CORE 2/2: INIA Stress and Chronic Alcohol Interactions: CIE-Stress Mouse Brain Activity Mapping Core (BAMC)

CORE 2/2：INIA 压力和慢性酒精相互作用：CIE-压力小鼠大脑活动图核心 (BAMC)

• 批准号: 10410788
• 负责人: Marcelo F. Lopez
• 金额: $ 39.97万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410788
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohols; Automobile Driving; BRAIN initiative; Behavior; Behavioral; Biological; Brain; Brain Mapping; Brain imaging; Brain region; Cells; Chromosome Mapping; Chronic; Chronic stress; Cognitive deficits; Communities; Complex; Computer Analysis; Coping Skills; Data; Development; Doxazosin; Ethanol; Ethanol dependence; FOS gene; Funding; Gene Expression; Generations; Goals; Heavy Drinking; Image; Imaging technology; Immediate-Early Genes; Impaired cognition; Individual; Inhalation; Light; Maintenance; Metaplasia; Modeling; Mus; Nature; Neurobiology; Neurosciences; Pathway Analysis; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacology Study; Phenotype; Play; Recording of previous events; Relapse; Reproducibility; Research Personnel; Resources; Risk; Risk Factors; Role; Statistical Data Interpretation; Statistical Models; Stress; Stressful Event; Swimming; System; Technology; Testing; Work; alcohol exposure; alcohol relapse; alcohol use disorder; alpha-adrenergic receptor; anxiety-like behavior; behavioral phenotyping; brain circuitry; drinking; experience; genetic signature; hypothalamic-pituitary-adrenal axis; innovation; insight; kappa opioid receptors; mouse model; negative affect; neural circuit; neuroadaptation; noradrenergic; novel; open data; preclinical study; relating to nervous system; response; stressor; tool; vapor

SUMMARY Stressful life experiences are risk factors that play considerable roles in the development and maintenance of alcohol (ethanol) abuse, excessive drinking, and relapse. Preclinical studies from the INIAstress Consortium that examined chronic ethanol-stress interactions in mice have demonstrated elevations in ethanol drinking, cognitive deficits, metaplastic adaptations, and emergence of negative affective behaviors. The INIAstress investigators also performed mechanistic and pharmacological studies that revealed key biological targets that are responsible for driving these aberrant behaviors in stressed, chronic intermittent ethanol (CIE) exposed mice. However, the brain-wide neural adaptations produced by ethanol-stress interactions are unknown, and a better understanding of the brain-wide activity patterns that underlie alcohol and stress interactions will lead to effective strategies for treating individuals with alcohol use disorder. Recent advancements in brain-wide mapping and innovative network neuroscience statistical approaches prompted the formation of the CIE-Stress Mouse Brain Activity Mapping Core (BAMC). In this application, we provide preliminary data showing whole-brain light sheet imaging of c-Fos expression and functional connectivity mapping in CIE-FSS treated mice and in mice drinking in the intermittent access model. Thus, the primary goals of the BAMC are to 1) apply cutting-edge technology in whole- brain light sheet imaging and expertise in network analyses to provide investigators in the INIAstress Consortium and the scientific community with novel brain regions, circuits, and networks that drive increased drinking in mice with a history of forced swim stress (FSS) and CIE exposure, and 2) provide brain-wide signatures of immediate early gene (IEG) activity in response to pharmacological agents that are known to reduce the excessive drinking phenotype in stress, ethanol dependent mice. The secondary goals of the BAMC are to 1) provide the whole- brain mapping data to the Computational and Statistical Analysis Core (CSAC) for integration with additional neural and behavioral data collected across all components, and 2) perform cross-INIA Consortia analyses of whole-brain IEG expression. In Aim 1, the BAMC will generate whole-brain IEG mapping data using the standard INIAstress Consortium model of stress-induced excessive drinking for INIAstress investigators and the scientific community. Studies in Aim 2 will determine brain-wide IEG signatures after pharmacological treatment of drugs that reduce drinking in the CIE-FSS model. By applying cutting-edge light sheet imaging, advanced network analysis, and pharmacological interrogation of IEG expression across the whole mouse brain using a reliable model that results in escalated voluntary ethanol intake in stressed, ethanol dependent mice, the BAMC will help to generate new hypotheses and unbiased insights into systems and circuitry underlying alcohol-stress interactions. Finally, through its interactions with the CSAC and BRAIN Initiative investigators, the Brain Activity Mapping Core will contribute to Open Science practices that will provide the greater scientific community with whole-brain IEG mapping data from excessively drinking mice.

总结 紧张的生活经历是危险因素，在发展和维持 酒精（乙醇）滥用，过量饮酒和复发。来自INIAstress联盟的临床前研究， 在小鼠中研究的慢性乙醇应激相互作用表明，乙醇饮用，认知， 缺陷、化生适应和消极情感行为的出现。INIA压力研究人员 还进行了机制和药理学研究，揭示了负责的关键生物靶点， 在应激、慢性间歇性乙醇（CIE）暴露的小鼠中驱动这些异常行为。但 乙醇-压力相互作用产生的全脑神经适应尚不清楚， 酒精和压力相互作用的大脑活动模式将导致有效的策略， 治疗酒精使用障碍患者全脑映射和创新的最新进展 网络神经科学的统计方法促使CIE-应激小鼠脑活动的形成 映射核心（BAMC）。在这个应用中，我们提供了初步的数据，显示全脑光片成像 c-Fos表达和功能连接图在CIE-FSS处理的小鼠和饮用水的小鼠中 间歇访问模型。因此，BAMC的主要目标是：1）整体应用尖端技术- 脑光片成像和网络分析方面的专业知识，为INIAstress联盟的研究人员提供 以及科学界新的大脑区域，电路和网络，驱动小鼠饮酒增加 具有强迫游泳应激（FSS）和CIE暴露史的人，和2）提供立即的脑内信号， 早期基因（IEG）活性对已知可减少过量饮酒的药物的反应 在应激、乙醇依赖小鼠中的表型。BAMC的第二个目标是：1）提供整体- 将大脑映射数据传输到计算和统计分析核心（CSAC），以便与其他 在所有组件中收集的神经和行为数据，以及2）执行跨INIA联盟分析， 全脑IEG表达。在目标1中，BAMC将使用标准的 INIAstress研究人员和科学家的INIAstress联盟压力诱导过度饮酒模型 社区目标2中的研究将确定药物治疗后全脑IEG特征 在CIE-FSS模型中减少饮酒。通过应用先进的光片成像技术， 分析，并使用可靠的方法对整个小鼠脑中IEG表达进行药理学询问。 模型，导致自愿乙醇摄入量增加，在强调，乙醇依赖小鼠，BAMC将有助于 产生新的假设和公正的见解系统和电路的基础酒精压力 交互.最后，通过与CSAC和BRAIN Initiative研究人员的互动， Mapping Core将有助于开放科学实践，为更大的科学界提供 过量饮酒小鼠的全脑IEG映射数据。