Alterations to corticothalamic circuitry in a mouse model of autism

自闭症小鼠模型中皮质丘脑回路的改变

• 批准号: 9068345
• 负责人: CHARLES C LEE
• 金额: $ 11.03万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068345
• 关键词: Accounting; Affect; Area; Autistic Disorder; Behavior; Behavioral; Biological Models; Brain; CNTNAP1 gene; Cells; Cognitive deficits; Communication; Cortical Dysplasia; Development; Disease; Employee Strikes; Environmental Risk Factor; Exhibits; Foundations; Future; Genes; Genetic; Glutamates; Goals; Health; In Vitro; Individual; Investigation; Knockout Mice; Knowledge; Lead; Link; Methods; Mission; Motor; Mus; Mutation; Neurologic; Neurons; Outcome; Partial Epilepsies; Pathway interactions; Pattern; Perception; Phenotype; Physiological; Preparation; Preventive measure; Process; Property; Prosencephalon; Public Health; Research; Risk; Role; Sensory; Slice; Social Interaction; Synapses; Syndrome; Testing; Thalamic Nuclei; Thalamic structure; autism spectrum disorder; autistic behaviour; base; disability; improved; in vivo; innovation; migration; mouse model; nervous system disorder; neural circuit; neurobehavioral; optogenetics; patch clamp; prevent; prospective; relating to nervous system; research study; response; restrictive repetitive behavior; therapeutic target

 DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) comprise a wide constellation of neurobehavioral conditions that arise from abnormal patterns of brain development. Several genetic and environmental factors predispose individuals to developing ASDs, each manifesting in certain core behaviors. The long-term goals of our research are to understand the relative contributions of these factors in producing the neural changes that underlie ASDs. The primary objective here is to characterize the alterations to cortical layer 5 projections in the CNTNAP2-/- mouse model of autism. The central hypothesis is that the aberrant migration of neurons to layer 5 in these mice results in enhanced sensorimotor activity from cortical layer 5 to the thalamus and motor centers. Several anatomical and behavioral features of autistic subjects have been identified, which forms the basis for the proposed investigation. The specific aims of the project are to: 1) Determine the neuroanatomical connections of the ectopic neurons that have migrated improperly to layer 5 in the primary sensory cortical areas of CNTNAP2-/- mice and 2) Assess the synaptic properties and functional topography of the layer 5 projections to the thalamus in CNTNAP2-/- mice. This study will utilize a mouse model of the disease to examine the resultant pathological alterations to these forebrain components, which are predicted to account for aspects of the core behaviors associated with ASDs: abnormal social interactions, reduced vocal communication, and repetitive and restrictive behaviors. The proposed experiments are expected to clarify the roles of these and other forebrain components in ASDs and guide our future investigations aimed at directly linking these morphological alterations with autism and ultimately restoring normal behavior in this model system. These experiments will have a positive impact by illuminating the previously unappreciated role of the corticothalamic pathways in ASDs.

 描述（由适用提供）：自闭症谱系障碍（ASDS）构成了由脑发育异常模式引起的神经行为状况的广泛星座。几个遗传和环境因素使个体倾向于发展ASD，每个人都以某些核心行为表现出来。我们研究的长期目标是了解这些因素在产生ASD的神经变化方面的相对贡献。这里的主要目的是表征CNTNAP2 - / - 自闭症鼠标模型中皮质层5项目的改动。中心假设是，这些小鼠中神经元向第5层的异常迁移导致从皮质5层到丘脑和运动中心的感觉运动活性增强。已经确定了加速受试者的几个解剖和行为特征，这构成了拟议研究的基础。该项目的具体目的是：1）确定Ecopic神经元的神经解剖连接，这些连接在CNTNAP2-/ - 小鼠的主要感觉皮质区域中不当迁移到第5层和2）评估Cntnap2 - / - / - 鼠标中Thalamus的第5层项目的突触特性和函数地形。这项研究将利用疾病的小鼠模型来检查这些前脑组成部分的病理改变，这些病理变化可以解释与ASDS相关的核心行为的各个方面：社交互动异常，声音交流减少以及重复性和限制性行为。预计拟议的实验将阐明这些和其他前脑组成部分在ASD中的作用，并指导我们未来的研究，旨在将这些形态学变化与自闭症直接联系起来，并最终恢复该模型系统中的正常行为。这些实验将通过阐明ASD中皮质丘脑途径的先前未欣赏的作用，从而产生积极的影响。