Metabolic underpinnings of age-dependent cognitive and neural circuit decline in Drosophila

大脑功能的下降，以及随之而来的认知能力的丧失，是衰老最具致残性的后果之一。虽然越来越清楚的是，并非所有的神经回路和大脑功能都受到衰老的影响，但我们仍然不知道使某些细胞或回路更容易功能障碍的生理特征。代谢缺陷、氧化损伤和神经元信号改变是许多物种脑组织衰老的三种功能表现。本项目的目的是确定这些模式的下降和它们在衰老引起的记忆缺陷中的含义之间的因果关系。果蝇的神经系统满足解决这个问题的主要要求，因为，第一，在细胞和电路水平的特点，第二，自然老化的时间尺度上兼容的科学研究，最后，适合在体内成像的这些方式。该项目汇集了两个团队，联合收割机结合了果蝇先天和后天嗅觉行为的长期专业知识，以及最近的补充重点氧化应激，能量代谢和神经胶质细胞的相互作用，最近的高调出版物和未发表的数据。这两个伙伴之间的专题和技术互补性对于实施跨模式办法至关重要，而跨模式办法是实现本项目目标的关键。通过本提案中定义的三个目标，我们将建立（i）参与嗅觉和嗅觉记忆的神经元回路和神经胶质细胞功能衰退的多模态图，（ii）挑战记忆回路-神经元和神经胶质细胞-对氧化应激的敏感性，最后（iii）调查能量代谢障碍和认知缺陷之间的因果关系。该项目的目标是在果蝇中描述年龄诱导的脑功能衰退的基本机制，并回答为什么一些神经回路和神经过程对衰老更敏感的问题，期望我们的研究结果为识别并最终保护人类对年龄敏感的脑细胞和回路铺平道路。

Decline in brain function, and the accompanying loss in cognitive abilities, is one of the most incapacitating consequences of aging. Although it is becoming clear that not all neural circuits nor brain functions are equally affected by aging, we still do not know the physiological characteristics that render certain cells or circuits more prone to dysfunction. Metabolic deficits, oxidative damage, and altered neuronal signaling are three functional manifestations of aging in brain tissues in many species. The objective of this project is to determine the causal relationships between declines of these modalities and their implication in aging-induced memory deficits. The Drosophila nervous system meets the major requirements to address this question, as being, first, well characterized at the cellular and circuit level, second, subject to natural aging on a time scale compatible with scientific research, and finally, amenable to in vivo imaging of these modalities. This project brings together two teams that combine long-standing expertise in innate and learned olfactory behavior in Drosophila, as well as a recent complementary focus on oxidative stress, energy metabolism and neuron-glia interaction as witnessed by recent high-profile publications and unpublished data. The thematic and technical complementarities between the two partners are essential to implement a cross-modality approach that is key to reach the objective of this project. Through the three aims defined in this proposal, we will establish (i) a multimodal map of functional decline in neuronal circuits and glial cells involved in olfaction and olfactory memory, (ii) challenge the sensitivity of memory circuits –neurons and glia– to oxidative stress, and finally (iii) investigate the causal link between impairments in energy metabolism and cognitive deficits. The ambition of this project is to characterize in Drosophila, the fundamental mechanisms responsible for age-induced functional decline of brain function, and answer the question why some neural circuits and neural processes are more sensitive to aging, with the expectation that our findings shall pave the way to identify and ultimately protect age-sensitive brain cells and circuits in humans.