A novel neural circuit analysis paradigm to model autism in mice

一种新颖的神经回路分析范例来模拟小鼠自闭症

基本信息

批准号：
8917303
负责人：
YONG-HUI JIANG
金额：
$ 23.85万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8917303
关键词：
Address Animals Area Autistic Disorder Behavior Behavioral Biological Markers Biological Neural Networks Brain Brain region Collection Communication Deep Brain Stimulation Defect Development Disease Disease model Distal Electrodes Electroencephalography Environmental Risk Factor Exhibits Exons Experimental Designs Exploratory/Developmental Grant Face Frequencies Functional Magnetic Resonance Imaging Functional disorder Generations Genes Genetic Goals Grooming Health Heterogeneity Hippocampus (Brain)Human Knowledge Lead Learning Link Magnetoencephalography Methods Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutation Pacemakers Pathogenesis Pathway interactions Pharmaceutical Preparations Physiology Positron-Emission Tomography Prefrontal Cortex Process Research Research Personnel Rodent Series Slice Social Behavior Social Interaction Synapses Techniques Time Transcranial magnetic stimulation Validation autism spectrum disorder autistic behaviour base behavioral impairment clinical Diagnosis effective therapy electrical measurement endophenotype gene function high reward high risk in vivo insight millisecond mouse model neural circuit neurophysiology neuropsychiatry neuroregulation novel relating to nervous system repaired research study skills social stem trait

项目摘要

DESCRIPTION (provided by applicant): A Novel Neural Circuit Analysis Paradigm to Model Autism in Mice The circuit defects underlying the behavioral impairments of autism spectrum disorders (ASD) remains poorly understood. This knowledge is critical for development of effective treatments. The considerable molecular heterogeneity in human ASD and the apparent limitations in human studies renders mutant mice with targeted mutations equivalent to humans a unique opportunity because it allows manipulation at both molecular and circuit levels. There is an increasing list of ASD models with both "construct" (molecular defect mimics human ASD) and "face" (behavioral impairments equivalent to core feature of human ASD) validity. The current analytic paradigm of modeling human ASD in mutant mice focuses on analyzing synaptic development and function using slice physiology and behavior analysis. These studies have produced evidence supporting a general conclusion of synaptic dysfunction in ASD models. However, these findings offer little insight into the circuit mechanism underlying behavioral impairments because the findings from studying the synapses in select brain regions are frequently variable and inconsistent among different studies. The fundamental challenge of ASD research lies within the complexity of understanding how alterations in gene function disrupt large scale brain networks responsible for normal functional process underlying autistic behaviors. For these reasons, the field of modeling human ASD in genetically modified mutant mice demands a new analytic paradigm to dissect the dysfunction at circuit or network levels. We have developed a novel multi-unit in vivo recoding technique that can acquire neural activity from as many as 11 brain regions in free moving animals simultaneously. This novel technique offers a feasibility to detect dysfunctional neural circuit and network. We have also produced and characterized unique Shank2 exon 24 (Shank3e24) and Shank3 exon 4-22 (Shank3e4- 22) deletion mutant mice that have strong construct and face validity for human ASD. These mutant mice provide unique opportunities to develop a novel analytic paradigm for dissecting circuit dysfunction. The long term goal of this project is to define dysfunctional circuit underlying ASD behaviors using ASD mouse models. The central hypothesis is dysfunction synchrony across distinct relevant neural circuits will be observed in Shank3e4-22 and Shank2e24 mutant mice. The specific objective is to identify the dysfunctional neural circuits underlying social deficits nd repetitive behaviors in these mutant mice using a novel in vivo multiple-unit recording technique pioneered by our team. These experiments will lead to the identification of electrophysiological biomarkers of endophenotypes that will aid in the validation of novel molecular targets for novel neuropsychiatric drugs, enhance the targeting of current neuromodulatory therapies for use in ASD and facilitate the development of closed loop neuromodulatory "pacemakers" which directly repair the dysfunctional brain circuits underlying the behavioral manifestations in ASD. These findings will address a significant gap in our knowledge and provide evidence to support a paradigm shift in modeling human ASD using mutant mice.

描述（由申请人提供）：小鼠自闭症模型的新型神经回路分析范式对于自闭症谱系障碍（ASD）行为障碍背后的神经回路缺陷仍然知之甚少。这些知识对于开发有效的治疗方法至关重要。人类自闭症谱系障碍中相当大的分子异质性和人类研究中的明显局限性为具有与人类等同的靶向突变的突变小鼠提供了独特的机会，因为它允许在分子和电路水平上进行操作。越来越多的 ASD 模型同时具有“结构”（模仿人类 ASD 的分子缺陷）和“面孔”（相当于人类 ASD 核心特征的行为障碍）有效性。当前在突变小鼠中模拟人类 ASD 的分析范式侧重于使用切片生理学和行为分析来分析突触发育和功能。这些研究提供的证据支持 ASD 模型中突触功能障碍的一般结论。然而，这些发现对行为障碍背后的回路机制几乎没有提供任何见解，因为研究特定大脑区域突触的结果在不同的研究中经常变化且不一致。自闭症谱系障碍研究的根本挑战在于理解基因功能的改变如何破坏负责自闭症行为背后正常功能过程的大规模大脑网络的复杂性。出于这些原因，在转基因突变小鼠中模拟人类 ASD 领域需要一种新的分析范式来剖析电路或网络水平的功能障碍。我们开发了一种新颖的多单元体内记录技术，可以同时从自由活动的动物的多达 11 个大脑区域获取神经活动。这项新技术提供了检测功能失调的神经回路和网络的可行性。我们还生产并表征了独特的 Shank2 外显子 24 (Shank3e24) 和 Shank3 外显子 4-22 (Shank3e4-22) 缺失突变小鼠，它们对人类 ASD 具有强大的结构和表面有效性。这些突变小鼠提供了独特的机会来开发一种新的分析范式来剖析电路功能障碍。该项目的长期目标是使用 ASD 小鼠模型定义 ASD 行为背后的功能失调电路。中心假设是在 Shank3e4-22 和 Shank2e24 突变小鼠中观察到不同相关神经回路的同步功能障碍。具体目标是使用我们团队首创的新型体内多单元记录技术来识别这些突变小鼠的社交缺陷和重复行为背后的功能失调的神经回路。这些实验将导致内表型电生理生物标志物的鉴定，这将有助于验证新型神经精神药物的新分子靶点，增强当前用于自闭症谱系障碍的神经调节疗法的靶向性，并促进闭环神经调节“起搏器”的开发。直接修复自闭症谱系障碍行为表现背后的功能失调的大脑回路。这些发现将弥补我们知识中的重大差距，并为支持使用突变小鼠模拟人类自闭症谱系障碍的范式转变提供证据。