B03
Grid cells are a special type of neurons in the brain that could help us understand why some individuals have a better sense of direction than others and how navigation and spatial memory could be improved. To address these important questions, this interdisciplinary project will combine research in rodents and humans across the lifespan and determine whether grid cells contribute to the preservation of cognitive abilities in so-called ‘SuperAgers’.
Principal Investigators
Dr. Vladislava Segen
Prof. Dr. Thomas Wolbers
Co-Workers
Tugce Belge
Marzieh Fereidouni
What are grid cells?
Grid cells form a neurocognitive circuit that provides a fundamental computation for navigation. As an animal moves around, a grid cell is active at a set of locations called firing fields. Strikingly, these firing fields are organized as a grid of equilateral triangles covering the floor of an environment. First discovered in the entorhinal cortex of rodents, grid cells have since been observed in multiple species, including humans (Jacobs et al., 2013). The key function of grid cells is to keep track of where we are in an environment, but they also seem to contribute more generally to the formation of episodic memories.
Are grid cells responsible for cognitive decline in old age?
A gradual decline of episodic memory capacity and spatial abilities is a typical finding in studies on cognitive ageing. While these deficits have often been linked to a degradation of hippocampal functioning, recent work has shown that impaired grid cell activity may also play a key role for the decline in navigation among older adults (Stangl et al., 2018). Furthermore, it has been proposed that the grid cell system also supports episodic memory (Sugar & Moser, 2019) and the organization of conceptual knowledge (Aronov, Nevers, & Tank, 2017; Constantinescu, O’Reilly, & Behrens, 2016). Thus, degradation of the grid cell system may be responsible for a more general cognitive decline observed in aging, but this hypothesis has yet to be tested.
Is it possible to improve computations in the grid cell network?
The hippocampus contains so-called place cells that are also involved in navigation and episodic memory formation. Importantly, place cells form representations that are unique to each environment, and these representations are consolidated during rest and sleep via a phenomenon called reactivation (Csicsvari & Dupret, 2014).
It is possible that the consolidation of place cell representations during rest and sleep contributes to the stability of grid cells. Supporting this idea is the observation that inactivation of hippocampal neurons leads to a sharp reduction in grid cell stability/periodicity (Bonnevie et al., 2013).
In humans, using conditions that are thought to encourage neural replay led to improvement in spatial and temporal memory tasks. However, it is currently unknown if the observed improvements on the behavioural level are associated with improved grid cell firing patterns.
What are the goals of this project?
The key goal of the project is tounderstand if grid cells represent a flexible neural resource that supports a wide range of cognitive functions including navigation and episodic memory and whether intact grid cells contribute to superior aging.
To do so the project will:
- Characterize the physiological mechanisms that result in a decline in grid cell function.
- Test if it is possible to improve grid cell computations by manipulating the neural replay of recent experiences.
- Characterize grid cell representations in older adults with superior cognitive functions (SuperAgers) and test if preserved grid cell function contributes to superior navigational and episodic memory performance in this special population.
This will be achieved using an interdisciplinary approach that capitalizes on single cell recordings in rodents and functional and structural neuroimaging in humans.
Mechanisms of grid cell stability in mice
Previous work in rodents has shown that visual landmarks play a key role in stabilising the firing fields of grid cells (Perez-Escobar et al., 2016). We hypothesize that when one explores a novel environment, associations between visual landmarks and the grid cell representation are formed so that on subsequent visits to this novel environment, the firing fields of grid cells remain stable. Critically, inter-individual differences in grid cell stability in new environments is expected to be a key determinant of individual levels of memory performance. We will test these hypotheses by recording grid cells as mice learn to navigate in environments with new configurations of visual landmarks. We expect that rapid stabilisation of grid cell representations will correlate with better navigation and spatial memory. In a second set of experiments, we will test whether place cell reactivation is associated with grid cell stability. We will use optogenetic tools to prolong place cell reactivation and determine whether this improves grid cell stability and memory performance. Finally, we will assess individual differences and age-related variability in cognitive performance of mice and test whether the cognitive profiles of mice are associated with grid cell stability.
Grid cell coding in SuperAgers
Previous human spatial navigation research has repeatedly shown that a fraction of older adults can perform similarly to young healthy controls. Furthermore, in our work we found that older adults who perform similarly to younger adults on a spatial navigation task also showed intact grid coding. Given that grid cell coding is likely to be a fundamental cognitive resource for episodic memory more generally, we will probe the relationship between grid cell integrity, age-related entorhinal pathology, and preserved mnemonic performance. To do this, we will determine whether firing properties of grid cells, head direction and speed cells in old mice are related to preserved performance in established memory tests (e.g. rewarded alternation, place preference). Secondly, in humans, we will test whether grid cell function in SuperAgers is comparable to their younger counterparts (50-60 year olds) and whether their grid cell function is related to performance on episodic memory and spatial navigation tasks. Importantly, we will also test whether SuperAgers show preserved grid cell function despite microstructural changes in EC, which would point to an increased resilience of the grid cell network to neurodegenerative processes.
A glimpse into the future
This project aims at establishing grid cell computations as a central neural resource that can support many facets of cognition across the lifespan. Based on this fundamental work, the long-term perspective of our project is to develop novel interventions – for example using immersive virtual reality or physical exercise – that can induce long-lasting improvements in the precision and stability of grid cell computations. If successful, this work would open up novel avenues for enhancing both navigation capacity and episodic memory across the lifespan, which would be an important contribution to helping older people maintain mobility and independence.