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

动物通过学习环境中的特定线索可靠地与环境中的特定线索配对，从而预测重要的结果，如获得食物或危险的存在，从而发展对环境的理解。基于这些预测的结果期望的概念对哺乳动物联想学习研究的发展产生了影响。这些分析对理解人类与结果相关的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。结果预期的神经基础在哺乳动物中的研究尤其具有挑战性，因为实验操作需要精致的细胞、时间和遗传特异性。果蝇一直是研究学习和记忆的遗传和神经基础的一个有价值的模型，包括学习线索-结果关联的学习。最近在苍蝇大脑中识别的神经元及其详细连接的工作的发展，使幼虫和成年果蝇的大脑成熟，作为促进对哺乳动物结果预期学习的神经基础的理解的模型。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，研究小组调查了果蝇的复杂记忆表征。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生物学课堂材料，并与亚利桑那州立大学获奖的Ask-A-生物学家项目合作。早期和大多数当前对果蝇(Drocinila Blackogaster)学习和记忆的研究使用基本的行为条件调节协议来研究受控实验室环境中的学习。以精致的特异性转基因操作果蝇中的许多脑神经元的能力，以及最近对果蝇大脑突触“连接体”的了解，使这些动物几乎是独一无二的，成为研究学习、记忆和动机行为的综合模型。在此背景下，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模型指导下的连接体信息相结合，将大大加强对学习和记忆的研究。为此，研究人员研究了强化通路在缺乏预期强化的情况下的功能。具体地说，研究人员研究了当条件刺激的预期结果没有发生时，果蝇的记忆表征。通过一系列实验，他们测试了这样的预测：在果蝇中，当条件刺激与食欲增强的失败预期有关时，条件刺激将获得厌恶的价值，反之亦然。研究人员将这些研究与中枢神经系统强化通路的操作结合起来，根据最近发布的苍蝇脑连接体识别和选择。这项实验工作是用已建立的计算模型迭代完成的。法国国家研究机构(ANR)正在资助一个配套项目。这个奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.