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:10558680
- 负责人:
- 金额:$ 54.42万
- 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 MicroscopyLearningLiteratureMapsMeasuresMediatingMediatorMethodsMicrodialysisMotivationMotorMotor outputNeuromodulatorNeuronsOperant ConditioningOpticsOutcomeOutputPathway interactionsPerformancePeriodicityPharmacologyPhysiologicalPopulationPopulation HeterogeneityProcessPropertyRegulationRewardsRoleScanningShapesSignal TransductionSliceSpecificitySynapsesSynaptic plasticitySystemTestingThalamic structureVertebral columnViralWorkcell typedopaminergic neurondriving behaviorfollow-upimprovedin vivoin vivo imaginginhibitory neuronintegration sitemotor controlneural circuitneuronal excitabilityneuropsychiatric 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
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)
专利数量(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:
$ 54.42万 - 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:
$ 54.42万 - 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:
$ 54.42万 - 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:
$ 54.42万 - 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:
$ 54.42万 - 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:
$ 54.42万 - 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:
$ 54.42万 - 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
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Synaptic Analysis of Neuroligin1 function
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Synaptic Analysis of Neuroligin1 function
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7895499 - 财政年份:2009
- 资助金额:
$ 54.42万 - 项目类别:
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