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
基本信息
- 批准号:10338165
- 负责人:
- 金额:$ 56.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-07 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAnatomyAnimalsAutomobile DrivingBehaviorBehavioralCalciumCalcium SignalingCellsCognitiveComplexCorpus striatum structureDataDendritesDopamineDown-RegulationElectrophysiology (science)Excitatory SynapseExhibitsGoalsImageInterneuronsLaser Scanning MicroscopyLearningLiteratureMapsMeasuresMediatingMediator of activation proteinMethodsMicrodialysisMotivationMotorMotor outputNeuronsOperant ConditioningOpticsOutcomeOutputPathway interactionsPerformancePeriodicityPharmacologyPhysiologicalPopulationPopulation HeterogeneityProcessPropertyRegulationRewardsRoleScanningShapesSignal TransductionSliceSpecificitySynapsesSynaptic plasticitySystemTestingThalamic structureVertebral columnViralWorkcell typedopaminergic neurondriving behaviorfollow-upimprovedin vivoin vivo imaginginhibitory neuronintegration sitemotor controlneural circuitneuropsychiatric disorderneurotransmissionnoveloptogeneticsresponsesensortransmission processtwo photon microscopytwo-photonvirus genetics
项目摘要
Summary
Deficits in goal-directed behavior are the hallmark of many neuropsychiatric diseases. The dorsomedial
striatum (DMS) has emerged as a key mediator of goal-directed actions, serving as a critical node for
integration of sensorimotor, motivational, and cognitive information. Nevertheless, the cellular mechanisms
mediating these fundamental behaviors remain largely unclear. We have recently discovered that the low
threshold spiking interneuron (LTSI) subtype within the DMS is a key regulator of early goal-directed actions.
Performing the first in vivo imaging of this cell type during behavior, we uncovered robust reward-related
activity that was down-regulated as animals learned an instrumental response task. Via subsequent neural
circuit manipulations, we demonstrated that this reduction in LTSI activity could drive learning, while sustained
activity slowed learning. In this proposal, we follow up these initial studies to explore the cellular and neural
circuit mechanisms of these effects. We hypothesize that downregulation of LTSIs enhances the
responsiveness of striatal circuits, a key step in driving behavior during early learning. We suggest LTSI
downmodulation enhances striatal gain via two synergistic mechanisms: (1) increased local striatal dopamine
levels and (2) enhanced corticostriatal input to SPNs via reductions in feedforward inhibition. Preliminary work
demonstrates that LTSI inhibition can enhance striatal DA release, which may be an underlying mechanism
driving enhanced acquisition. We will test whether LTSI inhibition enhances striatal DA during learning via
calcium imaging of DA neuron terminals and virally-expressed DA sensors. To better understand the
mechanism of this modulation, we will employ acute slice electrochemical measures of optically-evoked
dopamine release during manipulation of LTSI activity. Finally, we will use circuit-targeted manipulations of DA
neurons projecting to DMS to test whether enhanced striatal DA release is a mediator of the enhanced learning
accompanying LTSI down regulation. Existing literature and preliminary data also suggest that LTSI are
engaged in feed-forward control of SPN dendrites – a key site for the integration of incoming neural signals.
First, we describe both anatomically and electrophysiologically, how LTSIs integrate within key cortico- and
thalamostriatal circuits. Next we use 2-photon microscopy to zoom into the level of SPN dendrites and synaptic
spines, to understand how LTSIs regulate calcium signaling in these important compartments. In parallel, we
explore long-term synaptic changes that accompany learning. Finally, we test whether LTSI-mediated gain
changes within specific striatal circuits accounts for altered learning. When completed, these aims will provide
our first glimpse into how striatal LTSIs gate learning, improving our understanding of the cellular mechanisms
modulating goal-directed behavior.
总结
目标导向行为的缺陷是许多神经精神疾病的标志。背内侧
纹状体(DMS)已经成为目标导向行动的关键调解人,作为一个关键节点,
感觉运动、动机和认知信息的整合。然而,细胞机制
调节这些基本行为的机制在很大程度上仍不清楚。我们最近发现,
DMS内的阈值尖峰中间神经元(LTSI)亚型是早期目标导向动作的关键调节器。
在行为过程中对这种细胞类型进行了首次体内成像,我们发现了与奖励相关的强有力的
当动物学习工具性反应任务时,这种活性被下调。通过随后的神经
电路操作,我们证明了LTSI活动的减少可以驱动学习,同时持续
活动减缓了学习。在这个建议中,我们跟进这些初步研究,以探索细胞和神经
这些效应的电路机制。我们假设LTSIs的下调增强了
纹状体回路的反应性,在早期学习过程中驾驶行为的关键步骤。我们建议LTSI
下调通过两种协同机制增强纹状体增益:(1)增加局部纹状体多巴胺
水平和(2)通过减少前馈抑制增强皮质纹状体对SPN的输入。前期工作
表明LTSI抑制可以增强纹状体DA释放,这可能是一个潜在的机制
推动增强收购。我们将通过以下方式测试LTSI抑制是否在学习过程中增强纹状体DA
DA神经元末梢和病毒表达的DA传感器的钙成像。更好地了解
这种调制的机制,我们将采用急性切片电化学措施的光诱发
多巴胺释放过程中操纵LTSI活动。最后,我们将使用DA的电路目标操作
投射到DMS的神经元,以测试是否增强的纹状体DA释放是增强学习的介质
伴随着LTSI下调。现有的文献和初步数据也表明,LTSI是
参与SPN树突的前馈控制-输入神经信号整合的关键部位。
首先,我们从解剖学和电生理学两方面描述了LTSI如何整合到关键的皮质和
丘脑纹状体回路接下来,我们使用双光子显微镜放大到SPN树突和突触的水平。
脊椎,了解LTSIs如何调节这些重要的车厢钙信号。同时,我们
探索伴随学习的长期突触变化。最后,我们测试LTSI介导的增益是否
特定纹状体回路内的变化解释了学习的改变。这些目标完成后,
我们第一次看到纹状体LTSIs如何控制学习,提高了我们对细胞机制的理解,
调节目标导向行为
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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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:
$ 56.89万 - 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:
$ 56.89万 - 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:
$ 56.89万 - 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:
10300008 - 财政年份:2017
- 资助金额:
$ 56.89万 - 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:
$ 56.89万 - 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:
$ 56.89万 - 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:
$ 56.89万 - 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:
$ 56.89万 - 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:
$ 56.89万 - 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:
$ 56.89万 - 项目类别:
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