Activity-dependent degradation of a neuromodulator
神经调节剂的活性依赖性降解
基本信息
- 批准号:10651741
- 负责人:
- 金额:$ 40.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:2-arachidonylglycerol2-arachidonylglycerol signalingAccelerationAffectAlcohol abuseAttentionBindingBrain regionCNR1 geneCerebellar AtaxiaCerebellumClinicalCouplesDevelopmentEndocannabinoidsEnzymesFrightFunctional disorderGeneral PopulationGenetic TranscriptionGlutamatesHourInterneuronsInvestigationLearningMAGL inhibitorMemoryMonoacylglycerol LipasesMotorNeurodegenerative DisordersNeurogliaNeuromodulatorNeuronal PlasticityNeuronsPPAR alphaParkinson DiseasePathway interactionsPhysiologicalPilot ProjectsPost-Traumatic Stress DisordersPotassium ChannelProcessPurkinje CellsRegulationRodentRoleSignal TransductionStimulusStressSynaptic TransmissionTestingTherapeuticantagonistanxiety reductionanxiety-like behaviorconditioned feardesensitizationendocannabinoid signalingendogenous cannabinoid systemexperiencefear memorygamma-Aminobutyric Acidgranule cellin vivoinhibitormemory consolidationmotor controlnervous system disorderneuronal circuitryneuronal excitabilityneurotransmitter releasenew therapeutic targetoptogeneticspreventpromoterreceptorstellate celltheoriestranscription factortraumatic event
项目摘要
Neuromodulators control both synaptic transmission and the intrinsic excitability of neurons and are essential
for CNS function. Most studies of neuroplasticity have focused on the regulation of neuromodulator synthesis
or the receptors through which they signal. In contrast, the enzymatic degradation of these compounds has
received less attention even though this controls the temporal profile of their modulatory action. This is
surprising given the therapeutic potential of regulating the rate of degradation. For example inhibition of
endocannabinoid degradation can reduce anxiety-like behaviors in rodents. In theory, an activity-dependent
change in degradation would be expected to alter local neuromodulator levels and provide a powerful
mechanism to regulate the activity of an entire neuronal circuit. Surprisingly studies of physiological regulation
of degradation have lagged compared to its use clinically. We propose that neuronal activity can regulate the
degradation of a neuromodulator, endocannabinoids. Endocannabinoids such as 2-AG, are released when
neurons are activated (“on-demand”) and suppress neurotransmitter release and intrinsic excitability. MAGL
(Monoacylglycerol lipase), a 2-AG degrading enzyme, terminates their activity and this process can be altered
by experience because the level of MAGL changes following stress and alcohol abuse. In this application, we
propose to investigate whether neuronal activity can regulate the degradation of 2-AG in the cerebellum, a
brain region critical for motor control and associative fear memory formation. While searching for a
physiological stimulus that could activate this pathway we found that fear conditioning can elevate both MAGL
levels and 2-AG degradation, and furthermore these effects were blocked by administration of a PPARα
inhibitor. We therefore propose that PPARα acts as a master regulator of MAGL/2-AG signaling, in that it
couples a change in neuronal activity to a change in 2-AG degradation. Our central hypothesis is that
neuronal activity upregulates 2-AG degradation via a PPARα-dependent pathway and thereby
increases the activity of this cerebellar circuit. In aim 1 we will test whether neuronal activity induces a
lasting increase in MAGL and 2-AG degradation via a PPARα-dependent pathway. In aim 2 we will determine
whether fear learning elevates 2-AG degradation via a PPARα-MAGL dependent pathway and alters the
activity of a cerebellar circuit. Investigation of how neuronal activity regulates endocannabinoid degradation is
fundamental to our understanding of neuronal plasticity at the circuit level. If we can confirm a role for PPARα
in an activity-dependent increase in MAGL expression this may allow us to selectively prevent, or facilitate,
MAGL-dependent plasticity without affecting the basal level of this enzyme. This could provide a distinct
therapeutic advantage over inhibitors of MAGL which elevate 2-AG levels and can lead to functional
desensitization of the endocannabinoid system. Such regulation of MAGL expression in the cerebellum is likely
to contribute to fear memory formation and motor function.
神经调节剂控制突触传递和神经元的内在兴奋性,是必不可少的
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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Siqiong June Liu其他文献
phenotype in mouse cerebellar stellate cells channel activity alters synaptic AMPA receptor + -activated large-conductance K 2+ Inhibition of Ca
小鼠小脑星状细胞表型通道活性改变突触 AMPA 受体激活的大电导 K 2 抑制 Ca
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
J. Savtchouk;S. Acharjee;Siqiong June Liu - 通讯作者:
Siqiong June Liu
Emotional stress increases GluA2 expression and potentiates fear memory via adenylyl cyclase 5
情绪应激通过腺苷酸环化酶 5 增加 GluA2 表达并增强恐惧记忆。
- DOI:
10.1016/j.celrep.2024.115180 - 发表时间:
2025-01-28 - 期刊:
- 影响因子:6.900
- 作者:
Qian Yang;Ahmad Abdulla;Muhammad Farooq;Yoshihiro Ishikawa;Siqiong June Liu - 通讯作者:
Siqiong June Liu
Alteration of AMPA Receptor-Mediated Synaptic Transmission by Alexa Fluor 488 and 594 in Cerebellar Stellate Cells123
Alexa Fluor 488 和 594 对小脑星状细胞中 AMPA 受体介导的突触传递的改变123
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:3.4
- 作者:
Matthieu Maroteaux;Siqiong June Liu - 通讯作者:
Siqiong June Liu
Stellate Cells: Synaptic Processing and Plasticity
星状细胞:突触处理和可塑性
- DOI:
10.1007/978-3-319-97911-3_33-2 - 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
Siqiong June Liu;C. Dubois - 通讯作者:
C. Dubois
HippocampusSynapses in Area CA3 of the Mouse Y5 Receptors Mediate Neuropeptide Y Actions at
小鼠 Y5 受体 CA3 区的海马突触介导神经肽 Y 的作用
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
P. A. Castro;R. Palmiter;S. Baraban;C. Dubois;P. Ramamoorthy;M. Whim;Siqiong June Liu;B. Beck;G. Pourié - 通讯作者:
G. Pourié
Siqiong June Liu的其他文献
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{{ truncateString('Siqiong June Liu', 18)}}的其他基金
Activity-dependent degradation of a neuromodulator
神经调节剂的活性依赖性降解
- 批准号:
10460492 - 财政年份:2019
- 资助金额:
$ 40.54万 - 项目类别:
Activity-dependent degradation of a neuromodulator
神经调节剂的活性依赖性降解
- 批准号:
10189725 - 财政年份:2019
- 资助金额:
$ 40.54万 - 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
- 批准号:
10292952 - 财政年份:2018
- 资助金额:
$ 40.54万 - 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
- 批准号:
9452362 - 财政年份:2018
- 资助金额:
$ 40.54万 - 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
- 批准号:
10046274 - 财政年份:2018
- 资助金额:
$ 40.54万 - 项目类别:
Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments
心理压力降低内源性大麻素张力:机制和可能的治疗方法
- 批准号:
10616660 - 财政年份:2018
- 资助金额:
$ 40.54万 - 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
- 批准号:
8446283 - 财政年份:2012
- 资助金额:
$ 40.54万 - 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
- 批准号:
9027880 - 财政年份:2012
- 资助金额:
$ 40.54万 - 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
- 批准号:
8297527 - 财政年份:2012
- 资助金额:
$ 40.54万 - 项目类别:
Impact of stress on GluR2 transcription and learning-induced synaptic plasticity
压力对 GluR2 转录和学习诱导的突触可塑性的影响
- 批准号:
8826180 - 财政年份:2012
- 资助金额:
$ 40.54万 - 项目类别:














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