontal cortex and orbitofrontal cortex, such as behavioral flexibility, including outcome expectancy in goal directed behavior, and working memory. Our rationale for use of specific behavioral assessments aimed at prefrontal systems is grounded in research that 1) documents the critical role of prefrontal cortex (PFC) circuitry in the information encoding mechanisms required to support behavioral performance in these paradigms across rodent and primate species, 2) implicates PFC systems supporting these functions in SZ by anatomical and physiological/neuroimaging evidence from patients, 3) demonstrates a vulnerability of such PFC-mediated behaviors/networks to stress exposure, including underlying mechanisms in PFC. Importantly, the assessments hold potential for the study of species-conserved cognitive mechanisms in the human brain to provide translational opportunities based on this preclinical research program. As such, the work in Core C is consistent with the Research Domain Criteria (RDoC) approach for advancing a biological understanding of the pathophysiology of major psychiatric illness and creating a platform for discovery of new therapeutics. Core C will consult with the investigators of the Projects both for conducting basic behavioral assays, for implementing behavioral experiments with a focus on analytically powerful protocols targeting PFC-mediated behaviors, and will lead data analysis and interpretation of findings in behavioral studies under the research program. In addition to its scientific value to the immediate objectives of the research program, the work of this Core may have broader translational significance in the neuropsychiatric field. As the molecular pathways under investigation are better understood in the context of behavioral profiling, the work of the core could identify assessments that are best suited to target dysfunctional mechanisms in animal models of SZ. In this way the proposed behavioral research may yield innovative findings of more general preclinical importance.

根据目前的建议进行的研究旨在确定与精神分裂症相关的行为改变 (SZ)这是由应激相关级联反应的激活和前额叶E-I失衡引起的 在携带微管相关遗传变异的小鼠模型中，我们还将研究青少年如何 社会隔离在分子、电路和行为水平上加剧了这些变化 有三个项目。除了对小鼠模型进行基本的行为表征外， 将对由内侧前额叶皮层介导的神经认知领域进行行为评估 和眶额皮质，如行为灵活性，包括目标导向行为中的结果预期， 和工作记忆我们使用针对前额叶系统的特定行为评估的理由是 基于以下研究：1）记录前额叶皮层（PFC）电路在信息传递中的关键作用 支持啮齿动物和其他动物在这些范式中的行为表现所需的编码机制 灵长类物种，2）涉及PFC系统支持这些功能，在SZ的解剖和 来自患者的生理/神经成像证据，3）证明了这种PFC介导的 行为/网络的压力暴露，包括PFC的潜在机制。重要的是， 评估具有研究人类大脑中物种保守的认知机制的潜力， 提供基于此临床前研究计划的翻译机会。因此，Core C中的工作是 与研究领域标准（RDoC）方法一致，以促进对生物学的理解。 主要精神疾病的病理生理学，并为发现新的治疗方法创造一个平台。芯C 我将与项目的调查人员协商，进行基本的行为分析，实施 行为实验，重点是针对PFC介导行为的分析功能强大的协议，以及 将领导研究计划下行为研究的数据分析和结果解释。在 除了对研究计划的直接目标具有科学价值外，本核心的工作还可 在神经精神领域有着更广泛的意义。因为分子途径 在行为特征分析的背景下更好地理解调查，核心小组的工作可以确定 最适合于SZ动物模型中靶向功能障碍机制的评估。以这种方式 拟议的行为研究可能会产生更普遍的临床前重要性的创新发现。