Ethanol and brain state-dependent neural signaling

饮酒会损害运动协调性、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%，导致10076人死亡，与撞车相关的成本为590亿美元。我们建议研究酒精影响脑状态依赖神经的机制。 发信号。大脑状态依赖的信号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背景下处理信息。我们和其他人使用了一种移动 范式揭示，当这种优化发生时，去甲肾上腺素能信号参与其中。在过渡阶段 从静息到运动的星形胶质细胞是中枢神经系统中的支持细胞，在小脑和初级视觉等不同的脑区同时激活去甲肾上腺素。 大脑皮层。去甲肾上腺素系统参与支持注意力的努力和控制突触的可塑性。它 很早就知道酒精可以抑制蓝斑的活动，蓝斑的结构 去甲肾上腺素能神经元是聚集在一起的；然而，对于去甲肾上腺素能神经元活性的影响仍不清楚。 活跃行为中的单个脑细胞。我们建议检验酒精严重损害人体健康的假设 以星形胶质细胞依赖的方式进行脑状态依赖的去甲肾上腺素能神经调节。我们的方法是 将特定的小鼠品系用于细胞类型选择的遗传操作和钙离子传感器的表达 我们的电动直线跑步机和双光子显微镜研究了钙动力学和电活动 良好控制的行为状态。这些体内研究将与急性切片钙离子相辅相成。 影像和电生理学实验。我们将把研究重点放在小脑上 相对简单的电路安排，便于机械学研究。一种新的使用方法 特定的Cre小鼠品系将使我们能够选择性地操纵Bergmann胶质细胞，即 小脑分子层，而不是颗粒细胞层的星形胶质细胞。我们将追求以下目标：(1) 我们将确定急性乙醇对运动诱导的Bergmann胶质细胞的影响程度和机制 钙离子被激活。(2)我们将揭示运动诱导的浦肯野细胞的乙醇敏感成分。 并剖析其与Bergmann神经胶质细胞功能的关系。(3)我们将调查移动是如何- 诱导的浦肯野细胞钙动力学调节内源性和突触活性。在我们的建议结束后 研究我们将了解大脑状态依赖的去甲肾上腺素能神经信号的哪些组成部分 因酒精而受损。这项工作将揭示酒精如何对注意力产生有害影响。 在细胞和电路层面的努力和记忆。这些研究将进一步为今后的工作奠定基础 神经退行性变和神经行为条件下脑状态依赖神经信号的研究 与去甲肾上腺素能信号的变化有关，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.