Ethanol and brain state-dependent neural signaling

乙醇和大脑状态依赖性神经信号传导

基本信息

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
项目类别：
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&apos 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

项目摘要

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，注意力和记忆功能。酒精受损 2013年，驾驶占所有交通事故的31％，导致10,076人死亡和590亿美元与坠机相关的费用。我们建议研究乙醇如何影响脑状态依赖性神经的机制信号。大脑状态依赖性信号传导包括细胞和电路活性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运动范式表明，当进行这种优化时涉及去甲肾上腺素能信号传导。在过渡中从静止到运动的星形胶质细胞，中枢神经系统中的支撑细胞是无肾上腺素依赖性地依赖性地在大脑区域中同时激活的，如小脑和主要视觉皮质。甲肾上腺素能系统涉及支持注意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凝固层的活性，该结构是去甲肾上腺素能神经元聚集；但是，目前尚不清楚对活动的影响在主动行为过程中，单个脑细胞。我们建议测试酒精严重损害的假设大脑状态依赖性去肾上腺素能神经调节以星形胶质细胞依赖性方式。我们的方法是将特定的小鼠系组合用于细胞类型选择性遗传操纵和CA2+传感器的表达我们的电动线性跑步机和两光子显微镜研究CA2+动力学和电活动控制良好的行为状态。这些体内调查将与急性切片Ca2+补充成像和电生理实验。我们将把调查集中在小脑上相对简单的电路布置，促进机械研究。新颖的利用特定的CRE鼠标线将使我们能够选择性地操纵Bergmann Glia，即星形胶质细胞小脑分子层，而不是颗粒细胞层的星形胶质细胞。我们将追求以下目标：（1）我们将定义急性乙醇对运动诱导的Bergmann Glia的影响的程度和机制 Ca2+激活。（2）我们将揭示运动诱导的Purkinje细胞Ca2+的乙醇敏感成分动力学并解剖与伯格曼胶质功能的关系。（3）我们将研究运动方式诱导的Purkinje细胞Ca2+动力学调节固有和突触活性。根据我们提议的结论研究我们将了解脑状态依赖性去肾上腺素能神经信号的哪些组成部分是乙醇受损。这项工作将揭示乙醇如何对注意力产生不利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树立基础在神经退行性和神经行为条件下的大脑状态依赖性神经信号传导的研究与脱甲肾上腺素信号的变化有关，例如阿尔茨海默氏病，帕金森氏病和自闭症谱系障碍。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.