Identifying how alcohol-evoked changes in neural firing affect systems level computations during decision-making

项目摘要 行政补充摘要：本行政补充的目的是提供额外的 财务支持，以便有更多的时间来完成母K99/R 00奖励的原始目标。这 由于新型冠状病毒疫情的影响，需要额外的时间（请参阅 补充文件，以提供充分理由）。该补充的科学和职业发展目标是 与原项目相同。在这段补充时间里，蒂姆博士将进行重要的实验 在最初的建议中概述（特别是，飞行员头部固定的电生理记录），并继续 追求教职。 原始项目摘要：本K99/R 00应用程序K99阶段的主要培训目标是 为候选人提供最先进的电生理技术培训，为职业生涯做准备， 酒精研究领域的独立调查员这一提议的首要假设是， 酒精使用障碍（AUD）中的决策障碍是由同时发生的神经活动变化引起的 在多个关键的大脑区域，这些区域通过不同的回路来路由决策过程。解决 这个假设，这个奖项将使用高密度神经探针记录数百个神经元的电活动。 在决定喝酒的过程中，头部固定的老鼠大脑中许多区域的神经元。候选人将获得 在使用这些神经探针以生成可以被识别的大型神经记录数据集方面的必要训练。 用于直接观察AUD中决策故障背后的神经回路的变化。到 获得这一必要的培训，候选人将与领先的研究人员已经使用这些工具， 国际脑实验室合作，并参加培训讲习班。候选人的职业发展 还将通过在高影响力期刊上发表成果，参加会议和参加相关的 校内研讨会拟议的指导小组包括克里斯托弗拉皮什博士，伍迪霍普夫博士，博士。 苏珊·桑加，肯尼斯·哈里斯医生，和大卫·卡瑞肯医生。这些人是系统专家， 计算神经科学，恐惧和奖励的神经回路，酒精研究，头部固定小鼠研究， 和性别作为一个生物变量。IUPUI长期的合作研究环境将提供 候选人有必要的资源来完成本建议书中概述的目标。的结束holdsduring K99阶段的奖励，候选人将寻求一个教师的立场，作为一个独立的调查员，开始在 R 00阶段的奖励开始。在这个新的位置，研究将扩大到包括神经 厌恶刺激的相关性，以便更好地理解继续在脸上饮酒的决定 消极后果。这项工作将导致R 01赠款申请的候选人有关进一步 记录和干预神经回路来治疗决策失误。通过识别 神经回路故障决策的基础，这项研究将指导未来的研究，寻求 为那些患有或有风险患上AUD的人开发新的治疗方法。该奖项将奠定基础 在酒精研究中的独立职业，有可能大大改善人们的生活 受到这种疾病的影响。

Project Summary Administrative Supplement Summary: The purpose of this administrative supplement is to provide additional financial support in order to allow for more time to complete the original goals of the parent K99/R00 award. This additional time is necessary due to the impacts of the Covid-19 pandemic (please see Introduction to the Supplement document for full justification). The scientific and career development goals of the supplement are identical to the original project. During this supplemental time period, Dr. Timme will conduct crucial experiments outlined in the original proposal (specifically, pilot head-fixed electrophysiological recordings) and continue to pursue faculty appointments. Original Project Summary: The primary training objective of the K99 phase of this K99/R00 application is to provide the candidate with training in state-of-the-art electrophysiology techniques in preparation for a career as an independent investigator in the field of alcohol research. The overarching hypothesis of this proposal is that decision-making malfunctions in alcohol use disorder (AUD) are caused by concurring neural activity changes in multiple key brain regions that serve to route the decision-making process through different circuits. To address this hypothesis, this award will use high-density neural probes to record the electrical activity of hundreds of neurons across many brain regions in head-fixed mice during the decision to drink. The candidate will obtain the necessary training in the use of these neural probes to generate large neural recording data sets that can be used to directly observe changes in the neural circuits underlying malfunctioning decision-making in AUD. To obtain this necessary training, the candidate will work with leading researchers already using these tools in the International Brain Laboratory collaboration and attend a training workshop. The candidate’s career development will also be furthered by publishing results in high-impact journals, attending conferences, and attending relevant on-campus seminars. The proposed mentoring team includes Dr. Christopher Lapish, Dr. Woody Hopf, Dr. Susan Sangha, Dr. Kenneth Harris, and Dr. David Kareken. These individuals are experts in systems and computational neuroscience, the neural circuitry of fear and reward, alcohol research, head-fixed mouse studies, and sex as a biological variable. The long-standing collaborative research environment at IUPUI will provide the candidate with the necessary resources to complete the aims as outlined in this proposal. During the end of the K99 phase of the award, the candidate will seek out a faculty position as an independent investigator to begin at the start of the R00 phase of the award. In this new position, the studies will expand to include the neural correlates of aversive stimuli in order to better understand the decision to continue drinking alcohol in the face of negative consequences. This work will lead to R01 grant applications by the candidate related to further recordings and interventions in neural circuits to treat malfunctioning decision-making. By identifying changes in the neural circuits underlying malfunctioning decision-making, this research will guide future studies that seek to develop novel treatments for those people suffering from or at risk for AUD. This award will lay the foundation for an independent career in alcohol research which has the potential to greatly improve the lives of people impacted by this disease.