Molecular and Circuit Mechanisms of Neurexin1-Mediated Goal-Directed Dysfunction

Neurexin1 介导的目标导向功能障碍的分子和电路机制

基本信息

批准号：
10058775
负责人：
Marc V Fuccillo
金额：
$ 46.1万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058775
关键词：
Acute Affect Alleles Anatomy Anterior Architecture Behavior Behavioral Behavioral Assay Brain Cell Adhesion Molecules Cells Cognitive Corpus striatum structure Dissection Electrophysiology (science)Exhibits Feedback Foundations Functional disorder Future Genes Genetic Goals Human Impairment Infection Intervention Lead Link Maintenance Measures Mediating Methods Molecular Motor Mus Mutant Strains Mice Mutation Mutation Analysis Neurons Outcome Parafascicular Nucleus Pathway Analysis Performance Physiological Physiology Rewards Shapes Site Slice Synapses System Techniques Testing Thalamic structure Therapeutic Intervention Transgenic Mice Viral Virus Wild Type Mouse Work base behavioral phenotyping cell type cingulate cortex daily functioning genetic risk factor insight loss of function mutant neural circuit neuropsychiatric disorder novel optogenetics presynaptic recruit relating to nervous system retrograde transport reward processing success synaptic inhibition

项目摘要

Project Summary Synaptic adhesion molecules (SAMs) are implicated in the formation, specification and maintenance of neuronal connections. Pathway analyses of mutations associated with neuropsychiatric disease implicate synaptic dysfunction as a pathophysiological mechanism, making SAMs important candidates for deeper functional exploration. Studies in humans suggest that Neurexin1α (Nrxn1α), a presynaptically-localized organizer of synaptic architecture, is a partially penetrant genetic risk factor for multiple neuropsychiatric diseases displaying altered goal-directed processing. We demonstrate that Nrxn1α mutants exhibit robust changes in how rewards shape future choices, and may provide a neural circuit framework for understanding inflexible and perseverative actions associated with many neuropsychiatric disorders. This proposal therefore employs genetic, viral, electrophysiological and behavioral approaches in mice to explore how Nrxn1α mutations lead to neural circuit changes capable of altering reward processing. Nrxn1α is widely expressed in brain, but exhibits peak levels throughout cortex and thalamus, sites whose extensive projections to striatum regulate reward processing. Using retrograde-transported viruses or region-specific Cre transgenic mice, together with our Nrxn1α conditional allele, we will ablate Nrxn1α from cortex, thalamus or projection neurons targeting specific striatal compartments. Mice will be tested in our goal-directed tasks to reveal neural circuits wherein Nrxn1α dysfunction precipitates reward abnormalities. To elucidate how these circuits are physiologically altered in Nrxn1α mutants, we will electrophysiologically probe the synaptic strength of cortical and thalamic inputs to the DMS. Preliminary results suggest enhancements in basal excitatory synaptic drive onto both DMS spiny neuron subtypes. Using optogenetic-mediated afferent recruitment and field-normalized synaptic efficacy measures, we will determine input-specific synaptic strength changes in Nrxn1α mutants. Furthermore, we will employ sparse infections of a fused channelrhodopsin-Cre virus into our Nrxn1α conditionals together with acute slice electrophysiology to permit selective recruitment of Nrxn1α-null terminals, thereby gaining mechanistic insight into the cell-autonomous anatomical and synaptic abnormalities caused by Nrxn1α loss-of-function. The mere presence of circuit-specific physiological changes in Nrxn1α mutants does not functionally implicate them in goal-directed dysfunction. To prove this, and broaden our analyses of Nrxn1α disruption to a circuit level, we will use viral-based techniques for activity modulation to see whether mimicking Nrxn1α-associated physiological changes in wildtype mice can produce mutant-like GDB performance or whether counteracting these physiological alterations in mutant mice can suppress the mutant behavioral phenotype. Together, the proposed work investigates how goal-directed neural systems are altered by the synaptic and circuit changes accompanying Nrxn1α perturbation, and may provide a foundation for understanding common circuit changes in reward processing - a key step for circuit-specific intervention.

项目摘要突触粘附分子（SAM）在形成，规范和维护中实施神经元连接。与神经精神疾病有关的突变的途径分析突触功能障碍是一种病理生理机制，使SAMS成为重要的候选者功能探索。对人类的研究表明，神经毒素1α（NRXN1α），一种突触前定位的突触结构的组织者是多个神经精神病学的部分渗透遗传危险因素显示改变目标导向处理的疾病。我们证明了NRXN1α突变体暴露了鲁棒奖励如何塑造未来选择的变化，并可能提供一个神经电路框架以理解与许多神经精神疾病相关的僵化和毅力。因此，该建议在小鼠中采用遗传，病毒，电生理和行为方法来探索NRXN1α 突变会导致能够改变奖励处理的神经回路变化。 NRXN1α在大脑，但在整个皮质和丘脑中都表现出峰值水平，其广泛的纹状体项目调节奖励处理。使用逆行传播病毒或特异性的CRE转基因小鼠，与我们的NRXN1α条件等位基因一起，我们将从皮质，丘脑或投影神经元中消除NRXN1α 针对特定的纹状体室。小鼠将在我们的目标指导任务中进行测试，以揭示神经回路其中NRXN1α功能障碍会沉淀出奖励异常。阐明这些电路的方式在生理上改变了NRXN1α突变体，我们将在电生理上探测皮质的突触强度和DMS的丘脑输入。初步结果表明基本兴奋性突触驱动器的增强在两个DMS刺神经元亚型上。使用光遗传学介导的传入募集和现场归一化突触效率措施，我们将确定NRXN1α突变体的输入特异性合成强度变化。此外，我们将在我们的NRXN1α中采用融合通道Ropopsin-Cre病毒的稀疏感染条件与急性切片电生理学一起允许选择性募集NRXN1α无效末端，从而获得对细胞自治的解剖和突触异常的理解。 NRXN1α功能丧失。 NRXN1α突变体中的电路特异性生理变化仅存在在功能上没有将它们牵涉到目标指导的功能障碍中。证明这一点，并扩大了我们对NRXN1α的分析破坏电路水平，我们将使用基于病毒的技术进行活动调制，以查看是否模仿野生型小鼠中与NRXN1α相关的身体变化可以产生类似突变的GDB性能或在突变小鼠中抵消这些身体改变是否可以抑制突变体行为表型。拟议中的工作一起研究了目标指导的神经系统如何改变发生NRXN1α扰动发生的突触和电路变化，可能为了解奖励处理中的通用电路变化 - 特定电路干预的关键步骤。