Prefrontal circuit mechanisms of threat conditioning
Prefrontal circuit mechanisms of threat conditioning
批准号:
10332742
负责人:
Roger L Clem
金额:
$42.12万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-04-01 至 2023-12-31
关键词:
AddressAmygdaloid structureAnimalsAreaAttenuatedAuditoryAxonBehaviorBehavioralBrainBrain regionCalciumCellsChemosensitizationComplexConditioned StimulusCre driverDataDesire for foodDiseaseDisinhibitionDorsalElectrophysiology (science)EmotionalExhibitsExtinction (Psychology)FreezingFrightGeneticGenetic RecombinationGoalsHumanHyperactivityImageInterneuronsInvestigationLabelLearningMedialMediatingMemoryModelingModificationMood DisordersMusNeuronal PlasticityNeuronsNucleus AccumbensOutputPanicPanic DisorderParvalbuminsPathologicPeptidesPhobiasPopulationPost-Traumatic Stress DisordersPrefrontal CortexProcessRecruitment ActivityReportingResearchRodentRoleSignal TransductionSliceSomatostatinSourceStimulusSynapsesSynaptic TransmissionSynaptic plasticitySystemTechniquesTestingThalamic structureTimeViralWorkbasebehavioral outcomebehavioral responseclassical conditioningconditioned fearconditioningemotion dysregulationemotional reactionexcitatory neuronexperienceexperimental studyimprovedin vivomicroendoscopemidbrain central gray substanceneglectneocorticalneural circuitoptogeneticsrecruitstimulus processingtransmission process
中文摘要
精神疾病,如恐惧症,恐慌和创伤后应激障碍(PTSD)与
与恐惧有关的行为这部分归因于越来越多的收购和表达,
威胁记忆,当在威胁的情况下遇到无害的刺激时发生
成为防御性情绪反应的有力触发器。研究表明,这种形式的记忆
参与前边缘皮层,这是一个啮齿动物的大脑区域,类似于大脑中的病理性过度活跃区域,
人类内侧前额叶皮层(mPFC)。海马兴奋性神经元被认为介导记忆
通过向关键的下游大脑区域发出信号来表达。然而,回路和突触机制
这些细胞的潜在记忆特异性募集仍然知之甚少。本项目的目的是
确定小鼠中与威胁记忆形成相关的前边缘突触变化,阐明
这些修改发生的神经回路,并定义特定的前边缘输出连接,
介导威胁相关行为。基于初步的实验,这项工作将集中在稀疏人口的
抑制性中间神经元表达肽标记生长抑素,并表现出兴奋性突触增加,
威胁学习后的活动。我们的中心假设是,这些细胞经历了刺激相关的
活动后,学习,他们的功能,以抑制含小白蛋白的中间神经元,从而
缓解对兴奋性神经元放电的主要制动。在目标1中,我们将使用脑切片电生理学来
检查介导生长抑素中间神经元活性升高的突触以及它们与
小清蛋白中间神经元。在目标2中,我们将使用光遗传学和基于钙的成像技术,
动物以测试生长抑素和小清蛋白中间神经元在威胁记忆表达中的作用。最后在
目的3,我们将确定特定的兴奋性群体介导的行为结果的生长抑素
中间神经元操作以及建立这些神经元提供下游脑区域
突触输入这个项目代表了第一次尝试建立情绪学习如何改变复杂的
抑制刺激处理,以支持mPFC记忆功能,并将确定潜在的目标,
减弱病理活动和相关行为。
英文摘要
Psychiatric conditions such as phobia, panic and post-traumatic stress disorder (PTSD) are associated with
heightened fear-related behavior. This has been attributed in part to increased acquisition and expression of
threat memory, which occurs when an innocuous stimulus encountered under threatening circumstances
becomes a potent trigger for defensive emotional reactions. Research indicates that this form of memory
engages the prelimbic cortex, a rodent brain region that is analogous to an area of pathological hyperactivity in
the human medial prefrontal cortex (mPFC). Prelimbic excitatory neurons are thought to mediate memory
expression by signaling to key downstream brain regions. However, the circuit and synaptic mechanisms
underlying memory-specific recruitment of these cells remain poorly understood. The purpose of this project is
to identify prelimbic synaptic changes associated with threat memory formation in mice, to elucidate the role of
neural circuits where these modifications occur, and to define specific prelimbic output connections that
mediate threat-related behaviors. Based on preliminary experiments, this work will focus sparse populations of
inhibitory interneurons that express the peptide marker somatostatin and exhibit increased excitatory synaptic
activity after threat learning. Our central hypothesis is that these cells undergo an increase in stimulus-related
activity after learning and that they function to suppress parvalbumin-containing interneurons and thereby
relieve a major brake on excitatory neuronal firing. In Aim 1, we will use brain slice electrophysiology to
examine synapses mediating elevated activity of somatostatin interneurons as well as their interaction with
parvalbumin interneurons. In Aim 2, we will use optogenetics and calcium-based imaging in freely behaving
animals to test the role of somatostatin and parvalbumin interneurons in threat memory expression. Finally, in
Aim 3, we will identify specific excitatory populations mediating behavioral outcomes of somatostatin
interneuron manipulations as well as establish downstream brain regions to which these neurons provide
synaptic input. This project represents the first attempt to establish how emotional learning alters complex
inhibitory stimulus processing to support mPFC memory functions, and will identify potential targets for
attenuating pathological activity and associated behaviors.
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DOI:
10.1016/j.nlm.2021.107504
发表时间:
2021-10
期刊:
Neurobiology of learning and memory
影响因子:
2.7
作者:
[Cummings KA, Lacagnina AF, Clem RL]
通讯作者:
Clem RL
DOI:
10.1016/j.neuron.2022.07.004
发表时间:
2022-09-21
期刊:
NEURON
影响因子:
16.2
作者:
[Cummings, Kirstie A., Bayshtok, Sabina, Dong, Tri N., Kenny, Paul J., Clem, Roger L.]
通讯作者:
Clem, Roger L.
DOI:
10.1016/j.brainresbull.2017.11.016
发表时间:
2018-07
期刊:
Brain research bulletin
影响因子:
3.8
作者:
[Lucas EK, Clem RL]
通讯作者:
Clem RL
DOI:
10.1038/s41598-021-02157-7
发表时间:
2021-11-22
期刊:
Scientific reports
影响因子:
4.6
作者:
[Roman-Ortiz C, Guevara JA, Clem RL]
通讯作者:
Clem RL
DOI:
10.1007/s00213-018-5001-x
发表时间:
2019-01
期刊:
Psychopharmacology
影响因子:
3.4
作者:
[Lucas EK, Wu WC, Roman-Ortiz C, Clem RL]
通讯作者:
Clem RL
共 6 条
Microcircuits governing conflicting memories of threat and safety
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批准号:10753931
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项目类别:
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资助金额:$62.24万
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Cellular substrates of early life trauma
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资助金额:$55.71万
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Cellular substrates of early life trauma
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资助金额:$55.71万
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负责人:Roger L Clem
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依托单位:
Noradrenergic circuit mechanisms of persistent fear
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批准号:8979721
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项目类别:
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资助金额:$42.38万
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财政年份:2014
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负责人:Roger L Clem
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依托单位:
Noradrenergic circuit mechanisms of persistent fear
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批准号:8800033
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项目类别:
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资助金额:$42.38万
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财政年份:2014
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负责人:Roger L Clem
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依托单位:
Noradrenergic circuit mechanisms of persistent fear
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批准号:9223120
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项目类别:
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资助金额:$4.21万
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财政年份:2014
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负责人:Roger L Clem
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依托单位:
Regulation of calcium-permeable AMPA receptors in associative memory
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批准号:7996558
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项目类别:
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资助金额:$5.3万
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财政年份:2010
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负责人:Roger L Clem
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依托单位:
Regulation of calcium-permeable AMPA receptors in associative memory
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批准号:7753061
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资助金额:$5.01万
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财政年份:2010
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负责人:Roger L Clem
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依托单位:
Regulation of calcium-permeable AMPA receptors in associative memory
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负责人:Roger L Clem
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依托单位: