CRCNS US-France Research Proposal: Collaborative Research: Encoding reward expectation in Drosophilia

CRCNS 美国-法国研究提案：合作研究：编码果蝇奖励期望

• 批准号: 2113179
• 负责人: Brian Smith
• 金额: $ 24.51万
• 依托单位: Arizona State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2113179&HistoricalAwards=false
• 关键词: CRCNS; US; France; Research; Proposal

Animals develop an understanding of their environment through learning that specific cues in the environment are reliably paired with and consequently predict important outcomes, such as access to food or the presence of danger. The concept of outcome expectation based on these predictions has been influential in the development of studies of associative learning in mammals. These analyses have had a profound impact on understanding of outcome-related behavior in humans, including monetary rewards and the consequences of traumatic experiences, and for pathologies of the reward systems in the brain. The neural underpinnings of outcome expectation are particularly challenging to study in mammals because of the requirement for exquisite cellular, temporal, and genetic specificity of experimental manipulations. The fruit fly Drosophila melanogaster has been a valuable model for investigating the genetic and neural bases that underlie learning and memory, including learning of cue-outcome associations. The recent development of work with identified neurons and their detailed connections in the fly brain makes the larval and adult fruit fly brains ripe as models for advancing understanding of neural bases for outcome expectation learning in mammals. Using the powerful experimental approaches available in the fruit fly model system and resources guided by computational modeling, the team of researchers investigate complex memory representations in Drosophila. This project also provides interdisciplinary training for postdoctoral researchers, and graduate and undergraduate students, development of new K-12 biology classroom material, and collaboration with Arizona State University’s award-winning Ask-A-Biologist program.Early and most current studies of learning and memory in the fruit fly (Drosophila melanogaster) use basic behavior conditioning protocols to study learning in controlled laboratory settings. The ability to transgenically manipulate many of the brain neurons in the fruit fly with exquisite specificity, and the recent knowledge of the synaptic ‘connectome’ of the fruit fly brain, makes these animals almost unique as a comprehensive model for studies of learning, memory and motivated behavior. Within this context, the investigators propose that studies of learning and memory will be greatly enhanced by using more sophisticated means for evaluating memory representations, and by combining those studies with information from the connectome guided by computational modelling. To that end, the investigators examine the function of reinforcement pathways in relation to the absence of expected reinforcement. Specifically, the investigators study the memory representations in fruit flies when an expected consequence of a conditioned stimulus fails to occur. Through a series of experiments, they test the prediction that in Drosophila when a conditioned stimulus is associated with a failed expectation of an appetitive food reinforcement, the conditioned stimulus will acquire aversive value, and vice versa for a failed expectation of an aversive reinforcer. The investigators combine these studies with manipulations of reinforcement pathways in the central nervous system identified and selected based on the recently released fly brain connectome. The experimental work is iteratively knitted in with established computational models.A companion project is being funded by the French National Research Agency (ANR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

动物通过学习环境中的特定线索与重要结果（如获得食物或危险的存在）可靠地配对并因此预测重要结果，从而发展对环境的理解。基于这些预测的结果期望的概念已经在哺乳动物的联想学习研究的发展中产生了影响。这些分析对理解人类的结果相关行为产生了深远的影响，包括金钱奖励和创伤经历的后果，以及大脑奖励系统的病理学。结果预期的神经基础在哺乳动物中的研究特别具有挑战性，因为实验操作需要精致的细胞，时间和遗传特异性。果蝇（Drosophila melanogaster）是研究学习和记忆（包括线索-结果关联学习）的遗传和神经基础的有价值的模型。最近的发展工作与确定的神经元和它们的详细连接在苍蝇的大脑，使幼虫和成年果蝇的大脑成熟的模型，为推进理解的神经基础，在哺乳动物中的结果预期学习。利用果蝇模型系统中可用的强大实验方法和计算建模指导的资源，研究人员研究了果蝇中复杂的记忆表征。该项目还为博士后研究人员、研究生和本科生提供跨学科培训，开发新的K-12生物课堂材料，并与亚利桑那州立大学屡获殊荣的Ask-A-Biologist项目合作。果蝇（Drosophila melanogaster）的学习和记忆的早期和最新研究使用基本的行为条件反射协议来研究受控实验室环境中的学习。转基因操纵果蝇大脑神经元的能力，以及最近对果蝇大脑突触“连接体”的了解，使这些动物几乎成为学习，记忆和动机行为研究的综合模型。在这种背景下，研究人员提出，通过使用更复杂的方法来评估记忆表征，并将这些研究与计算机建模指导的连接体信息相结合，学习和记忆的研究将得到极大的加强。为此，研究人员研究了强化途径的功能与预期强化的缺乏。具体来说，研究人员研究了果蝇在条件刺激的预期结果未能发生时的记忆表征。通过一系列的实验，他们测试了果蝇的预测，当条件刺激与食欲食物强化的预期失败相关联时，条件刺激将获得厌恶值，反之亦然，对于厌恶的食物强化者的预期失败。研究人员将这些研究与基于最近发布的苍蝇脑连接体识别和选择的中枢神经系统强化途径的操作相结合。 实验工作与已建立的计算模型反复结合。法国国家研究机构（ANR）正在资助一个配套项目。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。