The Nucleus Reuniens as a key control point for effects of light on learning and memory

认知的许多方面，包括决策、学习和记忆，都受到我们日常光照模式的影响。这些影响包括大脑功能的长期变化，包括光对我们体内生物钟的影响，以及由于持续的光暴露而导致的更直接的表现变化。我们的现代生活方式(减少暴露在自然日光下，夜间过量光线，倒班工作等)不以最佳方式进行此类行动，可能会损害绩效和生产力，并导致与衰老或神经退行性疾病相关的认知能力下降。这项提案将定义光线在认知功能上产生剧烈和长期变化的机制，这些信息对于我们优化环境和工作实践以最大化健康、福祉和生产力至关重要。我们的建议建立在我们令人兴奋的新的初步数据的基础上，这些数据已经确定了一个特定的大脑区域，即重新连接核(NRE)，它是时钟和光依赖的学习和记忆效应的关键枢纽。NRE已经被建立为两个对记忆和认知至关重要的大脑区域--海马体和内侧前额叶皮质(MPFC)之间沟通的重要中继站。因此，NRE活动对记忆获得和回忆的各个方面都是必不可少的。我们的新数据现在揭示，NRE包含不同的细胞组，大脑的中央时钟，视交叉上核(SCN)，驱动日常活动节律，以及其他通过部分视觉丘脑(IGL/vLGN)显示光依赖的活动变化。基于这些发现和该领域的其他最新进展，我们在这里测试了这些时钟和光依赖通路在以下方面的作用：1)调节NRE向海马体和mPFC的输出，2)影响这些大脑区域和学习和记忆相关方面的沟通(和功能)，以及3)在与记忆破坏或增强相关的环境条件下推动神经和认知功能的长期变化。为此，我们的建议借鉴了项目组在涉及昼夜、视觉和记忆处理的神经网络中大规模记录活动的免费专业知识，以及记忆获取和提取的整个动物评估方法。与最新的神经科学工具一起，有选择地操纵大脑回路的活动。使用这些方法，我们将能够专门识别SCN、IGL/vLGN和NRE中的关键细胞群，定义它们的独特属性，并选择性地操纵它们的活动，最终确定它们在网络(包括与记忆相关的急性和长期变化)和整个动物水平上调节认知功能的角色。关键的是，我们还处于独特的地位，可以解决将动物研究的发现转化为人类应用的特定障碍。到目前为止，这一领域的研究绝大多数使用了夜间活动的啮齿动物(小鼠和大鼠)，对于时钟或光驱动的认知功能控制的重要方面将在多大程度上保留在像我们这样的白天物种中，仍然存在不确定性。我们已经建立了一个强大的新的白天活跃的实验室啮齿动物模型，该模型与小鼠Rhabdomys密切相关，使我们能够解决这些重要的未知问题，最大限度地发挥我们的发现的翻译潜力，并为认知控制和昼夜偏好的潜在机制提供亟需的洞察。总而言之，这项工作将全面定义NRE在光对学习和记忆的即时和长期影响中的作用，这些作用如何影响白天和夜间活动的哺乳动物的环境，并为促进人类和动物最佳认知功能的实际应用提供洞察。

Many aspects of cognition, including decision making learning and memory, are influenced by our daily patterns of light exposure. Such influences encompass long-term changes in brain function, involving effects of light on our internal body clock, as well as more immediate changes in performance as a result of ongoing light exposure. Our modern lifestyles (reduced exposure to natural daylight, excess nighttime light, shift work etc.) do not optimally engage such actions and can impair performance, productivity and contribute to the cognitive decline associated with ageing or neurodegenerative diseases. This proposal will define mechanisms by which light produces acute and longer-term changes in cognitive function, information that is critical if we are to optimise environments and working practices to maximise health, well-being and productivity. Our proposal builds on our exciting new preliminary data which has identified a specific brain region, the nucleus reuniens (NRe) as a key hub for clock and light-dependent effects on learning and memory. The NRe is already established as an essential relay station for communication between two brain regions critical for memory and cognition - the hippocampus and medial prefrontal cortex (mPFC). Accordingly NRe activity is essential for various aspects of memory acquisition and recall. Our new data now reveals that the NRe contains distinct groups of cells where the brain's central clock, the suprachiasmatic nucleus (SCN), drives daily activity rhythms and others that show light-dependent changes in activity via a portion of the visual thalamus (IGL/vLGN). Based on these finds, and other latest advances in the field, we here test the roles of these clock and light-dependent pathways in: 1) regulating NRe output to the hippocampus and mPFC, 2) influencing communication between (and function of) those brain regions and associated aspects of learning and memory and 3) driving long-term changes in neural and cognitive function under environmental conditions associated with memory disruption or enhancement.To this end, our proposal draws on the complimentary expertise of the project team in large scale recording activity across neural networks involved in circadian, visual and memory processing and approaches for whole animal assessments of memory acquisition and retrieval, alongside the latest neuroscience tools for selectively manipulating the activity of brain circuity. Using such approaches we will be able to specifically identify key cell populations in SCN, IGL/vLGN and NRe, define their unique properties and selectively manipulate their activity to definitively determine their roles in modulating cognitive function at the network (including both acute and long-lasting changes associated with memory) and whole animal levels. Critically, we are also uniquely placed to address a particular barrier towards translating findings from animal research to inform applications in humans. To date, studies in this area have overwhelmingly employed nocturnal rodents (mice and rats) and there remains uncertainty regarding to extent to which important aspects of clock or light-driven controls on cognitive function will be retained in diurnal species such as ourselves. We have established a powerful new day-active laboratory rodent model that is closely related to mice, Rhabdomys, allowing us to address these important unknowns, maximising the translational potential of our findings and providing much-needed insight into mechanisms underlying cognitive control and day/night preference. Collectively then this work will comprehensively define the roles of the NRe in both immediate and long-term effects of light on learning and memory, how these contribute to impacts of the environment across day and night-active mammals and provide insight into practical applications that could promote optimal cognitive function in humans and animals.