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 财政支持，以便有更多的时间完成家长K99/R00奖的最初目标。这 由于新冠肺炎大流行的影响，需要额外的时间(请参阅 补充文件以获得充分的理由)。副刊的科学和职业发展目标是 与原始项目完全相同。在这段补充时间内，蒂姆博士将进行重要的实验 在原提案中概述(具体地说，飞行员固定头部的电生理记录)，并继续 寻求教职员工的任命。 原始项目摘要：此K99/R00应用程序K99阶段的主要培训目标是 为应聘者提供最先进的电生理学技术培训，为其职业生涯做准备 酒精研究领域的独立调查员。这项提议的首要假设是 酒精使用障碍(AUD)的决策障碍是由伴随的神经活动变化引起的 在多个关键的大脑区域中，这些区域通过不同的回路传递决策过程。致信地址 这个假设，这个奖项将使用高密度神经探头来记录数百个 在决定饮酒的过程中，头部固定的小鼠大脑的许多区域都有神经元。候选人将获得 在使用这些神经探针生成大型神经记录数据集方面进行必要的培训，这些数据集可以 用于直接观察AUD中潜在故障决策的神经回路的变化。至 获得必要的培训后，应聘者将与已经在 与国际脑实验室合作并参加培训研讨会。候选人的职业发展 还将通过在影响较大的期刊上发表成果、参加会议和参加有关 校园研讨会。拟议的指导团队包括克里斯托弗·拉皮什博士、伍迪·霍普夫博士、胡迪·霍普夫博士、 苏珊·桑加、肯尼斯·哈里斯博士和大卫·卡瑞肯博士。这些人是系统和 计算神经科学，恐惧和奖励的神经回路，酒精研究，固定头部的小鼠研究， 而性则是一个生物变量。国际理工学院长期的合作研究环境将提供 拥有必要资源以完成本提案中概述的目标的候选人。在会议结束时 K99奖项阶段，候选人将从一开始就寻求独立调查员的教职 颁奖典礼R00阶段的开始。在这一新职位上，研究将扩大到包括神经 厌恶刺激的相关性，以便更好地理解面部继续饮酒的决定 负面后果的影响。这项工作将导致候选人提出R01拨款申请，涉及进一步 神经回路的录音和干预，以治疗失灵的决策。通过识别中的更改 故障决策背后的神经回路，这项研究将指导未来寻求 为那些患有或有AUD风险的人开发新的治疗方法。这一奖项将奠定基础 独立从事酒精研究，这有可能极大地改善人们的生活 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.