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

该项目的主要目的是了解单基因突变在自闭症谱系障碍（ASD）和智力残疾（ID）动物模型中皮层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，最初由自发性驱动，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，它仍然在很大程度上是未知的，这种细胞的变化如何影响神经回路中的活动，以及如何，这反过来，导致ASD/ID的表型特征的多样性。此外，最近的工作表明，这些变化中的一些是次要的性质，并可能导致从一个发展的稳态补偿的主要缺陷。在这种情况下，初始缺陷导致改变的细胞和/或网络活动，这反过来又被细胞反馈过程补偿。因此，不同的主要原因，例如脆性X综合征和SYNGAP单倍不足中的可塑性缺陷，可能会导致回路水平的类似缺陷。这种融合可能为针对成人细胞和电路功能障碍的干预提供了机会。解决这一知识差距需要全面了解成人ASD/ID的电路水平损伤。到目前为止，很少有研究调查疾病模型中的网络活动，而不是全球特征，如癫痫发作，目前还没有连贯的图片存在。在这里，我们计划使用Fmr 1-/y和Syngap+/-小鼠作为两个完善的ASD/ID模型，以确定这些突变如何影响通过皮层网络的神经活动的传播，重点是感觉区域，在那里输入是容易controlled.AimsWe将检查以下三个假设在Fmr-/y和Syngap+/-小鼠在这个项目中：1。与野生型（WT）动物相比，ASD/ID模型中的皮质整体活动一致地改变，并且偏向于降低的代表性能力。在ASD/ID模型中，单眼剥夺诱导的皮层可塑性改变.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体活性和可塑性。为了揭示ASD/ID模型中相关的电路缺陷，我们将使用双光子钙成像同时在初级视觉和顶叶皮质中超过1000个神经元，并采用计算数据分析和建模。不同类型的中间神经元的遗传标记将使电路病理的详细解剖。我们将调查经验依赖性可塑性在回路水平的变化，这是迄今为止还没有尝试，并评估药物救援在成人中的回路范围的影响。总之，这些互补的方法将（i）帮助ASD/ID中的细胞和系统水平病理学相关，（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的计算工具。

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.