Award details

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

Reference	BB/W015692/1
Principal Investigator / Supervisor	Professor Timothy Brown
Co-Investigators / Co-Supervisors	Dr John Gigg, Professor Robert Lucas
Institution	The University of Manchester
Department	School of Medical Sciences
Funding type	Research
Value (£)	674,649
Status	Current
Type	Research Grant
Start date	01/11/2022
End date	31/10/2025
Duration	36 months

Abstract

It is well established that light exposure exerts practically important acute and longer-term effects on cognition, including modulating learning and memory, and that modern patterns of light exposure often do not optimally engage such actions. Hence there is significant interest in defining mechanisms underlying beneficial and detrimental effects of light exposure with a view to improving health, productivity and performance. Such mechanisms are, currently, incompletely understood but are known to involve actions on the central circadian clock (suprachiasmatic nucleus, SCN) as well as clock-independent effects of light. Our latest data identifies the thalamic nucleus reuniens (NRe) as ideally positioned to mediate both such effects of light. The NRe is critical for communication between hippocampus and medial prefrontal cortex (mPFC) and necessary for aspects of memory known to be circadian and/or light regulated. Accordingly, we find the NRe receives input from the SCN and visual thalamic regions (IGL/vLGN) which drive circadian and light-dependent activity in distinct neuronal subpopulations. Here, we employ large-scale multielectrode recordings, behavioural assessments and the latest systems neuroscience tools to comprehensively define: 1) the properties of SCN and IGL/vLGN neurons innervating the NRe and their influence on output to hippocampus and mPFC, 2) their roles in regulating hippocampal-mPFC communication and function (including cellular correlates of memory) and associated aspects of memory and 3) their contributions to long-term beneficial and/or detrimental effects associated with altered lighting environments. Critically, throughout, we maximise both fundamental biological insight and translational potential by incorporating complimentary studies in mice and a closely-related diurnal species, Rhabdomys. In sum, this will significantly advance understanding of environmental impacts on mammalian health and inform future practical applications.

Summary

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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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