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: 8970178
• 负责人: CHARLES C LEE
• 金额: $ 7.4万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970178
• 关键词: Accounting; Affect; Area; Autistic Disorder; Behavior; Behavioral; Biological Models; Brain; Cells; Cognitive deficits; Communication; Cortical Dysplasia; Development; Disease; Employee Strikes; Environmental Risk Factor; Exhibits; Foundations; Future; Genes; Genetic; Glutamates; Goals; In Vitro; Individual; Investigation; Knockout Mice; Knowledge; Lead; Link; Measures; Methods; Mission; Motor; Mus; Mutation; Neurologic; Neurons; Outcome; Partial Epilepsies; Pathway interactions; Pattern; Perception; Phenotype; Physiological; Preparation; Preventive; Process; Property; Prosencephalon; Proteins; Public Health; Relative (related person); Research; Risk; Role; Sensory; Slice; Social Interaction; Synapses; Syndrome; Testing; Thalamic Nuclei; Thalamic structure; autism spectrum disorder; autistic behaviour; base; contactin; disability; improved; in vivo; innovation; migration; mouse model; nervous system disorder; neural circuit; neurobehavioral; optogenetics; patch clamp; prevent; prospective; public health relevance; 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(由申请人提供)：自闭症谱系障碍(ASD)包括由大脑发育异常模式引起的一系列神经行为疾病。几个遗传和环境因素使个体容易患上自闭症，每个因素都表现在特定的核心行为上。我们研究的长期目标是了解这些因素在导致自闭症的神经变化中的相对贡献。这里的主要目的是描述在CNTNAP2/-小鼠自闭症模型中皮质第五层投射的变化。中心假设是，在这些小鼠中，神经元向第5层的异常迁移导致从皮质第5层到丘脑和运动中心的感觉运动活动增强。自闭症受试者的几个解剖学和行为特征已经被确定，这构成了拟议的调查的基础。该项目的具体目标是：1)确定CNTNAP2-/-小鼠初级感觉皮质区中不正确迁移到第5层的异位神经元的神经解剖学联系；2)评估CNTNAP2-/-小鼠第5层投射到丘脑的突触特性和功能地形图。这项研究将利用这种疾病的小鼠模型来检查这些前脑成分由此产生的病理变化，预计这些变化将解释与自闭症相关的核心行为的各个方面：异常的社交互动，声音交流的减少，以及重复和限制性行为。拟议的实验有望阐明这些和其他前脑成分在自闭症中的作用，并指导我们未来的研究，旨在将这些形态变化与自闭症直接联系起来，并最终恢复这个模型系统中的正常行为。这些实验将通过阐明皮质丘脑通路在自闭症中以前未被认识到的作用而产生积极的影响。