Activity-dependent degradation of a neuromodulator

神经调节剂的活性依赖性降解

• 批准号: 10651741
• 负责人: Siqiong June Liu
• 金额: $ 40.54万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10651741
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Acceleration; Affect; Alcohol abuse; Attention; Binding; Brain region; CNR1 gene; Cerebellar Ataxia; Cerebellum; Clinical; Couples; Development; Endocannabinoids; Enzymes; Fright; Functional disorder; General Population; Genetic Transcription; Glutamates; Hour; Interneurons; Investigation; Learning; MAGL inhibitor; Memory; Monoacylglycerol Lipases; Motor; Neurodegenerative Disorders; Neuroglia; Neuromodulator; Neuronal Plasticity; Neurons; PPAR alpha; Parkinson Disease; Pathway interactions; Physiological; Pilot Projects; Post-Traumatic Stress Disorders; Potassium Channel; Process; Purkinje Cells; Regulation; Rodent; Role; Signal Transduction; Stimulus; Stress; Synaptic Transmission; Testing; Therapeutic; antagonist; anxiety reduction; anxiety-like behavior; conditioned fear; desensitization; endocannabinoid signaling; endogenous cannabinoid system; experience; fear memory; gamma-Aminobutyric Acid; granule cell; in vivo; inhibitor; memory consolidation; motor control; nervous system disorder; neuronal circuitry; neuronal excitability; neurotransmitter release; new therapeutic target; optogenetics; prevent; promoter; receptor; stellate cell; theories; transcription factor; traumatic event

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 对于CNS功能。神经可塑性的研究大多集中在神经调节剂合成的调节上。 或者它们发出信号的受体。相比之下，这些化合物的酶降解 受到的关注较少，尽管这控制了他们调制作用的时间轮廓。这是 令人惊讶的是，它具有调节降解速度的治疗潜力。例如，抑制 内源性大麻素的降解可以减少啮齿动物的焦虑样行为。从理论上讲，依赖于活动的 降解率的变化有望改变局部神经调节剂水平，并提供强大的 调节整个神经元回路活动的机制。令人惊讶的生理调节研究 与其临床使用相比，降解的可能性有所滞后。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，在以下情况下释放 神经元被激活(按需)，并抑制神经递质的释放和内在的兴奋性。MAGL (单酰甘油脂肪酶)是一种2-AG降解酶，它终止了它们的活性，这一过程可以改变 根据经验，因为MAGL水平在压力和酗酒后会发生变化。在此应用程序中，我们 建议研究神经元活动是否可以调节小脑中2-氨基丁酸的降解， 大脑区域对运动控制和关联恐惧记忆的形成至关重要。在搜索一个 可以激活这一通路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，而且这些作用可被PPARα阻断 抑制剂。因此，我们建议PPARα作为MAGL/2-AG信号的主调节器，因为它 将神经元活动的变化与2-AG降解的变化结合起来。我们的中心假设是 神经元活动通过PPARα依赖途径上调2-AG降解，从而 增加这个小脑回路的活动。在目标1中，我们将测试神经元活动是否诱导 MAGL和2-AG降解通过依赖于α的PPAR途径持续增加。在目标2中，我们将确定 恐惧学习是否通过PPARα-MAGL依赖途径增加2-AG的降解并改变 小脑环路的活动。神经元活动如何调节内源性大麻素降解的研究 这是我们在电路水平上理解神经元可塑性的基础。如果我们可以确认PPARα的角色 在MAGL表达的活性依赖的增加中，这可能允许我们选择性地防止或促进， MAGL依赖的可塑性，而不影响该酶的基础水平。这可能会提供一种独特的 与MAGL抑制剂相比，MAGL具有治疗优势，MAGL可提高2-AG水平，并可导致功能性 内源性大麻素系统的脱敏。这种对小脑MAGL表达的调节很可能是 有助于形成恐惧记忆和运动功能。