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:
    10189725
  • 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

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.
神经调质控制突触传递和神经元的内在兴奋性, 中枢神经系统功能。神经可塑性的研究主要集中在神经调质合成的调控上 或者说它们传递信号的受体。相比之下,这些化合物的酶促降解具有 受到较少的关注,即使这控制了他们的调节作用的时间概况。这是 考虑到调节降解速率的治疗潜力,这是令人惊讶的。例如抑制 内源性大麻素降解可以减少啮齿类动物的焦虑样行为。从理论上讲, 预计降解的变化将改变局部神经调质水平,并提供强有力的 调节整个神经回路活动的机制。令人惊讶的生理调节研究 与临床使用相比,降解的速度已经滞后。我们认为,神经元活动可以调节 神经调节剂内源性大麻素的降解。内源性大麻素,如2-AG,在 神经元被激活(“按需”)并抑制神经递质释放和内在兴奋性。MAGL (单酰基甘油脂肪酶),一种2-AG降解酶,终止它们的活性,并且可以改变该过程 因为MAGL的水平会随着压力和酒精滥用而变化。在本申请中,我们 建议研究神经元活动是否可以调节小脑中2-AG的降解, 大脑区域对运动控制和关联恐惧记忆的形成至关重要。在寻找一个 可以激活这一途径的生理刺激,我们发现恐惧条件反射可以提高MAGL 水平和2-AG降解,而且这些作用被给予PPARα阻断。 抑制剂.因此,我们认为,PPARα作为MAGL/2-AG信号传导的主要调节因子, 将神经元活性的变化与2-AG降解的变化相结合。我们的核心假设是, 神经元活性通过PPARα依赖性途径上调2-AG降解, 增加了小脑回路的活动在目标1中,我们将测试神经元活动是否诱导了一个神经元活动。 通过PPARα依赖性途径持续增加MAGL和2-AG降解。在目标2中,我们将确定 恐惧学习是否通过PPARα-MAGL依赖性途径提高2-AG降解, 小脑回路的活动。神经元活动如何调节内源性大麻素降解的研究是 这是我们在回路水平上理解神经元可塑性的基础。如果我们能够确认PPARα的作用 在MAGL表达活性依赖性增加中,这可能允许我们选择性地预防或促进, MAGL依赖的可塑性,而不影响这种酶的基础水平。这可以提供一个独特的 相对于MAGL抑制剂的治疗优势,MAGL抑制剂提高2-AG水平并可导致功能性 内源性大麻素系统的脱敏。小脑中MAGL表达的这种调节可能是 有助于恐惧记忆的形成和运动功能。

项目成果

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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
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:
    10651741
  • 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:
    10460492
  • 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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