Alcohol and cerebellar circuits

酒精和小脑回路

基本信息

批准号：
8291442
负责人：
Carlos Fernando Valenzuela
金额：
$ 9.12万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291442
关键词：
AMPA Receptors Accidental Injury Action Potentials Acute Affect Alcohol consumption Alcohols Area Attention Autistic Disorder Axon Brain Stem Brain region Cell physiology Cells Cerebellar Diseases Cerebellar cortex structure Cerebellum Cessation of life Chemosensitization Cities Cognitive Collaborations Communication Complement Computer Simulation Cytoplasmic Granules Data Development Disease Dyes Elements Emotional Equilibrium Ethanol Exposure to Feedback Fetal Alcohol Spectrum Disorder Fiber Figs - dietary Fire - disasters Foundations Frequencies Functional disorder Funding Gait Generations Glutamates Goals Golgi Apparatus Imaging Techniques In Vitro Individual Injury Institutes Interneurons Kansas Label Laboratories Lead Link Long-Term Effects Long-Term Potentiation Mediating Mediator of activation protein Membrane Potentials Mental Depression Mental Processes Missouri Modeling Molecular Movement Myoepithelial cell N-Methyl-D-Aspartate Receptors N-Methylaspartate Na(+)-K(+)-Exchanging ATPase Neurons Pacemakers Patients Physiological Play Potassium Channel Preparation Pump Rattus Recovery Regulation Rest Reverse Transcriptase Polymerase Chain Reaction Role Schizophrenia Science Sensory Series Slice Solid Spinal Cord Structure of molecular layer of cerebellar cortex Study models Synapses Synaptic Transmission Synaptic plasticity System Techniques Technology Therapeutic Intervention Time United States alcohol effect alcohol exposure base computational neuroscience executive function gamma-Aminobutyric Acid granule cell in vivo infancy mind control mossy fiber multidisciplinary neuron loss neuropsychiatry novel optical imaging patch clamp postsynaptic presynaptic problem drinker public health relevance receptor receptor function relating to nervous system research study response stellate cell transmission process white matter

项目摘要

DESCRIPTION (provided by applicant): Acute and long-term ethanol (EtOH) exposure produces cerebellar dysfunction, leading to alterations in gait, balance and coordination that are responsible for a large number of injuries and deaths in the United States. Recent evidence indicates that EtOH affects executive functions and this could be a consequence of disruptions in frontocerebellar circuitry. However, our understanding of the mechanism of action of EtOH in the cerebellum is still in its infancy. Excitatory input from the brain stem and spinal cord enters the cerebellar cortex at the granule cells via the mossy fibers. These neurons also receive inhibitory input from the Golgi cells, which are the major granule cell layer interneuronal subtype. Golgi cells, in turn, receive feedforward excitatory input from mossy fibers, feedback excitatory input from granule cell axons and inhibitory input from molecular layer interneurons. Our overarching hypothesis is that acute EtOH exposure impairs the normal functioning of granule layer circuitry by decreasing glutamatergic and increasing GABAergic transmission at both granule and Golgi cells. Specific Aim #1 is to characterize the effect of EtOH on glutamatergic transmission at granule cells. During the previous funding period, we determined that EtOH increases tonic and phasic GABAergic input to granule cells without affecting spontaneous glutamatergic transmission mediated by AMPA receptors. Using the acute cerebellar slice preparation and patch-clamp electrophysiological techniques, we will now study the effect of EtOH on NMDA receptor function and long- term potentiation at mossy fiber-to-granule cell synapses. We will investigate its effects on granule cell activation by sensory-like patters of mossy fiber activation; for these studies, single-neuron recordings will be complemented by autofluorescence optical imaging of [the mossy fiber area of activation]. Specific Aim #2 is to further characterize the effects of EtOH on Golgi cells. During the previous funding period, we demonstrated that EtOH increases Golgi cell firing and propose to characterize the mechanism responsible for this effect. [Based on a combination of computer modeling and experimental studies, we propose to characterize IA, Na+/K+ pump and persistent Na+ currents as potential mediators of EtOH's effect]. We will also investigate EtOH's effect on GABAergic and/or glutamatergic input to Golgi cells. These studies with acute slices will be complemented with in vivo electrophysiological experiments of the acute effects of EtOH on the function of these neurons. In Specific Aim #3, we will investigate the effect of EtOH on network activity in the granule cell layer as a whole using a data-driven computational neuroscience approach. These multidisciplinary studies will significantly increase our understanding of the acute effects of EtOH on the cerebellar granule cell layer, forming the basis for the identification of new targets for therapeutic interventions against EtOH-induced cerebellar dysfunction. PUBLIC HEALTH RELEVANCE: The cerebellum is a portion of the brain that controls gait, balance, coordination and certain internal mental processes such as attention and planning. Ingestion of alcohol profoundly affects normal cerebellar functioning and our understanding of the mechanisms responsible for these effects of alcohol is very limited. The goal of this project is to characterize the effect of alcohol on communication between cerebellar neurons, forming the basis for the development of novel treatments that may aid in the recovery of alcoholic patients.

描述（由申请人提供）：急性和长期乙醇（ETOH）暴露会导致小脑功能障碍，从而导致步态，平衡和协调的改变，这是美国大量伤害和死亡的原因。最近的证据表明，ETOH会影响执行功能，这可能是额叶电路电路中断的结果。但是，我们对ETOH在小脑中作用机理的理解仍处于起步阶段。来自脑干和脊髓的兴奋性输入通过苔藓纤维进入颗粒细胞的小脑皮质。这些神经元还接收来自高尔基细胞的抑制性输入，后者是主要的颗粒细胞层间神经元亚型。反过来，高尔基细胞从苔藓纤维，颗粒细胞轴突的反馈兴奋性输入以及分子层中间神经元的抑制输入中接收前馈激发输入。我们的总体假设是，急性ETOH暴露通过减少谷氨酸能和增加颗粒和高尔基细胞的Gabaergic透射来损害颗粒层回路的正常功能。特定目的＃1是表征EtOH对颗粒细胞谷氨酸能传播的影响。在上一个资金期间，我们确定ETOH会增加对颗粒细胞的滋补和质量GABA能输入，而不会影响由AMPA受体介导的自发性谷氨酸能传播。使用急性小脑切片制剂和贴片钳电生理技术，我们现在将研究EtOH对NMDA受体功能和长期增强在苔藓纤维到颗粒细胞突触中的影响。我们将通过苔藓纤维激活的感觉样模式研究其对颗粒细胞激活的影响。在这些研究中，单神经元的记录将通过[苔藓纤维激活面积]的自动荧光光学成像进行补充。具体目的＃2是进一步表征EtOH对高尔基细胞的影响。在上一个资金期间，我们证明ETOH增加了高尔基细胞的射击，并提出表征负责这种效果的机制。 [基于计算机建模和实验研究的组合，我们建议将IA，Na+/K+泵和持续的Na+电流表征为ETOH效应的潜在介体]。我们还将研究EtOH对高尔基细胞的GABA能和/或谷氨酸能输入的影响。这些用急性切片的研究将与ETOH对这些神经元功能的急性作用的体内电生理实验相辅相成。在特定的目标＃3中，我们将使用数据驱动的计算神经科学方法研究ETOH对颗粒细胞层中网络活性的影响。这些多学科研究将显着提高我们对ETOH对小脑颗粒细胞层的急性影响的理解，这为鉴定针对EtOH诱导的小脑功能障碍的治疗干预措施的新靶标构成了基础。公共卫生相关性：小脑是控制步态，平衡，协调和某些内部心理过程（例如注意力和计划）的大脑的一部分。酒精的摄入深刻影响着小脑的正常功能，我们对造成这些饮酒影响的机制的理解非常有限。该项目的目的是表征酒精对小脑神经元之间通信的影响，为开发新型治疗的基础，这可能有助于酗酒患者的恢复。