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 突触粘附分子(SAM)参与了突触膜的形成、特化和维持。 神经元连接与神经精神疾病相关的突变的途径分析 突触功能障碍作为一种病理生理机制,使SAM的重要候选人,更深的 功能探索对人类的研究表明,Neurexin 1 α(Nrxn 1 α),一种突触前定位的神经递质, 突触结构的组织者,是多种神经精神疾病的部分外显遗传危险因素, 显示目标导向加工改变的疾病。我们证明,Nrxn 1 α突变体表现出强大的 改变奖励如何塑造未来的选择,并可能提供一个神经回路框架, 与许多神经精神疾病有关的不灵活和顽固的行为。因此,这项建议 在小鼠中采用遗传、病毒、电生理和行为方法来探索Nrxn 1 α 突变导致神经回路的变化,能够改变奖励处理。Nrxn 1 α在哺乳动物中广泛表达, 大脑,但在整个皮质和丘脑中显示出峰值水平,这些部位向纹状体的广泛投射 规范奖励处理。使用逆行转运病毒或区域特异性Cre转基因小鼠, 与我们的Nrxn 1 α条件等位基因一起,我们将从皮层、丘脑或投射神经元中清除Nrxn 1 α, 针对特定的纹状体区室老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Nrxn 1 α功能障碍导致奖励异常。为了阐明这些电路是如何 在Nrxn 1 α突变体的生理改变,我们将电生理探测皮层突触强度 和丘脑对DMS的输入。初步结果表明基础兴奋性突触驱动增强 两种DMS多刺神经元亚型。使用光遗传学介导的传入募集和场标准化 突触效能的措施,我们将确定输入特异性突触强度的变化在Nrxn 1 α突变体。 此外,我们将采用融合的通道视紫红质-Cre病毒的稀疏感染到我们的Nrxn 1 α中, 条件刺激与急性切片电生理学一起允许选择性募集Nrxn 1 α-null终末, 从而获得对细胞自主解剖学和突触异常的机制性洞察, Nrxn 1 α功能丧失。在Nrxn 1 α突变体中,仅仅存在电路特异性生理变化就可以证明, 而不是在功能上将他们与目标导向功能障碍联系起来。为了证明这一点,并扩大我们对Nrxn 1 α的分析 中断到电路水平,我们将使用基于病毒的活动调制技术,看看是否模仿 野生型小鼠中Nrxn 1 α相关的生理变化可产生类似于MUR的GDB表现, 是否抵消突变小鼠的这些生理变化可以抑制突变小鼠的行为, 表型总之,拟议的工作调查如何目标导向的神经系统被改变的 突触和电路的变化伴随着Nrxn 1 α扰动,并可能提供了基础, 了解奖励处理中常见的回路变化-这是回路特定干预的关键步骤。

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
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Marc V Fuccillo其他文献

Marc V Fuccillo的其他文献

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{{ 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:

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