Activity-dependent degradation of a neuromodulator

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 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 我们发现，恐惧条件反射可以提高MAGL和MAGL， 水平和2-AG降解，而且这些作用被给予PPAR α阻断。 抑制剂.因此，我们认为，PPAR α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PPAR α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PPAR α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PPAR α-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。如果我们能证实过氧化物酶体增殖物激活受体α 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。

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.