Biology subjects

Moser, M.-B.

Publications and source records attributed to Moser, M.-B..

At least 19 recordsLinked to original sources

bioRxiv2026

Toroidal topology of grid-cell activity precedes spatial navigation during development

The medial entorhinal cortex (MEC) is a central component of the mammalian navigation system1-5, in which spatially and directionally tuned neurons, including grid cells and head-direction cells, encode an animals position and orientation6-8. These cells form internal maps with periodic topologies: head-direction cells traverse ring-like manifolds9,10, while grid cells are organized on toroidal manifolds11. The persistence of these topologies across behavioral states and environments11,12 raises the possibility that they arise intrinsically from network architecture rather than through sensory experience4,5,13-17. Consistent with this view, observations in juvenile rats have shown that rudimentary spatial tuning appears in place cells, head direction cells and grid cells almost as soon as pups begin to explore their surroundings at 2-3 weeks of age18-20. However, it remains unclear whether spatial experience is required for the initial emergence of positional tuning and for the organization of tuned cells into periodic maps. Here we show, using large-scale ensemble recordings in rat pups, that toroidal manifolds emerge in MEC subnetworks as early as postnatal day 10 (P10), preceding eye and ear opening, upright posture, quadrupedal gait, and active exploration21,22. These toroidal networks were modular from the beginning, with increasing differentiation of their dynamics appearing on P11-12. The onset of toroidal topology coincided with a transition in MEC network activity characterized by desynchronization and increased inhibitory connectivity, a developmental shift observed broadly across cortical regions at this age23,24. In contrast, ring-like manifolds were already detectable by P9, with traces of directional tuning appearing in individual cells at P8 -- consistent with an earlier maturation of subcortical circuitry25. As pups subsequently began to explore the environment around P15-16, these internally generated maps progressively aligned with external landmarks, culminating in stable, periodic firing fields by three weeks of age. Taken together, these findings identify ring-like and toroidal manifolds as instinctive computational motifs of the developing brain. Their early emergence, preceding major sensory input and navigation, supports the view that spatial representations are preconfigured and later anchored to the external world through experience-dependent plasticity.

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bioRxiv2026

Attention-like regulation of theta sweeps in the brain's spatial navigation circuit

Spatial attention supports navigation by prioritizing information from selected locations. A candidate neural mechanism is provided by theta-paced sweeps in grid- and place-cell population activity, which sample nearby space in a left-right-alternating pattern coordinated by parasubicular direction signals. During exploration, this alternation promotes uniform spatial coverage, but whether sweeps can be flexibly tuned to locations of particular interest remains unclear. Using large-scale Neuropixels recordings in freely-behaving rats, we show that sweeps and direction signals are rapidly and dynamically modulated: they track moving targets during pursuit, precede orienting responses during immobility, and reverse during backward locomotion--without prior spatial learning. Similar modulation occurs during REM sleep. Canonical head-direction signals remain head-aligned. These findings identify sweeps as a flexible, attention-like mechanism for selectively sampling allocentric cognitive maps.

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bioRxiv2025

Functional independence of entorhinal grid cell modules enables remapping in hippocampal place cells

A systems-level understanding of cortical computation requires insight into how neural codes are transformed across distinct brain circuits. In the mammalian cortex, one of the few systems where such transformations are tractable is the spatial mapping circuit. This circuit comprises interconnected regions of medial entorhinal cortex (MEC) and hippocampus, which encode location using fundamentally different neural codes. A key distinction is that neural activity in MEC, including that of directionally tuned cells and grid cells, evolves along low-dimensional manifolds, preserving stable phase relationships across different environments and behaviors1-8. In contrast, hippocampal place cells frequently undergo global remapping: their collective firing patterns reorganize randomly across different environments9-12, revealing an apparently limitless repertoire of orthogonal spatial representations12-14. The mechanisms by which spatial maps are transformed between the two coding schemes remain unresolved. Here, we used large-scale multi-area Neuropixels recordings to show that when rats were transferred from one familiar environment to another, each module of grid cells underwent a unique change in phase on its low-dimensional manifold, at the same time as simultaneously recorded place cells exhibited global remapping. In contrast, training conditions that produced smaller differences in the phase shifts of simultaneously recorded grid modules resulted in incomplete place cell remapping, mirroring previous reports of partial remapping15-19. Hippocampal remapping was not associated with rotational differences between grid modules under any condition. Taken together, these findings suggest that differential phase shifts across grid cell modules form the basis for the orthogonalization of downstream hippocampal spatial codes during remapping. The transformation from low-dimensional spatial representations in the MEC to high-dimensional codes in the hippocampus may underlie the hippocampus ability to support high-capacity memory storage3,13,14,20-22.

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bioRxiv2024

Event structure sculpts neural population dynamics in the lateral entorhinal cortex

Our experience of the world is a continuous stream of events which must be segmented and organized simultaneously at multiple timescales. The neural mechanisms underlying this process remain unknown. Here, we simultaneously recorded many hundreds of neurons in the lateral entorhinal cortex (LEC) of freely behaving rats as we manipulated event structure at multiple timescales. During foraging as well as during sleep, population activity drifted continuously and unidirectionally along a one-dimensional manifold. Boundaries between events were associated with discrete shifts in state space, suggesting that LEC dynamics directly reflect event segmentation. During tasks with a recurring temporal structure, activity traveled additionally in directions orthogonal to the flow of drift, enabling the LEC population to multiplex event information across different timescales. Taken together, these results identify a hierarchically organized neural coding scheme for segmenting and organizing events in time.

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bioRxiv2024

Left-right-alternating theta sweeps in the entorhinal-hippocampal spatial map

Place cells in the hippocampus and grid cells in the entorhinal cortex are elements of a neural map of self-position1-5. To benefit navigation, this representation must be dynamically related to surrounding locations2. A candidate mechanism for linking places along an animals path has been described in place cells, where the sequence of spikes within each cycle of the hippocampal theta oscillation encodes a trajectory from the animals current location towards upcoming locations6-8. In mazes that bifurcate, such trajectories alternately traverse the two upcoming arms as the animal approaches the choice point9,10, raising the possibility that the trajectories express available forward paths encoded on previous trials10. However, to bridge the animals path with the wider environment, beyond places previously or subsequently visited, an experience-independent spatial sampling mechanism might be required. Here we show in freely moving rats, that within individual theta cycles, ensembles of grid cells and place cells encode a position signal that sweeps linearly outwards from the animals location into the ambient environment, with sweep direction alternating stereotypically between left and right across successive theta cycles. These sweeps were accompanied by, and aligned with, a similarly alternating directional signal in a discrete population of parasubiculum cells with putative connections to grid cells via conjunctive gridxdirection cells. Sweeps extended into never-visited locations that were inaccessible to the animal and persisted during REM sleep. Sweep directions could be explained by an algorithm that maximizes cumulative coverage of surrounding space. The sustained and unconditional expression of theta-patterned left-right-alternating sweeps in the entorhinal-hippocampal positioning system provides an efficient look-around mechanism for sampling locations beyond the travelled path.

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bioRxiv2023

Investigating egocentric tuning in hippocampal CA1 neurons using simulated data

Navigation requires integrating sensory information with a stable schema to create a dynamic map of an animals position using egocentric and allocentric coordinate systems. In the hippocampus, place cells encode allocentric space, but their firing rates may also exhibit directional tuning within egocentric or allocentric reference frames. We compared experimental and simulated data to assess the prevalence of tuning to egocentric bearing (EB) among hippocampal cells in rats foraging in an open field. Using established procedures, we confirmed egocentric modulation of place cell activity in recorded data; however, simulated data revealed a high false positive rate. When we accounted for false positives by comparing with shuffled data that retain correlations between the animals direction and position, only a very low number of hippocampal neurons appeared modulated by EB. Our study highlights biases affecting false positive rates and provides insights into the challenges of identifying egocentric modulation in hippocampal neurons.

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bioRxiv2023

The influence of environment geometry on subiculum boundary vector cells in adulthood and early development

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animals location as a vector displacement from boundaries. Here we report the first objective characterisation of the prevalence and spatial tuning of subiculum BVCs. Manipulations of boundary geometry reveal two novel features of BVC firing. Firstly, BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Secondly, inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space.

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bioRxiv2022

Object-centered population coding in CA1 of the hippocampus

Objects and landmarks are crucial for guiding navigation and must be integrated into the cognitive map of space. Studies of object coding in the hippocampus have primarily focused on activity of single cells. Here we record simultaneously from large numbers of hippocampal CA1 neurons to determine how the presence of a salient object in the environment alters single-neuron and neural-population dynamics of the area. Only a small number of cells fired consistently at the object location, or at a fixed distance and direction from it; yet the majority of the cells showed some change in their spatial firing patterns when the object was introduced. At the neural population level, these changes were systematically organized according to the animals distance from the object. This organization was widely distributed across the cell sample, suggesting that some features of cognitive maps - including object representation - are best understood as emergent properties of neural populations.

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bioRxiv2022

Minute-scale oscillatory sequences in medial entorhinal cortex

The medial entorhinal cortex (MEC) hosts many of the brains circuit elements for spatial navigation and episodic memory, operations that require neural activity to be organized across long durations of experience1. While location is known to be encoded by a plethora of spatially tuned cell types in this brain region2-6, little is known about how the activity of entorhinal cells is tied together over time. Among the brains most powerful mechanisms for neural coordination are network oscillations, which dynamically synchronize neural activity across circuit elements7-10. In MEC, theta and gamma oscillations provide temporal structure to the neural population activity at subsecond time scales1,11-13. It remains an open question, however, whether similarly powerful coordination occurs in MEC at behavioural time scales, in the second-to-minute regime. Here we show that MEC activity can be organized into a minute-scale oscillation that entrains nearly the entire cell population, with periods ranging from 10 to 100 seconds. Throughout this ultraslow oscillation, neural activity progresses in periodic and stereotyped sequences. This activity was elicited while mice ran at free pace on a rotating wheel in darkness, with no change in its location or running direction and no scheduled rewards. The oscillation sometimes advanced uninterruptedly for tens of minutes, transcending epochs of locomotion and immobility. Similar oscillatory sequences were not observed in neighboring parasubiculum or in visual cortex. The ultraslow oscillation of activity sequences in MEC may have the potential to couple its neurons and circuits across extended time scales and to serve as a scaffold for processes that unfold at behavioural time scales, such as navigation and episodic memory formation.

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bioRxiv2021

All-viral tracing of monosynaptic inputs to single birthdate-defined neurons in the intact brain

Neuronal firing patterns are the result of inputs converging onto single cells. Identifying these inputs, anatomically and functionally, is essential to understand how neurons integrate information. Single-cell electroporation of helper genes and subsequent local injection of recombinant rabies viruses enable precise mapping of inputs to individual cells in superficial layers of the intact cortex. However, access to neurons in deeper structures requires more invasive procedures, including removal of overlying tissue. We have developed a method that through a combination of virus injections allows us to target [≤]4 hippocampal cells 48% of the time and a single cell 16% of the time in wildtype mice without the use of electroporation or tissue aspiration. We identify local and distant monosynaptic inputs that can be functionally characterised in vivo. By expanding the toolbox for monosynaptic circuit tracing, this method will help further our understanding of neuronal integration at the level of single cells.

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bioRxiv2021

Large-scale two-photon calcium imaging in freely moving mice

We developed a miniaturized two-photon microscope (MINI2P) for fast, high-resolution, multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice. With a microscope weight below 3g and a highly flexible connection cable, MINI2P allowed imaging to proceed with no impediment of behavior in half-hour free-foraging trials compared to untethered, unimplanted animals. The improved cell yield was achieved through a new optical system design featuring an enlarged field of view (FOV) and a new micro-tunable lens with increased z-scanning range and speed that allowed for fast and stable imaging of multiple, interleaved planes as well as 3D functional imaging. A novel technique for successive imaging across multiple, adjacent FOVs enabled recordings from more than 10,000 neurons in the same animal. Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing spatial tuning of cells in all areas, including visual cortex. HighlightsWe developed a lightweight 2-photon miniscope for imaging in freely-foraging mice Activity can be monitored in volumes of over 1,000 visual or entorhinal-cortex cells A new z-scanning module allows fast imaging across multiple interleaved planes Successive imaging from adjacent regions enables imaging from more than 10,000 cells

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bioRxiv2021

Functional network topography of the medial entorhinal cortex

The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here we examined the topographic arrangement of spatially modulated neurons in MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD and OV cells tended to intermingle. These data suggest that grid-cell networks might be largely distinct from those of border, HD and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types. Highlights- Grid and object vector cells show low levels of regional co-occurrence - Grid cells exhibit the strongest tendency to cluster among all spatial cell types - Grid cells stay separate from border, head direction and object vector cells - The territories of grid, head direction and border cells remain stable over weeks

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bioRxiv2021

Grid-cell modules remain coordinated when neural activity is dissociated from external sensory cues

The representation of an animals position in the medial entorhinal cortex (MEC) is distributed across several modules of grid cells, each characterized by a distinct spatial scale. The population activity within each module is tightly coordinated and preserved across environments and behavioral states. Little is known, however, about the coordination of activity patterns across modules. We analyzed the joint activity patterns of hundreds of grid cells simultaneously recorded in animals that were foraging either in the light, when sensory cues could stabilize the representation, or in darkness, when such stabilization was disrupted. We found that the states of different grid modules are tightly coordinated, even in darkness, when the internal representation of position within the MEC deviates substantially from the true position of the animal. These findings suggest that internal brain mechanisms dynamically coordinate the representation of position in different modules, to ensure that grid cells jointly encode a coherent and smooth trajectory of the animal.

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bioRxiv2021

Stimulus features that elicit activity in object-vector cells

Object-vector (OV) cells are cells in the medial entorhinal cortex (MEC) that track an animals distance and direction to objects in the environment. Their firing fields are defined by vectorial relationships to free-standing 3-dimensional (3D) objects of a variety of identities and shapes. However, the natural world contains a panorama of objects, ranging from discrete 3D items to flat two-dimensional (2D) surfaces, and it remains unclear what are the most fundamental features of objects that drive vectorial responses. Here we address this question by systematically changing features of experimental objects. Using an algorithm that robustly identifies OV firing fields, we show that the cells respond to a variety of 2D surfaces, with visual contrast as the most basic visual feature to elicit neural responses. The findings suggest that OV cells use plain visual features as vectorial anchoring points, allowing vector-guided navigation to proceed in environments with few free-standing landmarks.

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bioRxiv2021

Toroidal topology of population activity in grid cells

The medial entorhinal cortex (MEC) is part of a neural system for mapping a subjects position within a physical environment1,2. Grid cells, a key component of this system, fire in a characteristic hexagonal pattern of locations3, and are organized in modules4,5 which collectively form a population code for the animals allocentric position1,6-8. The invariance of the correlation structure of this population code across environments9,10 and behavioural states11,12, independently of specific sensory inputs, has pointed to intrinsic, recurrently connected continuous attractor networks (CANs) as a possible substrate of the grid pattern1,2,13-16. However, whether grid cell networks show continuous attractor dynamics, and how they interface with inputs from the environment, has remained elusive due to the small samples of cells obtained to date. Here we show, with simultaneous recordings from many hundreds of grid cells, and subsequent topological data analysis, that the joint activity of grid cells from an individual module resides on a toroidal manifold, as expected in a two-dimensional CAN. Positions on the torus correspond to the moving animals position in the environment. Individual cells are preferentially active at singular positions on the torus. Their positions are maintained, with minimal distortion, between environments and from wakefulness to sleep, as predicted by CAN models for grid cells but not by alternative feed-forward models where grid patterns are created from external inputs by Hebbian plasticity17-22. This demonstration of network dynamics on a toroidal manifold provides the first population-level visualization of CAN dynamics in grid cells.

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bioRxiv2020

Task-dependent mixed selectivity in the subiculum

CA1 and subiculum (SUB) connect the hippocampus to numerous output regions. Cells in both areas have place-specific firing fields, although they are more dispersed in SUB. Weak responses to head direction and running speed have been reported in both regions. However, how such information is encoded in CA1 and SUB, and the resulting impact on downstream targets, is poorly understood. Here we estimate the tuning of simultaneously recorded CA1 and SUB cells to position, head direction, and speed. Individual neurons respond conjunctively to these covariates in both regions but the degree of mixed representation is stronger in SUB, and more so during goal-directed spatial navigation than free foraging. Each navigational variable could be decoded with higher precision, from a similar number of neurons, in SUB than CA1. The findings point to a possible contribution of mixed-selective coding in SUB to efficient transmission of hippocampal representations to widespread brain regions.

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bioRxiv2019

During hippocampal inactivation, grid cells maintain their synchrony, even when the grid pattern is lost

The grid cell network in the MEC has been subject to thorough testing and analysis, and many theories for their formation have been suggested. To test some of these theories we re-analyzed data from Bonnevie et al. (2013), in which the hippocampus was inactivated and grid cells were recorded in the MEC, to investigate whether the firing associations of grid cells depend on hippocampal inputs. Specifically, we examined temporal and spatial correlations in the firing times of simultaneously recorded grid cells before and during hippocampal inactivation. Our analysis revealed evidence of network coherence in grid cells even in the absence of hippocampal input to the MEC, both in regular grid cells and in those that became head-direction cells after hippocampal inactivation. This favors models which suggest that phase relations between grid cells in the MEC are dependent on intrinsic connectivity within the MEC.

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bioRxiv2018

Object-vector coding in the medial entorhinal cortex

Mammals use distances and directions from local objects to calculate trajectories during navigation but how such vectorial operations are implemented in neural representations of space has not been determined. Here we show in freely moving mice that a population of neurons in the medial entorhinal cortex (MEC) responds specifically when the animal is at a given distance and direction from a spatially confined object. These object-vector cells are tuned similarly to a spectrum of discrete objects, irrespective of their location in the test arena. The vector relationships are expressed from the outset in novel environments with novel objects. Object-vector cells are distinct from grid cells, which use a distal reference frame, but the cells exhibit some mixed selectivity with head-direction and border cells. Collectively, these observations show that object locations are integrated in metric representations of self-location, with specific subsets of MEC neurons encoding vector relationships to individual objects.

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