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.

神经调节剂控制着突触传播和神经元的内在刺激性，并且是必不可少的 用于CNS功能。大多数神经塑性研究都集中在神经调节剂合成的调节上 或他们发出信号的接收器。相反，这些化合物的酶促降解具有 即使这控制了其调节作用的临时概况，也受到了更少的关注。这是 考虑到确定降解率的治疗潜力，令人惊讶的是。例如抑制 内源性大麻素降解可以减少啮齿动物的焦虑样行为。从理论上讲，一个与活动有关的 预计降解的变化将改变局部神经调节剂水平，并提供强大的 调节整个神经元电路活性的机制。令人惊讶的是对身体调节的研究 与临床使用相比，降解的降解滞后。我们建议神经元活性可以调节 神经调节剂内源性大麻素的降解。内源性大麻素（例如2-ag）在 神经元被激活（“按需”），并抑制神经递质的释放和内在的刺激性。 magl （单酰基甘油脂肪酶），一个2-ag降解酶，终止其活性，并且可以改变该过程 通过经验，因为压力和酗酒后MAGL的水平会改变。在此应用程序中，我们 提议研究神经元活性是否可以调节小脑中2-AG的降解，A 大脑区域对于运动控制和联想恐惧记忆形成至关重要。在寻找一个 可以激活这一途径的物理刺激我们发现恐惧调节可以提升两个磁 水平和2-ag降解，此外，这些效应被PPARα的施用阻止 抑制剂。因此，我们建议PPARα充当MAGL/2AG信号的主调节器，因为 伴侣神经元活动的变化是2-AG降解的变化。我们的中心假设是 神经元活性通过PPARα依赖性途径上调2-Ag降解，从而 增加了该小脑回路的活性。在AIM 1中，我们将测试神经元活动是否诱导A 通过PPARα依赖性途径持续增加MAGL和2-AG降解。在AIM 2中，我们将确定 恐惧学习是否通过PPARα-MAGL依赖途径提高了2-AG降解并改变 小脑电路的活性。研究神经元活性如何调节内源性大麻素降解是 我们对电路水平上神经元可塑性的理解为基础。如果我们可以确认PPARα的角色 在活动依赖于MAGL表达的增加中，这可能使我们能够选择性地预防或促进， MAGL依赖性可塑性，而不会影响该酶的基本水平。这可以提供独特的 比MAGL的抑制剂的治疗优势，该抑制剂提高2-AG水平并可能导致功能性 内源性大麻素系统的脱敏。这种对小脑中MAGL表达的调节很可能是 为恐惧记忆形成和运动功能做出贡献。