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: 10401784
• 负责人: John R Huguenard
• 金额: $ 47.4万
• 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/10401784
• 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： 怀孕期间的母体感染是神经发育障碍（包括自闭症谱系障碍（ASD））的一个既定危险因素，但人们对免疫损伤如何改变发育中的大脑中的神经回路并从而损害免疫行为的一个潜在部位知之甚少。影响神经发育障碍的内侧前额皮质 (mPFC) 在高阶社交和认知功能中发挥着关键作用。在探索性 R21 资助的支持下，我们使用了小鼠模型。我们研究了母体免疫激活 (MIA) 的研究，并开发了一种基于硅探针的多通道记录系统，用于对 mPFC 电路进行高通量功能分析。 (I:C))，并将第 5 层投射神经元的输出纤维中意外的功能减退确定为 mPFC 的中心缺陷，特别是第 5 层轴突。长时间活动期间维持输出的能力较差，并且 mPFC 的转录组学分析显示细胞粘附分子 L1cam 的下调，该分子是轴突兴奋性的假定调节剂。这里提出的工作将使用相同的小鼠 MIA 模型。确定轴突功能减退对 mPFC 特定远程目标的功能影响，mPFC 介导自闭症谱系障碍 (ASD) 和相关疾病中的行为失调 - 丘脑内侧该提案的目标 1 将测试暴露于母体免疫激活的后代中这些皮层下区域主要细胞的直接募集和/或间接前馈抑制是否受到损害。 MIA）。第 5 层 mPFC 投影将专门针对病毒方法的光遗传学刺激。在目标 2 中，我们将通过互补遗传（L1cam 救援）或增强第 5 层输出。光遗传学（SSFO 驱动的兴奋性增强）方法来确定这是否可以恢复 L5 输出并挽救 ASD 相关缺陷。在目标 3 中，我们将测试我们在 MIA 模型和皮质区域中的发现的普遍性。脂多糖 (LPS) 对 mPFC 轴突功能具有与聚 (I:C) 相似的影响 接下来我们将确定体感皮层（另一个皮质区域）是否与之相关。在 ASD 行为中，还显示了特定的 MIA 诱导的第 5 层轴突功能的变化，如果妊娠中期 MIA 广泛影响第 5 层皮层神经元发育的关键步骤，那么这可能是预期的。所提出的实验结果都有助于解释 ASD 的发病机制。自闭症谱系障碍 (ASD) 和其他神经发育障碍，并确定了可用于恢复行为的分子途径。