Ethanol and brain state-dependent neural signaling

饮酒会损害运动协调、注意力和记忆功能。酒精受损 2013年，驾驶占所有交通事故的约31%，造成10，076人死亡和590亿美元的碰撞相关成本。我们拟研究乙醇对脑状态依赖性神经元的影响机制， 发信号。脑状态依赖性信号传导包括细胞和电路活动的调整，以优化 大脑如何在不同的行为环境中处理信息。我们和其他人使用了一种运动方式 范例，以揭示去甲肾上腺素能信号转导时，这种优化发生。过渡处 从静止到运动，星形胶质细胞，中枢神经系统的支持细胞，在小脑和初级视觉等不同的大脑区域同时被去甲肾上腺素依赖性激活。 皮层去甲肾上腺素能系统参与支持注意力的努力和门控突触可塑性。它 长期以来，人们一直知道酒精可以抑制蓝斑的活性，蓝斑的结构， 去甲肾上腺素能神经元是成簇的;然而，目前还不清楚去甲肾上腺素能神经元的活性的后果是什么。 个体脑细胞在活跃行为中的活动。我们建议检验酒精严重损害 脑状态依赖性去甲肾上腺素能神经调节的星形胶质细胞依赖性的方式。我们的做法是 联合收割机将用于细胞类型选择性遗传操作和Ca 2+传感器表达的特异性小鼠系与 我们的电动线性跑步机和双光子显微镜研究Ca 2+动力学和电活动， 良好控制的行为状态这些体内研究将补充急性切片Ca 2 + 成像和电生理学实验。我们将集中研究小脑， 相对简单的电路布置，便于机械研究。一种新的利用 特定的Cre小鼠系将使我们能够选择性地操纵Bergmann神经胶质细胞， 小脑分子层，而不是颗粒细胞层的星形胶质细胞。我们会致力达致以下目标：（1） 我们将明确急性乙醇对运动诱导的Bergmann胶质细胞的影响程度和机制 Ca 2+激活。(2)我们将揭示运动诱导的浦肯野细胞Ca 2+的乙醇敏感成分， 动力学和解剖的关系，伯格曼胶质细胞功能。(3)我们将研究运动- 诱导的浦肯野细胞Ca 2+动力学调节内在和突触活动。在我们的建议结束后， 研究，我们将了解什么成分的大脑状态依赖性去甲肾上腺素能神经信号是 被乙醇破坏。这项工作将揭示乙醇如何对注意力产生有害影响。 在细胞和电路水平上的努力和记忆。这些研究将进一步为未来的研究奠定基础。 神经退行性变和神经行为条件下的脑状态依赖性神经信号研究 与去甲肾上腺素能信号传导的变化相关，如阿尔茨海默病、帕金森病和 自闭症谱系障碍

Alcohol consumption impairs motor coordination, attentional efforts and memory function. Alcohol-impaired driving accounted in 2013 for ~31% of all traffic accidents resulting in 10,076 fatalities and $59 billion crash-related cost. We propose to study the mechanisms how ethanol affects brain state-dependent neural signaling. Brain state-dependent signaling comprises adjustments in cellular and circuit activity to optimize how the brain processes information in a distinct behavioral context. We and others have used a locomotion paradigm to reveal that noradrenergic signaling is involved when such optimizations occur. At transitions from rest to locomotion astroglia, the support cells in the central nervous system, are norepinephrine-dependently activated simultaneously in brain regions as disparate as the cerebellum and primary visual cortex. The noradrenergic system is involved to support attentional efforts and in gating synaptic plasticity. It has long been known that alcohol can suppress the activity of locus coeruleus, the structure where noradrenergic neurons are clustered; however, it is still unclear what the consequences are for the activity of individual brain cells during active behavior. We propose to test the hypothesis that alcohol severely impairs brain state-dependent noradrenergic neuromodulation in an astroglia-dependent manner. Our approach is to combine specific mouse lines for cell type-selective genetic manipulation and expression of Ca2+ sensors with our motorized linear treadmill and two-photon microscopy to study Ca2+ dynamics and electrical activity in well-controlled behavioral states. These in vivo investigations will be complemented with acute slice Ca2+ imaging and electrophysiology experiments. We will focus our investigations on the cerebellum for its relatively straightforward circuit arrangement that facilitates mechanistic studies. The novel utilization of a specific Cre mouse line will enable us to selectively manipulate Bergmann glia, the astrocytes of the cerebellar molecular layer, but not astrocytes of the granule cell layer. We will pursue the following aims: (1) We will define extent and mechanism of the effect of acute ethanol on locomotion-induced Bergmann glia Ca2+ activation. (2) We will reveal ethanol-sensitive components of locomotion-induced Purkinje cell Ca2+ dynamics and dissect the relationship to Bergmann glia function. (3) We will investigate how locomotion- induced Purkinje cell Ca2+ dynamics regulate intrinsic and synaptic activity. Upon conclusion of our proposed studies we will have learned what components of brain state-dependent noradrenergic neural signaling are impaired by ethanol. This work will reveal how ethanol might exert its detrimental effects on attentional efforts and memory on the cellular and circuit level. These studies will further build the groundwork for future research on brain state-dependent neural signaling under neurodegenerative and neurobehavioral conditions associated with changes in noradrenergic signaling, such as Alzheimer's disease, Parkinson's disease and autism spectrum disorder.