Disrupted auditory cortical plasticity and behavior in a model of Rett syndrome

雷特综合征模型中听觉皮层可塑性和行为的破坏

• 批准号: 9028931
• 负责人: STEPHEN D SHEA
• 金额: $ 52.74万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-08 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028931
• 关键词: Adult; Affect; Area; Auditory; Auditory area; Behavior; Behavioral; Behavioral Assay; Biological Assay; Communication; Data; Development; Disease; Electrophysiology (science); Equilibrium; Event; Exhibits; Female; Gene Mutation; Genes; Genetic; Goals; Heterozygote; Knock-out; Language; Learning; Lesion; Link; Maternal Behavior; Methods; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Pathology; Perception; Performance; Production; Retrieval; Rett Syndrome; Rodent Model; Social Behavior; Stimulus; Structure; Therapeutic; Therapeutic Intervention; autism spectrum disorder; awake; cell type; clinically relevant; communication behavior; experience; extracellular; forging; genetic manipulation; immunohistochemical markers; in vivo; mouse model; mutant; neural circuit; neuronal circuitry; new therapeutic target; novel; novel strategies; public health relevance; pup; relating to nervous system; repaired; response; social communication; social learning; targeted treatment; tool; virus genetics; vocalization

 DESCRIPTION (provided by applicant): Impaired perception and production of language, as well as deficits in social behavior generally, are pervasive features among the autism spectrum disorders (ASD). However, the changes to in vivo circuitry that connect disordered molecular and developmental events to altered behavior are largely unknown. Therefore, the goals of this proposal are: 1) To identify inhibitory neuronal circuits that support vocal perception 2) To determine how they are impaired in a rodent model of Rett syndrome 3) To repair the inhibitory circuitry using novel genetic and pharmacological strategies. To achieve these goals, we propose to use a combination of novel behavioral assays, genetic methods, and electrophysiology. With these tools, we can observe plasticity in specific inhibitory circuits, assess the neural and behavioral consequences of perturbing these circuits, and ultimately restore behavioral function by repairing those circuits. In our preliminary data, we describe a simple, robust and ethologically relevant assay of maternal behavior in a model of Rett syndrome (mice carrying only one copy of the gene MeCP2 - `hets'). Our results with this assay reveal a profound deficit of maternal social learning in hets that we hypothesize is related to poor perception of pup vocalizations. Indeed, we link gathering behavior to function and plasticity of the auditory cortex by showing that: 1) MeCP2 expression in the auditory cortex is necessary for proficient maternal behavior. 2) Auditory cortical neurons in hets exhibit impaired plasticity of inhibitory responses to vocal stimuli. 3) Immunohistochemical marker data reflect dysregulated maturation of auditory cortical inhibitory networks in response to maternal experience. Crucially, the hets are characterized by enhanced expression of perineuronal nets (PNNs), structures that closely associate with inhibitory networks and are thought to limit plasticity. 4) A `genetic rescue' manipulation of GABAergic inhibitory function relieves the elevated PNN expression, and remarkably restores normal behavioral performance. 5) Pharmacological inhibition of PNNs selectively in the auditory cortex prior to maternal experience is sufficient to restore maternal learning as well. Our objectives are to identify specific auditory cortical circuits governing vocal perception, to determine the in vivo functional consequences of MeCP2 heterozygosity in these circuits, and to rescue circuit function and behavior with a genetic manipulation of these circuits. By achieving these goals, we will forge crucial links between molecular and circuit pathologies and impaired social communication in the Rett syndrome mouse model, and we will potentially identify candidate circuit targets for therapeutic intervention.

 描述（适用提供）：语言的感知和产生受损，以及在社会行为中定义的，通常是自闭症谱系障碍（ASD）的普遍特征。但是，将无序分子和发育事件与行为改变的体内电路的变化在很大程度上未知。因此，该提案的目标是：1）确定支持人声感知的抑制性神经元回路2）确定在RETT综合征的啮齿动物模型中如何损害它们，以使用新型的遗传和药物策略来修复抑制作用。为了实现这些目标，我们建议将新颖的行为评估，遗传方法和电生理学结合使用。使用这些工具，我们可以在特定的抑制回路中观察可塑性，评估扰动这些电路的神经和行为后果，并最终通过修复这些电路来恢复行为功能。在我们的初步数据中，我们描述了对Rett综合征模型中母体行为的简单，健壮和伦理上相关的评估（小鼠仅携带一个基因MECP2-“ HETS”的副本）。我们对这项评估的结果表明，我们假设的HET中孕产妇社会学习的赤字与对幼犬发声的不良看法有关。实际上，我们通过表明以下方式将收集行为与听觉皮层的功能和可塑性联系起来：1）听觉皮层中的MECP2表达对于专业成熟是必需的。 2）HET暴露的听觉皮质神经元影响了对声带刺激的抑制作用的可塑性。 3）免疫组织化学标志物数据反映了响应孕产妇经验的听觉皮质抑制网络的成熟失调。至关重要的是，HET的特征是增强的周围神经元网（PNN）的表达，这些结构与抑制网络紧密相关，并被认为限制了可塑性。 4）对GABA能抑制功能的“遗传救援”操纵可挽救PNN表达升高，并明显恢复正常的行为表现。 5）在孕产妇经验之前，在听觉皮层中有选择地对PNN的药理抑制也足以恢复母鸡学习。我们的目标是确定有关人声感知的特定听觉皮层电路，以确定体内功能 在这些电路中MECP2杂合性的后果，并通过对这些电路的遗传操纵来挽救电路功能和行为。通过实现这些目标，我们将建立分子和电路病理学之间的关键联系，并在RETT综合征小鼠模型中损害社交交流，我们将有可能确定候选电路目标进行治疗干预。