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）：一种新型的神经回路分析范式，以模拟小鼠自闭症的自闭症范围。自闭症谱系障碍行为障碍（ASD）行为障碍的基础电路缺陷（ASD）仍然很熟悉。这种知识对于开发有效治疗至关重要。人ASD中相当大的分子异质性和人类研究中的明显局限性使与人类等同的靶向突变的突变小鼠成为独特的机会，因为它允许在分子和电路水平上操纵。越来越多的ASD模型列表具有“构造”（分子缺陷模仿人ASD）和“ face”（行为障碍，等于人ASD的核心特征）有效性。突变小鼠中人ASD建模的当前分析范例着重于使用切片生理学和行为分析来分析突触的发展和功能。这些研究产生了支持ASD模型中突触功能障碍的一般结论的证据。但是，这些发现几乎没有对行为障碍的电路机制几乎没有深入的了解，因为研究精选大脑区域中突触的发现在不同研究中经常是可变的，并且不一致。 ASD研究的基本挑战在于理解基因功能的变化如何破坏负责自闭症行为基础的正常功能过程的大规模大脑网络的复杂性。由于这些原因，在转基因突变小鼠中对人ASD进行建模的领域需要新的分析范式，以剖析电路或网络水平下的功能障碍。我们已经开发了一种新型的多单元体内重新编码技术，该技术可以同时从自由移动动物中获得多达11个大脑区域的神经活动。这项新型技术提供了检测功能失调的神经电路和网络的可行性。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ASD具有很强的结构和面部有效性。这些突变小鼠提供了开发新的分析范式来解剖电路功能障碍的独特机会。该项目的长期目标是使用ASD鼠标模型定义ASD行为的功能失调的电路。中心假设是在Shank3E4-22和Shank2E24突变小鼠中观察到跨不同相关神经回路的功能障碍同步。具体的目标是使用我们团队率先使用的新型在体内多单元录制技术中确定这些突变小鼠中社会缺陷和重复行为的基础性神经回路。这些实验将导致鉴定内向型型的电生理生物标志物，这些标志物将有助于验证新型神经精神药物的新分子靶标，增强了当前神经调节疗法的靶向，用于在ASD中使用，并促进了封闭的封闭行为的“ Pacemaker”的循环“ PACEMAKER”，这些疗法直接修复了Dysf，Dysf the dysf the dysf the dysf the dysf the dysf the dysf the dysf。在ASD中。这些发现将解决我们知识的显着差距，并提供证据，以支持使用突变小鼠对人ASD进行建模的范式转移。