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

摘要 应激性生活经历是一种危险因素，在精神疾病的发展和维持中起着相当大的作用 酗酒、酗酒和旧病复发。来自INIAStress联盟的临床前研究 研究了小鼠慢性酒精与应激的相互作用，发现饮用酒精的人认知能力提高 缺陷、化生适应和消极情感行为的出现。INIAStress调查人员 还进行了机械学和药理学研究，揭示了与 用于在应激、慢性间歇性乙醇(CIE)暴露的小鼠中驱动这些异常行为。然而， 酒精-压力相互作用所产生的全脑神经适应是未知的，也是更好的理解 酒精和压力相互作用的全脑活动模式将导致有效的策略 治疗酒精使用障碍患者。全脑地图绘制和创新技术的最新进展 网络神经科学统计方法促进CIE应激小鼠脑活动的形成 映射核心(BAMC)。在本应用程序中，我们提供了显示全脑光片成像的初步数据 CIE-FSS处理小鼠和饮酒小鼠c-Fos表达和功能连接图谱的研究 间歇访问模式。因此，BAMC的主要目标是1)将尖端技术应用于整个- 脑光片成像和网络分析方面的专业知识，为INIAStress联合会的研究人员提供 科学界拥有新的大脑区域、回路和网络，可以推动小鼠饮酒增加 有强迫游泳应激(FSS)和CIE暴露的病史，以及2)提供即时的全脑信号 已知可减少过度饮酒的药物对早期基因(IEG)活性的影响 应激、酒精依赖小鼠的表型。BAMC的次要目标是1)提供完整的- 将脑图数据存储到计算和统计分析核心(CSAC)，以便与其他 收集所有组件的神经和行为数据，以及2)执行跨INIA财团分析 全脑IEG表情。在目标1中，BAMC将使用标准生成全脑IEG映射数据 INIAStress研究人员应激性过度饮酒的联合体模型及其科学性 社区。AIM 2的研究将确定药物药物治疗后的全脑IEG信号 在CIE-FSS模型中减少饮酒。通过应用尖端的光片成像、先进的网络 使用一种可靠的方法对整个小鼠脑内IEG的表达进行分析和药理学研究 导致应激、酒精依赖小鼠自愿酒精摄入量增加的模型，BAMC将提供帮助 对酒精压力背后的系统和回路产生新的假设和不偏不倚的见解 互动。最后，通过与CSAC和Brain Initiative调查人员的互动，大脑活动 测绘核心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图数据。

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.