Ethanol and brain state-dependent neural signaling

乙醇和大脑状态依赖性神经信号传导

• 批准号: 10190737
• 负责人: Martin Paukert
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190737
• 关键词: Acute; Adrenergic Receptor; Affect; Alcohol consumption; Alcohols; Alzheimer' s Disease; Astrocytes; Ataxia; Attention; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cerebellum; Complement; Data; Dose; Drunk driving; Electrophysiology (science); Ethanol; Exercise; Fiber; Foundations; GIRK2 subunit, G protein-coupled inwardly-rectifying potassium channel; GLAST Protein; Goals; Head; Image; Impairment; Individual; Inositol; Investigation; Knock-out; Knockout Mice; Link; Locomotion; Memory; Modeling; Molecular; Mouse Cell Line; Mus; Nerve Degeneration; Neuraxis; Neuroglia; Neurologic; Neurons; Norepinephrine; Parkinson Disease; Pharmacology; Phase; Physiology; Play; Process; Protocols documentation; Purkinje Cells; Rest; Role; Signal Transduction; Slice; Structure; Structure of molecular layer of cerebellar cortex; Structure of purkinje fibers; Supporting Cell; Synapses; Synaptic plasticity; System; Testing; Traffic accidents; Transgenic Mice; Work; alcohol effect; alcohol exposure; alcohol sensitivity; area striata; autism spectrum disorder; awake; brain cell; cell type; cost; experimental study; genetic manipulation; granule cell; in vivo; locus ceruleus structure; motor impairment; neurobehavioral; neuroregulation; neurotransmission; noradrenergic; novel; receptor; response; selective expression; sensor; treadmill; two photon microscopy; two-photon

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.

饮酒会损害运动协调性、注意力和记忆功能。酒精受损 2013 年，驾驶事故约占所有交通事故的 31%，导致 10,076 人死亡，事故相关损失达 590 亿美元。我们建议研究乙醇如何影响大脑状态依赖性神经元的机制 发信号。大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背景下处理信息。我们和其他人已经使用了一种运动 范例揭示了当这种优化发生时涉及去甲肾上腺素能信号传导。过渡时 从休息到运动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大脑区域同时依赖去甲肾上腺素被激活 皮质。去甲肾上腺素能系统参与支持注意力和控制突触可塑性。它 人们早就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呈簇状；然而，目前尚不清楚这会对活动造成什么后果 活跃行为期间的个体脑细胞。我们建议检验酒精严重损害的假设 以星形胶质细胞依赖性方式进行脑状态依赖性去甲肾上腺素能神经调节。我们的方法是 结合特定的小鼠品系进行细胞类型选择性遗传操作和 Ca2+ 传感器的表达 我们的电动线性跑步机和双光子显微镜用于研究 Ca2+ 动力学和电活动 良好控制的行为状态。这些体内研究将得到急性切片 Ca2+ 的补充 成像和电生理学实验。我们将重点研究小脑，因为它 相对简单的电路布置，有利于机械研究。新颖的利用 特定的 Cre 小鼠系将使我们能够选择性地操纵伯格曼神经胶质细胞，即星形胶质细胞 小脑分子层，但不包括颗粒细胞层星形胶质细胞。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伯格曼神经胶质细胞的影响程度和机制 Ca2+ 激活。 (2)我们将揭示运动诱导的浦肯野细胞Ca2+的乙醇敏感成分 动力学并剖析与伯格曼胶质细胞功能的关系。 (3) 我们将研究运动如何- 诱导的浦肯野细胞 Ca2+ 动力学调节内在和突触活动。在我们提出的建议结束后 通过研究我们将了解大脑状态依赖性去甲肾上腺素能神经信号传导的组成部分 受乙醇损害。这项工作将揭示乙醇如何对注意力产生有害影响 细胞和电路层面的努力和记忆。这些研究将为未来进一步奠定基础 神经退行性和神经行为条件下大脑状态依赖性神经信号传导的研究 与去甲肾上腺素能信号的变化有关，例如阿尔茨海默病、帕金森病和 自闭症谱系障碍。

项目成果

Noradrenergic terminal short-term potentiation enables modality-selective integration of sensory input and vigilance state.

• DOI: 10.1126/sciadv.abk1378
• 发表时间: 2021-12-17
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Gray SR;Ye L;Ye JY;Paukert M
• 通讯作者: Paukert M

Constraints of vigilance-dependent noradrenergic signaling to mouse cerebellar Bergmann glia.

警惕依赖性去甲肾上腺素能信号对小鼠小脑伯格曼神经胶质细胞的限制。

• DOI: 10.1002/glia.24350
• 发表时间: 2023
• 期刊: Glia
• 影响因子: 6.2
• 作者: Salinas-Birt,Angelica;Zhu,Xiangyu;Lim,EuniceY;CruzSantory,AryanaJ;Ye,Liang;Paukert,Martin
• 通讯作者: Paukert,Martin

Comparison of GCaMP3 and GCaMP6f for studying astrocyte Ca2+ dynamics in the awake mouse brain.

• DOI: 10.1371/journal.pone.0181113
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ye L;Haroon MA;Salinas A;Paukert M
• 通讯作者: Paukert M