Predictive coding impairment in mouse models of autistic spectrum disorders

理论工作和心理物理学研究导致了一种假设，即自闭症表型可能是预测能力潜在损害的表现。在这个理论框架下，自闭症的特点是在更新环境的内部表征时，感觉信息的权重更大。随着预测技能的下降，自闭症患者面临的环境是事件发生得出乎意料且没有原因。因此，坚持一成不变或千篇一律和重复的行为可被视为试图在一个充满意外变化的世界中提供一种可预测环境的令人放心的感觉。测试预测编码的假设需要一个实验设计，其中预测受到实验的限制。一种可能性是利用习得的行为和感觉反馈之间的联系。例如，感觉反馈以一种可预测的方式耦合到运动输出。因此，实验假设是，在运动过程中产生的反馈到感觉区域的信号应该构成对感觉反馈的经验依赖的预测。最近对小鼠初级视觉皮质(V1)的研究测试了自上而下向V1的投射是否带有基于运动输出的视觉输入预测。使用虚拟现实环境结合双光子钙成像，这些实验已经确定了皮质区域前扣带回(ACC)和V1之间的视觉血流预测的神经元电路(Leinweber等人，2017年)。目的本项目的目的是测试ASD小鼠模型的初级视皮层的视觉流量预测是否受到干扰。我们计划使用脆性X综合征(Fmr1-/y)和SynGAP单倍性不足(Syngap1+/-)的小鼠模型作为两个成熟的模型，以确定这些突变如何影响神经活动通过皮质网络的传播，重点放在输入容易控制的感觉区域。具体地说，该项目围绕三个目标组织：目标1：表征脆性X综合征(Fmr1-/y)和SynGAP单倍性功能不全(Syngap1+/-)小鼠模型V1中ACC轴突的运动相关活动。目的2：通过建立V1回路的计算模型，确定测量到的自上而下输入对V1活动的贡献。目的3.测试挽救Fmr1-/y和Syngap1+/-小鼠皮质功能障碍的药物治疗。参考Leinweber、Marcus、Daniel R.Ward、Jan M.Sobczak、Alexander Attinger和Georg B.Keller。2017年。“老鼠大脑皮层中用于视觉流量预测的感觉运动回路。”神经元95(6)：1420-1432.e5.2017年。

Theoretical work and psychophysical studies have led to the hypothesis that autism phenotypes may be manifestations of an underlying impairment in predictive abilities. Within this theoretical framework, autism is characterized by a greater weighting of sensory information in updating internal representations of the environment. With compromised prediction skills, an individual with autism faces an environment in which events occur unexpectedly and without cause. Therefore, an insistence on sameness or stereotyped and repetitive behaviours can be seen as attempts to provide a reassuring sense of a predictable environment in a world otherwise filled with unexpected changes. Testing the hypothesis of predictive coding requires an experimental design in which predictions are constrained experimentally. One possibility is to use learned associations between behaviour and sensory feedback. For example, sensory feedback couples in a predictable way to motor output. Hence, the experimental assumption is that signals generated during movement that are fed back to sensory areas should constitute an experience-dependent prediction of sensory feedback. Recent studies in the mouse primary visual cortex (V1) have tested whether top-down projections to V1 carry a prediction of visual input based on motor output. Using a virtual reality environment combined with two- photon calcium imaging, these experiments have identified a neuronal circuit for visual flow predictions between the cortical area Anterior Cingulate Cortex (ACC) and V1 (Leinweber et al., 2017). Aims The aim of this project is to test whether visual flow predictions are disrupted in the primary visual cortex of mouse models of ASDs. We plan to use mouse models of fragile X syndrome (Fmr1 -/y ), and SYNGAP happloinsufficiency (Syngap1 +/- ), as two well established models to determine how these mutations affect the propagation of neural activity through cortical networks, focussing on sensory areas where inputs are readily controllable. Specifically, the project is organized around 3 aims: Aim 1: To characterize movement-related activity of ACC axons in V1 of mouse models of fragile X syndrome (Fmr1 -/y ), and SYNGAP happloinsufficiency (Syngap1 +/- ). Aim 2: To establish the contribution of measured top-down inputs to V1 activity through the development of a computational model of the V1 circuit. Aim 3. To test pharmacological treatments that rescue cortical dysfunction in Fmr1 -/y and Syngap1 +/- mice.ReferencesLeinweber, Marcus, Daniel R. Ward, Jan M. Sobczak, Alexander Attinger, and Georg B. Keller. 2017. "A Sensorimotor Circuit in Mouse Cortex for Visual Flow Predictions." Neuron 95 (6): 1420-1432.e5. 2017.