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Deficits and rescue of neuronal population coding in the sensory cortex of mouse models of autism spectrum disorders

自闭症谱系障碍小鼠模型感觉皮层神经元群编码的缺陷和拯救

基本信息

批准号：
1937978
负责人：
金额：
--
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1937978
关键词：
Deficits rescue neuronal population coding

项目摘要

The central aim of this project is to understand the effects of single gene mutations at the level of cortical networks activity in animal models of Autism Spectrum Disorders (ASDs) and Intellectual disabilities (ID). Cortical circuits are initially defined by genetic programmes, followed by neural plasticity initially driven by spontaneous and later by evoked sensory activity. The investigation of monogenic ASD/ID animal models at the cellular level has revealed multiple alterations in neuronal properties, including changes in excitability, synaptic transmission and neural plasticity. Yet, it remains largely unknown how such cellular changes affect the activity in neural circuits, and how this, in turn, leads to the diversity of phenotypes characterising ASD/ID. Moreover, recent work indicates that some of these changes are of secondary nature, and likely result from a developmental homeostatic compensation of primary defects. In this scenario, an initial defect leads to altered cellular and/or network activity, which, in turn, is compensated by cellular feedback processes. It is therefore possible that different primary causes, for instance defective plasticity in Fragile X Syndrome and SYNGAP haploinsufficiency, can lead to similar defects at the circuit level. This convergence may provide an opportunity for interventions targeting the resulting cellular and circuit dysfunction in adults.Addressing this gap in knowledge requires a comprehensive understanding of the circuit-level impairments of ASD/ID in adults. Very few studies so far have investigated network activity in disease models beyond global features such as seizures, and currently no coherent picture exists. Here, we plan to use Fmr1-/y and Syngap+/- mice as two well established ASD/ID models to determine how these mutations affect the propagation of neural activity through cortical networks, focusing on sensory areas, where inputs are readily controllable.AimsWe will examine the following three hypotheses in Fmr-/y and Syngap+/- mice in this project:1. Cortical ensemble activity is consistently altered in ASD/ID models, compared to wild type (WT) animals, and biased towards reduced representational capabilities.2. Cortical plasticity induced by monocular deprivation is altered in ASD/ID models.3. Pharmacological treatments that rescue behavioural ASD/ID phenotypes in mouse models will modify cortical population activity and plasticity.To uncover the relevant circuit defects in ASD/ID models, we will use 2-photon calcium imaging of more than one thousand neurons simultaneously in the primary visual and parietal cortex, and employ computational data analysis and modelling. Genetically labelling of different interneuron types will enable a detailed dissection of the circuit pathology. We will investigate changes in experience-dependent plasticity at the circuit level, which has so far not been attempted, and evaluate the circuit-wide effects of pharmacological rescue in adults. Together, these complementary approaches will (i) help relate cellular and systems level pathologies in ASD/ID,(ii) explore avenues for treatment and interventions, and (iii) provide novel computational tools for analysis and interpretation of large neural population recordings.

该项目的中心目标是了解单基因突变对自闭症谱系障碍 (ASD) 和智力障碍 (ID) 动物模型皮质网络活动水平的影响。皮质回路最初由遗传程序定义，随后是神经可塑性，最初由自发驱动，后来由诱发的感觉活动驱动。在细胞水平上对单基因 ASD/ID 动物模型的研究揭示了神经元特性的多种改变，包括兴奋性、突触传递和神经可塑性的变化。然而，这种细胞变化如何影响神经回路的活动，以及这反过来又如何导致表征 ASD/ID 的表型多样性，目前仍不清楚。此外，最近的研究表明，其中一些变化是次要的，可能是由于主要缺陷的发育稳态补偿所致。在这种情况下，初始缺陷会导致细胞和/或网络活动发生改变，而细胞和/或网络活动又会通过细胞反馈过程得到补偿。因此，不同的主要原因（例如脆性 X 综合征中的可塑性缺陷和 SYNGAP 单倍体不足）可能会导致电路层面的类似缺陷。这种融合可能为针对成人所产生的细胞和回路功能障碍进行干预提供机会。解决这一知识空白需要全面了解成人 ASD/ID 的回路水平损伤。迄今为止，很少有研究调查疾病模型中除了癫痫发作等全局特征之外的网络活动，而且目前还不存在连贯的图像。在这里，我们计划使用 Fmr1-/y 和 Syngap+/- 小鼠作为两个成熟的 ASD/ID 模型，以确定这些突变如何影响神经活动通过皮层网络的传播，重点关注输入易于控制的感觉区域。目的在本项目中，我们将在 Fmr-/y 和 Syngap+/- 小鼠中检查以下三个假设：1。与野生型 (WT) 动物相比，ASD/ID 模型中的皮质整体活动持续发生变化，并且偏向于表征能力降低。2．单眼剥夺引起的皮质可塑性在 ASD/ID 模型中发生改变。 3．在小鼠模型中挽救行为 ASD/ID 表型的药物治疗将改变皮质群的活动和可塑性。为了揭示 ASD/ID 模型中的相关电路缺陷，我们将同时对初级视觉和顶叶皮质中的一千多个神经元使用 2 光子钙成像，并采用计算数据分析和建模。对不同中间神经元类型进行基因标记将能够对回路病理学进行详细剖析。我们将研究回路水平上经验依赖性可塑性的变化（迄今为止尚未尝试过），并评估药物救援对成人的全回路影响。总之，这些互补方法将（i）帮助将 ASD/ID 中的细胞和系统水平病理联系起来，（ii）探索治疗和干预的途径，以及（iii）为分析和解释大型神经群体记录提供新颖的计算工具。