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

探索与 Neurexin1 α 突变小鼠的动作控制缺陷相关的皮质纹状体动力学

• 批准号: 10606118
• 负责人: Sarah Ferrigno
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-04 至 2025-11-03
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606118
• 关键词: Acute; Area; Attention deficit hyperactivity disorder; Auditory; Automobile Driving; Basal Ganglia; Behavior; Behavior Control; Behavior assessment; Behavioral; Biological Assay; Cell Adhesion Molecules; Cell Nucleus; Characteristics; Code; Copy Number Polymorphism; Corpus striatum structure; Cues; Data; Disease; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dorsal; Electrophysiology (science); Event; Exhibits; Functional disorder; Ganglia; Genes; Gilles de la Tourette syndrome; Head; Impairment; Impulsivity; Knockout Mice; Medial; Mediating; Modification; Motor; Motor Activity; Motor Pathways; Mus; Mutant Strains Mice; Mutation; Neurodevelopmental Disorder; Neurons; Output; Pathology; Pathway interactions; Pattern; Performance; Phenotype; Population; Prefrontal Cortex; Process; Regulation; Rewards; Risk; Running; Site; Slice; Structure; Symptoms; Synapses; Task Performances; Techniques; Testing; Thalamic structure; Variant; Water; autism spectrum disorder; disorder risk; extracellular; in vivo; insight; motor control; neural; neural circuit; neuromechanism; neuropsychiatric disorder; neurotransmission; novel; optogenetics; presynaptic; receptor expression; recruit; selective expression; synaptic function; treadmill

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.

项目概要： 一些神经发育障碍包括自闭症谱系障碍，注意力- 缺陷/多动障碍和图雷特综合征表现出特征性运动相关症状， 重复或冲动的行为模式。这些行为很可能是失调行为的结果 通过皮质-基底-丘脑通路中断介导的控制机制。然而，目前还没有 我理解这些回路的改变如何引起这些实验中常见的动作控制缺陷。 紊乱编码突触粘附分子（如Neurexin 1 α）的基因拷贝数变异 （NRxN 1 α），已被证明赋予这些疾病的风险显着增加，然而，潜在的 神经病理学目前尚不清楚。最近在急性纹状体切片中的发现表明， NRXN 1 α功能导致内侧前额叶皮层输入到间接通路的突触强度降低 的背侧纹状体，提供了一个潜在的神经机制，不规则的行动控制。但目前尚不清楚 这些突触缺陷是否会导致与动作控制相关的更大尺度神经动力学的变化 体内功能障碍。我假设这些Nrxn 1 α突变通过以下途径驱动动作控制缺陷（Aim 1）： Nrxn 1a中特异于间接通路（Aim 2）的突变相关皮质纹状体回路改变 KO小鼠。为了分析动作控制的多个关键方面，我将采用一种新的基于铣床的操作性任务， 允许对动作的启动、抑制和调节进行全面的研究。使用体内双位点 电生理技术，我计划描述潜在的皮质纹状体人口招聘有关， Nrxn 1 α WT和Nrxn 1 α KO两种额-纹状体回路（mPFC→DMS和M2→DLS）的任务性能 小鼠这些发现将提供有价值的洞察神经病理参与许多神经精神疾病 和神经发育障碍以及阐明皮质纹状体神经机制参与行动 控制调节