Chronic Axon Hypofunction in Maternal Immune Activation Models of Neurodevelopmental Disorders

神经发育障碍母体免疫激活模型中的慢性轴突功能减退

• 批准号: 9916658
• 负责人: John R Huguenard
• 金额: $ 48.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916658
• 关键词: ANK3 gene; Acute; Adult; Adult Children; Affect; Amygdaloid structure; Anatomy; Area; Axon; Behavior; Behavior Disorders; Behavioral; Biological Assay; Brain; Cell Adhesion Molecules; Cells; Child; Chronic; Closure by clamp; Cognition; Cognitive; Communication; Corpus striatum structure; Coupled; Data; Defect; Development; Disease; Distal; Distant; Down-Regulation; Electrophysiology (science); Engineering; Environmental Risk Factor; Excitatory Synapse; Exposure to; Fiber; Gene Expression Profiling; Genes; Genetic; Grant; Immune; Impairment; Infection; Inflammation; Kinetics; Lifestyle-related condition; Light; Lipopolysaccharides; Maternal Exposure; Measures; Medial; Mediating; Modeling; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Nucleus Accumbens; Opsin; Output; Pathogenesis; Pathway interactions; Pattern; Phenotype; Physiologic pulse; Play; Poly C; Poly I-C; Population; Prefrontal Cortex; Pregnancy; Preparation; Probability; Pyramidal Cells; RBP4 gene; Research; Risk Factors; Role; Saline; Silicon; Site; Slice; Social Behavior; Social Functioning; Somatosensory Cortex; Source; Stains; Stereotyped Behavior; Structure; Susceptibility Gene; Synapses; System; Testing; Thalamic structure; Translating; Viral; Wild Type Mouse; Work; autism spectrum disorder; base; behavioral impairment; biocytin; cognitive function; density; emotional behavior; experimental study; flexibility; hippocampal pyramidal neuron; immune activation; improved; interest; mimetics; mouse model; multi-electrode arrays; neural circuit; neurodevelopment; offspring; optogenetics; overexpression; postsynaptic; prenatal exposure; presynaptic; reconstruction; recruit; repetitive behavior; small hairpin RNA; social; social deficits; stereotypy; tool; transcriptomics; two-photon

New Summary: Maternal infection during pregnancy is an established risk factor for neurodevelopmental disorders, including Autism Spectrum Disorders (ASD), yet little is known about how immune insults alter neural circuitry in the developing brain and, as a result, impair behavior. One potential site for immune effects is the medial prefrontal cortex (mPFC), which plays a critical role in the higher-order social and cognitive functions compromised in disorders of altered neural development. Through the support of an exploratory R21 grant, we used a mouse model of Maternal Immune Activation (MIA) and developed a silicon probe-based multichannel recording system for high-throughput functional analysis of mPFC circuitry. Using this approach, we examined mPFC in adult offspring following maternal exposure to a viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), and identified an unexpected hypofunction in the output fibers of layer 5 projection neurons as the central defect in the mPFC. In particular, layer 5 axons were less able to sustain output during prolonged activity, and their temporal precision was impaired. Transcriptomic profiling of the mPFC revealed a downregulation of the cell adhesion molecule L1cam, a putative regulator of axonal excitability. Here the proposed work will use the same mouse MIA model to determine the functional ramifications of axonal hypoactivity on specific long-range targets of the mPFC that mediate behaviors dysregulated in ASD and related disorders – mediodorsal thalamus (MD), basolateral amygdala (BLA), and nucleus accumbens (NAc). Aim 1 of this proposal will test whether direct recruitment and/or indirect feedforward inhibition of principal cells in these subcortical regions is impaired in offspring exposed to maternal immune activation (MIA). Layer 5 mPFC projections will be specifically targeted for optogenetic stimulation with viral approaches. In Aim 2, we will augment layer 5 output with complementary genetic (L1cam rescue) or optogenetic (SSFO-driven enhanced excitability) approaches to determine whether this restores L5 output and rescues ASD-related deficits. In Aim 3, we will test for generality of our findings in MIA models and cortical regions. First, we will test whether MIA induced by lipo-polysaccharide (LPS) has similar effects as poly(I:C) on mPFC axonal function. Next we will determine whether somatosensory cortex, another cortical region implicated in ASD behaviors, also shows specific MIA induced changes in layer 5 axonal function, as might be expected if midgestational MIA broadly affects layer 5 cortical neurons at a critical step in their development. The results of the proposed experiments could both help to explain pathogenesis of ASD and other neurodevelopmental disorders and identify a molecular pathway that could be targeted to restore behavior.

新摘要： 怀孕期间的产妇感染是神经发育障碍（包括自闭症谱系障碍（ASD））的既定危险因素，但对于免疫感染如何改变发育中的大脑中的神经电路以及结果却损害了行为。免疫感染的一个潜在部位是培养基前额叶皮层（MPFC），它在神经发育改变的疾病中损害的高阶社会和认知功能中起着至关重要的作用。通过支持探索性R21赠款，我们使用了孕妇免疫激活（MIA）的小鼠模型，并开发了一种基于硅探针的多通道记录系统，用于MPFC电路的高通量功能分析。使用这种方法，我们在接触病毒模拟聚激素含量后检查了成年后代的MPFC：多递这候酸（Poly（i：c）），并确定了第5层投影神经元的输出纤维中意外的功能率为MPFC中的中枢缺陷。特别是，第5层轴突在长时间的活动期间无法维持产量，并且它们的临时精度受到损害。 MPFC的转录组分析表明，细胞粘合分子L1CAM的下调是轴突刺激性的推定调节剂。在这里，提出的工作将使用相同的小鼠MIA模型来确定MPFC特定远程目标的轴突降低功能后果，即ASD和相关疾病中的媒体行为失调 - MediaDorsal Thalamus（MD），基础外侧杏仁核（BLA）（BLA）和Nucleus Accumbens（NAC）（NAC）。该提案的目标1将测试在暴露于母体免疫激活（MIA）的后代中，这些皮质下区域中主要细胞的直接募集和/或间接饲喂抑制是否受损。第5层MPFC项目将专门用于使用病毒方法进行光遗传学刺激。在AIM 2中，我们将使用完整的遗传（L1CAM Rescue）或光遗传学（SSFO驱动增强的令人兴奋性）的方法增强第5层输出，以确定这是否恢复了L5输出并挽救与ASD相关的缺陷。在AIM 3中，我们将测试MIA模型和皮质区域中发现的一般性。首先，我们将测试脂糖糖（LPS）诱导的MIA是否具有与Poly（I：C）对MPFC轴突函数的相似作用。接下来，我们将确定在ASD行为中实现的另一个皮质区域的体感皮质是否还显示了MIA诱导的第5层轴突功能的变化，如果中质MIA在其发育的关键步骤中广泛影响第5层皮质神经元，则可能预期。提出的实验的结果既可以帮助解释ASD和其他神经发育障碍的发病机理，又可以确定可以针对恢复行为的分子途径。