Award details

Vector Trace cells in the Subiculum of the hippocampal formation

Reference	BB/T014768/1
Principal Investigator / Supervisor	Professor Colin Lever
Co-Investigators / Co-Supervisors	Dr Steven Poulter
Institution	Durham University
Department	Psychology
Funding type	Research
Value (£)	380,430
Status	Current
Type	Research Grant
Start date	01/09/2020
End date	30/11/2023
Duration	39 months

Abstract

Understanding how the hippocampus supports spatial memory is a major goal of research globally. Here, we focus on one kind of spatial memory: remembering how far away and in what direction space-defining cues are located, that is, vector memory. Cognitive processes such as path-planning and imagination entail recall of vector representations, but single-neuron evidence for such vector memory has been lacking. Importantly, we have found exactly such evidence of vector memory: a novel neuron type, here called the Vector Trace cell (VTC), located in the subiculum. VTCs remember the distance and direction to an object for at least a few hours after that object is removed. VTCs likely support computing the spatial relationships between an animal and multiple cues (or between different cues), freed from the constraints of perceiving those cues. This enables more powerful spatial planning and imaginative cognition than would be the case for vector system without memory. Clearly, if we want to understand exactly how hippocampus supports spatial memory, then we must understand how the hippocampal produces vector-based spatial memory. This entails appreciating the particular role of the subiculum, where VTCs are located, and which is a key output region of the hippocampus. In humans at least, it may be the most crucial hippocampal region for interacting with the rest of the brain since it has been identified as the hippocampal node in the 'default mode network'. This grant aims to deliver a step-change in the understanding of hippocampal vector coding by delivering insights into: how the subiculum is organised functionally into different divisions, with one of these divisions supporting vector memory; the mechanisms of how individual vector trace cells generate vector coding and form and maintain vector memories, and how long this memory lasts; and finally how vector coding of external cues influences grid cell coding.

Summary

It is well established that the hippocampus supports spatial memory, navigation, planning, and imagination. Understanding how the hippocampus supports these functions is a major goal of intense, high-profile research globally. Here, we focus on a particular kind of spatial memory: remembering how far away and in what direction space-defining cues are located. This is called vector memory, and we think it is crucial to hippocampal function. Theoretical and empirical work has indicated that spatial mapping relies, broadly speaking, on two kinds of sensory inputs: one derived from self-motion cues, one from external environmental cues. Regarding self-motion, we can get some idea of where we are by estimating how far we have moved and in what direction, for instance from clues such as the motor and sensory systems informing us of the vigour and number of strides taken, and the degree of stride extension. Of course, the spaces around us are not 'empty', but filled with various external cues such as boundaries, objects and goals (like home bases). To navigate effectively, an animal must also encode how far away and in what direction such space-defining external cues are located. Cognitive processes such as path-planning and imagination entail the ability to remember such vector representations, but evidence that there are neurons that can provide such vector memory has been lacking. Importantly, then, we have recently found exactly such evidence of vector memory: a novel neuron type, which we call the Vector Trace cell (VTC), located in a region of the hippocampal formation called the subiculum. VTCs remember the distance and direction to an object for hours after that object is removed. We suspect that at least some VTCs can remember this for days, which we will test. It seems likely that VTCs provide memories for computing the spatial relationships between an animal and multiple cues (or between different cues), freed from the constraints of having to directly perceive those cues. This enables more powerful spatial planning and imaginative cognition than would be the case for a system that could not remember these spatial relationships. Indeed we speculate there might be some cognitive functions that are not obviously spatial, but rely on vector coding in more than one dimension, that VTCs could support, if the input to them was for example verbal information. Clearly, if we want to understand exactly how hippocampus supports spatial memory, navigation, planning, and imagination, which is intensively researched globally, then we will need to understand how the hippocampus produces vector-based spatial memory. This cannot be achieved without appreciating the particular contribution of the subiculum, where we have discovered Vector Trace cells, and which is a key output region of the hippocampal formation. In humans at least, it may be the most crucial hippocampal region for interacting with the rest of the brain in a network called the 'default mode network'. Autobiographical memories, creative thought, daydreaming, imagination and future-oriented speculation and plans are all thought to be highly dependent upon this 'default mode network'. We suspect that vector-based cognition and memories support these wider memory-based and creative functions. This grant aims to deliver a step-change in the understanding of hippocampal vector coding by delivering insights into: how the subiculum is organised functionally into different divisions, with one of these divisions supporting vector memory; the mechanisms of how individual vector trace cells generate vector coding and form and maintain vector memories, and how long this memory lasts; and finally how vector coding of external cues influences spatial mapping that is reliant, for its moment-to-moment activity, on self-motion.

Impact Summary

UUnderstanding how the hippocampus supports spatial memory, navigation, planning, and imagination is a major goal of intense, high-profile research globally. Accordingly, there is an established audience of researchers around the world who are interested in publications delivering insights into spatial neurons in the hippocampal formation. In particular, since vector coding in the hippocampal formation is emerging as a 'hot topic' internationally, we would anticipate that our findings will be of clear interest to these researchers, and inform their future research. Furthermore, neuron-level insights into spatial memory would be of interest to a wider community of researchers who are interested in the hippocampal mechanisms of memory, but not necessarily vector memory, and those who are interested in general principles of neural coding including vector coding memory in humans. Wider still, we suspect that our insights into vector memory will supply useful information for research in fields of computational modelling, robotics, and potentially linguistics, and supply models for cellular investigation in rodent models of dementia. Who will benefit? Beyond the clear benefits to the academic community described above, we have established clear pathways to ensure other communities can potentially profit from our research. These include clinicians, journalists, and interested members of the general public. How will they benefit? It is not within the scope of this research to generate insights which help to develop therapy cures for diseases and disorders affecting the hippocampal formation. However, many diseases and disorders involve neuronal damage in the hippocampal formation, and in the subiculum in particular, notably Alzheimer's disease, epilepsy, and depression. Thus, information on how vector memory operates in the subiculum can in principle, in the longer term, guide the development of diagnostic tools, such as for Alzheimer's. It is increasingly recognised that spatial memory may be a royal road to early detection of Alzheimer's disease in humans (Coughlan et al, 2018, Nature Neuroscience Reviews) and indeed, though it is not a primary focus of our group, we do participate in some of this work. In the longer term, findings may have relevance for modelling Alzheimer's Disease in rodents, as the early hippocampal pathology described in many mouse-AD models is actually subicular (e.g. arctic mutation, ABPP/PS1), concomitant with one high-sampling study (n>5000) in humans where the only one of 12 hippocampal regions whose volume predicted subsequent conversion to AD-dementia was subiculum (Evans et al, 2018, Neuroimage). We would argue much basic research needs to be reasonably mature before clinical advances can be realised. However, these advances are unlikely to be achieved without interactions with clinicians and medically-oriented researchers. To try to help with this, we run an annual meeting called NEURACLIN. The aims of NEURACLIN are to bring together academics and clinicians, but also the lay public. At our 2017, held at James Cook University Hospital (NHS South Tees), attendance was evenly split between academics, clinicians and the general public. NEURACLIN 2018, held at Durham University, saw many clinically focused talks. Furthermore, we have links to NHS Trusts in the North of England. CL is already collaborating with Dr Stephen Evans (NHS Consultant Clinical Psychologist, York Teaching Hospitals NHS Trust) on the 'Detecting Dementia Earlier' Project (REC ID: 207985). As part of this work, we also collaborate with the Tees, Wear and Esk Valley NHS Trust, South Tees NHS Trust, York and Leeds NHS Trust. This access to NHS clinicians and Trusts allows us to be better placed to disseminate and translate our work to the clinic.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
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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