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:
    10300008
  • 负责人:
  • 金额:
    $ 46.1万
  • 依托单位:
  • 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 2023-10-31
  • 项目状态:
    已结题

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 突触黏附分子(SAM)参与神经节细胞的形成、规范和维持。 神经元连接。与神经精神疾病相关的突变的通路分析 突触功能障碍作为一种病理生理机制,使SAMS成为更深层次研究的重要对象 功能探索。对人类的研究表明,神经毒素1α(NRXN1α)是一种突触前定位的 突触结构的组织者,是多发性神经精神疾病的部分穿透性遗传风险因素 疾病表现为目标导向加工的改变。我们证明了NRXN1α突变体表现出很强的健壮性 奖励如何塑造未来选择的变化,可能会提供一个神经电路框架来理解 与许多神经精神障碍相关的僵化和坚持不懈的行为。因此,这项提议 利用遗传、病毒、电生理和行为方法在小鼠中探索NRXN1α是如何 突变会导致神经回路发生变化,从而改变奖赏过程。NRXN1α广泛表达于 大脑,但在皮质和丘脑显示峰值水平,这两个部位的广泛投射到纹状体 规范奖励处理。使用逆行传播的病毒或区域特异性Cre转基因小鼠, 与我们的nrxn1α条件等位基因一起,我们将去除皮层、丘脑或投射神经元中的nrxn1α。 瞄准特定的纹状体隔间。小鼠将在我们的目标导向任务中进行测试,以揭示神经回路 其中,NRXN1α功能障碍会导致奖赏异常。为了阐明这些电路是如何 在NRXN1α突变体中发生生理变化,我们将从电生理学上探索大脑皮质突触强度 以及丘脑对DMS的输入。初步结果提示基础兴奋性突触驱动功能增强 两种DMS棘状神经元亚型。利用光遗传介导的传入招募和场归一化 突触效能测量,我们将确定NRXN1α突变体中输入特异性突触强度的变化。 此外,我们将使用融合通道视紫红质-Cre病毒的稀疏感染进入我们的NRXN1α 条件与急性切片电生理学一起允许选择性地招募NRXN1NRXN1零终端, 从而从机制上洞察由 Nrxn1α功能丧失。仅在NRXN1α突变体中存在电路特异性的生理变化就可以 而不是在功能上牵连到他们的目标导向功能障碍。为了证明这一点,并扩大我们对NRXN1α的分析 中断到电路层面,我们将使用基于病毒的技术进行活动调制,看看是否模仿 野生型小鼠中与NRXN1GDB相关的生理变化可产生突变型α表现或 对抗突变小鼠的这些生理变化是否能抑制突变行为 表型。总之,这项拟议的工作调查了目标导向的神经系统是如何被 突触和回路的变化伴随着NRXN1α的扰动,并可能为 了解奖赏加工中常见的回路变化--这是回路特异性干预的关键一步。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A blueprint for examining striatal control of cognition.
  • DOI:
    10.1016/j.tins.2022.05.009
  • 发表时间:
    2022-09
  • 期刊:
  • 影响因子:
    15.9
  • 作者:
    Holly, Elizabeth N.;Diaz-Hernandez, Edgar;Fuccillo, Marc, V
  • 通讯作者:
    Fuccillo, Marc, V
Ventral striatal islands of Calleja neurons control grooming in mice.
  • DOI:
    10.1038/s41593-021-00952-z
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    25
  • 作者:
    Zhang YF;Vargas Cifuentes L;Wright KN;Bhattarai JP;Mohrhardt J;Fleck D;Janke E;Jiang C;Cranfill SL;Goldstein N;Schreck M;Moberly AH;Yu Y;Arenkiel BR;Betley JN;Luo W;Stegmaier J;Wesson DW;Spehr M;Fuccillo MV;Ma M
  • 通讯作者:
    Ma M
Neurexin1⍺ differentially regulates synaptic efficacy within striatal circuits.
  • DOI:
    10.1016/j.celrep.2021.108773
  • 发表时间:
    2021-02-23
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Davatolhagh MF;Fuccillo MV
  • 通讯作者:
    Fuccillo MV
Copy number variants in neurexin genes: phenotypes and mechanisms.
Integrated anatomical and physiological mapping of striatal afferent projections.
  • DOI:
    10.1111/ejn.13829
  • 发表时间:
    2019-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Choi K;Holly EN;Davatolhagh MF;Beier KT;Fuccillo MV
  • 通讯作者:
    Fuccillo MV
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Marc V Fuccillo其他文献

Marc V Fuccillo的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Marc V Fuccillo', 18)}}的其他基金

Novel Role of a Ventral Striatal Circuit in Motor Control
腹侧纹状体电路在运动控制中的新作用
  • 批准号:
    10469310
  • 财政年份:
    2021
  • 资助金额:
    $ 46.1万
  • 项目类别:
Novel Role of a Ventral Striatal Circuit in Motor Control
腹侧纹状体电路在运动控制中的新作用
  • 批准号:
    10676802
  • 财政年份:
    2021
  • 资助金额:
    $ 46.1万
  • 项目类别:
A Novel Role for Local Striatal Interneuron Regulation of Goal-Directed Action
局部纹状体中间神经元调节目标导向行动的新作用
  • 批准号:
    10338165
  • 财政年份:
    2020
  • 资助金额:
    $ 46.1万
  • 项目类别:
A Novel Role for Local Striatal Interneuron Regulation of Goal-Directed Action
局部纹状体中间神经元调节目标导向行动的新作用
  • 批准号:
    10558680
  • 财政年份:
    2020
  • 资助金额:
    $ 46.1万
  • 项目类别:
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
  • 批准号:
    10058775
  • 财政年份:
    2017
  • 资助金额:
    $ 46.1万
  • 项目类别:
Linking Synaptic and Cognitive Deficits in a Model of Neuropsychiatric Disease
将神经精神疾病模型中的突触和认知缺陷联系起来
  • 批准号:
    9069064
  • 财政年份:
    2012
  • 资助金额:
    $ 46.1万
  • 项目类别:
Linking Synaptic and Cognitive Deficits in a Model of Neuropsychiatric Disease
将神经精神疾病模型中的突触和认知缺陷联系起来
  • 批准号:
    8547839
  • 财政年份:
    2012
  • 资助金额:
    $ 46.1万
  • 项目类别:
Linking Synaptic and Cognitive Deficits in a Model of Neuropsychiatric Disease
将神经精神疾病模型中的突触和认知缺陷联系起来
  • 批准号:
    8424086
  • 财政年份:
    2012
  • 资助金额:
    $ 46.1万
  • 项目类别:
Synaptic Analysis of Neuroligin1 function
Neuroligin1 功能的突触分析
  • 批准号:
    7676907
  • 财政年份:
    2009
  • 资助金额:
    $ 46.1万
  • 项目类别:
Synaptic Analysis of Neuroligin1 function
Neuroligin1 功能的突触分析
  • 批准号:
    7895499
  • 财政年份:
    2009
  • 资助金额:
    $ 46.1万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 46.1万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了