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

团聚核是光对学习和记忆影响的关键控制点

• 批准号: BB/W015692/1
• 负责人: Timothy Brown
• 金额: $ 85.96万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW015692%2F1
• 关键词: Nucleus; Reuniens; key; control; point

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.

认知的许多方面，包括决策学习和记忆，都受到我们日常曝光模式的影响。这些影响包括大脑功能的长期变化，包括光对我们内部生物钟的影响，以及由于持续的光照而导致的表现的更直接的变化。我们的现代生活方式（减少暴露于自然日光，过量的夜间光线，轮班工作等）不能最佳地参与这些行动，可能会损害表现，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。该提案将定义光在认知功能中产生急性和长期变化的机制，如果我们要优化环境和工作实践以最大限度地提高健康，福祉和生产力，这些信息至关重要。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，即核reuniens（NRe），作为学习和记忆的时钟和光依赖性影响的关键枢纽。NRe已经被确立为对记忆和认知至关重要的两个大脑区域-海马体和内侧前额叶皮层（mPFC）之间通信的重要中继站。因此，NRe活动对于记忆获得和回忆的各个方面都是必不可少的。我们的新数据现在显示，NRe包含不同的细胞群，其中大脑的中央时钟，视交叉上核（SCN），驱动日常活动节律和其他通过视觉丘脑（IGL/vLGN）的一部分显示光依赖性活动变化的细胞。基于这些发现，以及该领域的其他最新进展，我们在这里测试这些时钟和光依赖性通路的作用：1）调节NRe向海马和mPFC的输出，（2）影响沟通（和功能）这些大脑区域和相关方面的学习和记忆和3）驾驶长-在与记忆中断或增强相关的环境条件下，神经和认知功能的长期变化。为此，我们的建议借鉴了项目团队在跨昼夜节律、视觉和记忆处理所涉及的神经网络的大规模记录活动以及用于记忆获取和检索的整体动物评估的方法方面的互补专业知识，与最新的神经科学工具一起选择性地操纵大脑回路的活动。使用这些方法，我们将能够特异性地识别SCN，IGL/vLGN和NRe中的关键细胞群，定义它们的独特特性并选择性地操纵它们的活性，以确定它们在网络（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作用。至关重要的是，我们还处于独特的地位，可以解决将动物研究结果转化为人类应用的特殊障碍。到目前为止，这一领域的研究绝大多数采用了夜间活动的啮齿动物（小鼠和大鼠），并且仍然不确定生物钟或光驱动的认知功能控制的重要方面在白天活动的物种（如我们自己）中会保留到什么程度。我们已经建立了一个强大的新的白天活动的实验室啮齿动物模型，与小鼠密切相关，Rhabdomys，使我们能够解决这些重要的未知因素，最大限度地提高我们发现的转化潜力，并提供急需的洞察认知控制和昼夜偏好的机制。总的来说，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，并提供对实际应用的深入了解，可以促进人类和动物的最佳认知功能。