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：
10460492
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
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：
https://reporter.nih.gov/project-details/10460492
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Affect Alcohol abuse Alcohols Attention Binding Brain region CNR1 gene Cerebellar Ataxia Cerebellum Clinical Couples Cytoplasmic Granules Development Endocannabinoids Enzymes Fright Functional disorder General Population Genetic Transcription Glutamates Hour Interneurons Investigation Lead 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-like behavior conditioned fear desensitization endocannabinoid signaling endogenous cannabinoid system experience fear memory gamma-Aminobutyric Acid in vivo inhibitor memory consolidation motor control nervous system disorder neuronal circuitry neurotransmitter release new therapeutic target optogenetics prevent receptor stellate cell theories transcription factor traumatic 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，并且是必不可少的大多数神经可塑性研究都集中在神经调节剂合成的调节上。或它们发出信号的受体相反，这些化合物的酶促降解已经发生。尽管这控制了其调节作用的时间分布，但受到的关注较少。令人惊讶的是调节降解速率的治疗潜力，例如抑制。理论上，内源性大麻素的降解可以减少啮齿类动物的焦虑样行为。降解的变化预计会改变局部神经调节剂水平并提供强大的调节整个神经回路活动的机制令人惊讶。与临床使用相比，其降解速度滞后。我们认为神经活动可以调节。神经调节剂、内源性大麻素（例如 2-AG）的降解会在释放时释放。神经元被激活（“按需”）并抑制神经递质释放和内在兴奋性。（单酰基甘油脂肪酶）是一种 2-AG 降解酶，可终止其活性，并且可以改变此过程根据经验，因为 MAGL 水平会随着压力和酗酒而变化。提议研究神经活动是否可以调节小脑中 2-AG 的降解，在寻找恐惧记忆的过程中，大脑区域对于运动控制和联想恐惧记忆的形成至关重要。可以激活该通路的生理刺激我们发现恐惧调节可以提高 MAGL 水平和 2-AG 降解，而且这些效应可以通过施用 PPARα 来阻断因此，我们建议 PPARα 作为 MAGL/2-AG 信号传导的主要调节剂。将神经元活动的变化与 2-AG 降解的变化联系起来我们的中心假设是：神经元活动通过 PPARα 依赖性途径上调 2-AG 降解，从而在目标 1 中，我们将测试神经活动是否会诱发小脑回路的活动。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 降解并改变小脑回路的活动研究神经元活动如何调节内源性大麻素降解。如果我们能够确认 PPARα 的作用，这对于我们理解神经元可塑性在回路水平上至关重要。 MAGL 表达的活动依赖性增加，这可能使我们能够选择性地预防或促进 MAGL 依赖性可塑性不会影响这种酶的基础水平，这可以提供独特的效果。与 MAGL 抑制剂相比具有治疗优势，MAGL 抑制剂可提高 2-AG 水平并可导致功能性小脑中 MAGL 表达的这种调节可能是内源性大麻素系统的脱敏。有助于恐惧记忆的形成和运动功能。