Award details

Spatial coding in the hippocampal formation: boundaries and grids

Reference	BB/M008975/1
Principal Investigator / Supervisor	Professor Colin Lever
Co-Investigators / Co-Supervisors	Dr Thomas Wills
Institution	Durham University
Department	Psychology
Funding type	Research
Value (£)	400,662
Status	Completed
Type	Research Grant
Start date	16/03/2015
End date	15/03/2018
Duration	36 months

Abstract

The hippocampal formation (HF) is crucial for spatial & context-dependent (e.g. episodic) memory. Our sense of location & context is likely driven by HF place cells, which fire in context-dependent, specific locations. This sense-of-place derives from: 1) self-motion cues, and; 2) external environmental cues. Grid cells, which fire in a very geometric tile-like way throughout all environments, represent self-motion information. The recent discovery (by the PI & colleagues) of boundary vector cells (BVCs), which fire when an environmental boundary (e.g. walls, drop-offs) is located at a specific distance & allocentric direction from the subject, supplied the crucial missing piece in understanding the environmental cue contribution. What we now need is a systems-level understanding of how the representation of environmental boundaries is organised in the HF, and how boundary cells interact with other spatial cells. Performing 128-channel recording of ensembles of individual HF neurons and local field potentials in freely behaving rodents, and employing optogenetics to manipulate subsets of neurons and Virtual Reality to improve sensory control, we will: 1) explore functional anatomy of the subiculum and its role in HF processing; 2) establish causal relationships between fundamental units of spatial representation (boundary cells, grid cells, & place cells); 3) compare boundary cell responses, and the sensory mechanisms underlying boundary cell firing, in the subiculum vs entorhinal cortex. We will focus on: a) the role of the subiculum as an organizing centre for boundary representations; b) how the subiculum interacts with the entorhinal cortex & CA1. In doing so, we test our novel, provocative hypotheses that the subiculum contains an attractor network for boundary-dependent spatial coding, and that subiculum provides spatial input to the hippocampus. Our work may reveal general principles of the neural representation and organization of episodic memory.

Summary

Memory is central to our everyday lives, and make us who we are. An area of the brain called the hippocampal formation (HF) is crucial to some of the most useful memories we have (those that tell us where to find the people we care about, the food we want to eat, the places that promise excitement, and where to avoid places we might be scared of); and crucial to our most treasured memories (those memories of the events of our lives, such as first kisses, weddings, births, and deaths, that give us our identity and humanity). It turns out that the HF is crucial for a kind of spatial memory called allocentric spatial memory. Allocentric refers to large-scale or 'map-like' space, which is defined with reference to the environment as opposed to egocentric space, which is defined in relation to sensory organs like your retina and skin, and in relation to motor effectors like your limbs. Briefly, egocentric representations are crucial for behaviours such as catching a ball or picking fruit from a tree; but behaviours such as remembering the location of water-sources, and navigating long distances over natural terrain also require allocentric, map-like, representations. The hippocampal formation is also crucial for memory that relies on a representation of a context, such as episodic memory (for the events of our lives). It may be that the hippocampus provides a spatiotemporal context to which the contents of a memory (a bride, a mother, their seat locations, the chicken, bad jokes) can be bound. We know that the HF is crucial for these kinds of memories from many types of evidence, notably that patients with damaged hippocampi don't find their way about well, and can't easily form new episodic memories. Our sense of location & context is likely driven by HF 'place cells', that is, neurons which fire in context-dependent, specific locations. This sense-of-place derives from: 1) self-motion cues, and; 2) external environmental cues. 'Grid cells', which fire in a very geometric tile-like way throughout all environments, represent self-motion information. Like human A-Z atlases, tiling out equal-sided squares over town streets & buildings, the mammalian brain tiles out broadly-equilateral triangles over environments. The recent discovery by our research team of boundary vector cells. which fire when an environmental boundary (e.g. walls, drop-offs) is located at a specific distance & allocentric direction from the subject, supplied the crucial missing piece in understanding the environmental cue contribution. So we seem to know about neurons which establish spatial location based on our own movements, and about neurons which establish our spatial location based on where we are in relation to our surroundings. What we now need is a broad, systems-level understanding of how the representation of environmental boundaries is organised in the HF, and how boundary cells interact with other spatial cells. We go about this by recording a lot of individual neurons and also local field potentials (informing us about brain waves). To help us further manipulate particular subsets of neurons, while we record, we beam laser light at neurons that have been genetically modified to be affected (excited, inactivated) by laser light at particular frequencies. To be able to manipulate external environmental cues in a controlled way, we also employ Virtual Reality. We want to explore particular anatomical circuits in the HF, focusing on regions called the subiculum, which may be an organizing centre for boundary representations, and the entorhinal cortex and CA1, which are both strongly connected to the subiculum. We want to test our new ideas about how the subiculum is organised, and how it might provide boundary-related information to the HF. Our work is focused on spatial cognition and memory, but we hope to reveal general principles of the neural representation and organization of episodic memory.

Impact Summary

The immediate impact is driving fresh perspectives & new knowledge for academics working on the neuroscience of memory, spatial cognition, hippocampal formation, and computational modelling. Wider impact is mentioned below, & further detailed in the Pathways to Impact text. Long-term health benefits We describe engagement with other academics as a necessary first step towards health-related impacts. The transition from animal research to long-term health benefits is unlikely to bypass this route. The subiculum is a causally primary site in seizure generation in both human Temporal Lobe Epilepsy (TLE) and in the Pilocarpine rodent model of TLE. However, thus far, there has been a lack of exchange of ideas & findings between workers studying the normal function of the subiculum (physiology, memory, spatial cognition) and those working on disease states (epilepsies, dementia). Accordingly there is a real need to bring together subiculum researchers from both sides of the physiological/pathological coin. Our approach to meeting this need will be two-pronged. Firstly, we will organise a symposium on the subiculum, specifically inviting physiology-focused and pathology-focused researchers. The milestone target will be to have a Subiculum Symposium confirmed by April 2016. Secondly, we will organise a Special Issue devoted to the Subiculum. It will purposely be an Open Access Forum, such as provided by one of the Frontiers journals, in order to have the widest possible impact, allowing journalists and the public easy view. We expect that this will be an impactful coming-together, sparking up new dialogues and ideas, and we will hope to further build on this in the future. The first milestone target will be to have permission for the Subiculum Special Issue confirmed, with at least 10 contributors confirmed, by June 2017. The second milestone target will be to edit and publish the Special Issue by April 2018. We also set out potential long-term benefits relating to dementia models. The current grant studies both grid cells in the superficial entorhinal cortex, degeneration in which predicts dementia onset in humans, and spatial cells in the subiculum, which is the first site of pathology in many Alzheimer's-type dementia mouse models. Our work would provide a crucial functional characterisation at the cellular level, which is needed as an interface between molecular and behavioural levels. Analogously, one of us (TW) previously participated in a study of hippocampal place cells in the Tg2576 AD mouse, which involved a collaboration with a pharmaceutical company. In that study, we showed that disruptions to hippocampal place cell function in aged transgenic Tg2576 mice predicted memory impairment and correlated with plaque load. We believe that this kind of approach will become standard in sophisticated animal modelling to bridge the typically-large gap between molecular biology and gross behaviour. One lab may need first to characterise the subiculum spatial cells before another can design an experiment to assess how subicular cells are disrupted in an AD model, and to assess how prophylactic and therapeutic compounds may prevent or attenuate this disruption. Public engagement and societal impact We set out past examples of public engagement and societal impact as a guide to unpredictable future impact. We have both inspired and/or contributed to artistic ventures on neuroscientific concepts, as well as conventional public engagement. Both CL and TW will undertake to create free access websites giving information about the work of their labs within the grant period. Target milestone: Both websites up and running by June 2016. We describe past and suggest likely future contributions to economic and capacity-building benefits, and point out that we will be delivering a highly trained researcher with in-demand skills in techniques likely to be important in the foreseeable future.

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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