Exploring corticostriatal dynamics associated with action control deficits in Neurexin1 alpha mutant mice

项目总结： 一些神经发育障碍，包括自闭症谱系障碍，注意力- 缺陷/多动障碍和抽动症表现出典型的运动相关症状，如 重复的或冲动的行为模式。这些行为有可能是行为失控的结果。 通过皮质-基底-丘脑通路中断介导的控制机制。然而，它目前还不是 了解这些回路中的变化如何导致在这些 精神错乱。突触黏附分子编码基因的拷贝数变异，如神经毒素1α (Νrxn1α)，已被证明显著增加了这些疾病的风险，然而，潜在的 神经病因目前尚不清楚。最近在急性纹状体切片上的发现表明， Νrxn1α功能导致间接通路的内侧前额叶皮质输入突触强度降低 背侧纹状体，为控制不规则动作提供了潜在的神经机制。然而，目前还不清楚 这些突触缺陷是否会导致与动作控制相关的更大规模的神经动力学发生变化 体内功能障碍。我假设这些Νrxn1α突变通过以下途径驱动动作控制缺陷(目标1 Nrxn1a中间接通路(AIM 2)特异的突变相关皮质纹状体回路改变 Ko老鼠。为了分析动作控制的多个关键方面，我将采用一种基于跑步机的新型操作任务，该任务 允许对动作启动、抑制和调制进行全面研究。利用体内的双部位 电生理技术，我计划描述潜在的皮质纹状体种群招募相关 在→Rxn1→WT和ΝRxn1αKO中的两个前纹状体回路(mPFCΝDMS和M2αDLS)的任务绩效 老鼠。这些发现将为许多神经精神病学涉及的神经病理学提供有价值的见解。 和神经发育障碍，以及阐明参与作用的皮质纹状体神经机制 控制性监管。

Project Summary: A number of neurodevelopmental disorders including autism spectrum disorder, attention- deficit/hyperactivity disorder and Tourette syndrome exhibit characteristic motor-related symptoms such as repetitive or impulsive action patterns. It is possible that these behaviors are a result of dysregulated action control mechanisms mediated via cortico-basal-thalamic pathway disruption. However, it is not currently understood how alterations in these circuits give rise to the deficits in action control commonly observed in these disorders. Copy number variation of genes encoding for synaptic adhesion molecules, such as Neurexin1α (Νrxn1α), have been shown to confer a significantly increased risk for these disorders, however, the underlying neural etiopathology is currently unknown. Recent findings in acute striatal slices have revealed that loss of Νrxn1α function results in decreased synaptic strength of medial prefrontal cortical inputs to the indirect pathway of the dorsal striatum, providing a potential neural mechanism for irregular action control. However, it is unclear whether these synaptic deficits confer variations to larger scale neural dynamics related to action control dysfunction in vivo. I hypothesize that these Νrxn1α mutations drive action control deficits (Aim 1) via mutation-associated corticostriatal circuit alterations specific to the indirect pathway (Aim 2) in Nrxn1a KO mice. To assay multiple key aspects of action control, I will employ a novel treadmill-based operant task that allows for the comprehensive study of action initiation, suppression, and modulation. Using dual-site in vivo electrophysiological techniques, I plan to describe the underlying corticostriatal population recruitment related to task performance in two fronto-striatal circuits (mPFC→DMS and M2→DLS) in both Νrxn1α WT and Νrxn1α KO mice. These findings will provide valuable insight into the neural pathology involved in many neuropsychiatric and neurodevelopmental disorders as well as elucidate corticostriatal neural mechanisms involved in action control regulation.