Biology subjects

Guardamagna, M.

Publications and source records attributed to Guardamagna, M..

8 recordsLinked to original sources

bioRxiv2026

The emergence of a novel CA1 spatial map requires direct entorhinal input

The hippocampus and its main input, the entorhinal cortex, are essential for memory formation, yet how they interact to do so remains unresolved. Hippocampal CA1 pyramidal neurons exhibit spatial receptive fields which reorganize unpredictably upon exposure to a novel environment, a process called remapping, considered a model of memory formation. CA1 neurons integrate both hippocampal and direct entorhinal inputs, but their relative contributions to spatial coding are unclear. Here we combined population recordings of CA1 neurons with optogenetic silencing of their direct entorhinal input. While this manipulation did not impact spatial firing in a familiar environment, it impaired remapping in a novel environment, resulting in the emergence of a stable hybrid map combining features of both environments. This shows the direct entorhinal pathway plays a specific role in CA1 novelty detection, enabling the plasticity necessary to drive the reorganisation of spatial firing patterns, preventing interference between memories in different contexts.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2023

Direct Entorhinal Control of CA1 Temporal Coding

During behavior, hippocampal neurons fire in consistent theta sequences, organized by the theta rhythm, which have been linked to predictive coding of future actions. The mechanisms of sequence generation are yet unclear, but in the hippocampal CA1 subfield, are thought to involve both major input streams into CA1 neurons, from CA3 pyramidal neurons and directly from entorhinal cortex. We disentangled the role of these two afferent input with highly specific optogenetic inhibition limited to the direct entorhinal afferents of CA1, thereby leaving the rest of the hippocampal-entorhinal circuit intact. While CA1 spatial firing properties were largely unaffected, theta phase precession was largely abolished. Surprisingly, while theta phase precession is thought to generate theta sequences, theta sequences were actually strengthened when it was suppressed. These results suggest that sequence generation is internal to the hippocampus, while the entorhinal inputs may act as a supervisory signal driving learning and representational updates.

neuroscience↗

bioRxiv2022

State Dependent Coupling of Hippocampal Oscillations

Oscillations occurring simultaneously in a given area represent a physiological unit of brain states. They allow for temporal segmentation of spikes and support distinct behaviors. To establish how multiple oscillatory components co-varies simultaneously and influence neuronal firing during sleep and wakefulness, we describe a multi-variate analytical framework for constructing the state space of hippocampal oscillations. Examining the co-occurrence patterns of oscillations on the state space, across species, uncovered the presence of network constraints and distinct set of cross-frequency interactions during wakefulness as compared to sleep. We demonstrated how the state space can be used as a canvas to map the neural firing and found that distinct neurons during navigation were tuned to different set of simultaneously occurring oscillations during sleep. This multivariate analytical framework provides a window to move beyond classical bivariate pipelines, for investigating oscillations and neuronal firing, thereby allowing to factor-in the complexity of oscillation-population interactions.

neuroscience↗

bioRxiv2021

Distinct hippocampal network states support theta phase precession and theta sequences in CA1

Theta sequences and phase precession shape the activity time course of hippocampal place cells. Theta sequences are rapid sweeps of spikes from multiple cells, tracing trajectories from past to future. Phase precession is the correlation between a place cells theta firing phase and animal position. Here we present an analysis of the strongly variable character of these features in CA1. We identify a cell group that do not phase precess but reliably express theta sequences. The cells that do phase precess only do so when the medium gamma oscillations (60-90 Hz, linked to Entorhinal inputs) dominates but then they show less theta sequences. The same cells express more sequences but not precession when slow gamma (20-45 Hz, linked to CA3 inputs) dominates. Moreover, sequences occur independently in the two groups. Our results challenge a causal relationship between precession and sequences and highlights the highly heterogeneous character of the hippocampal output.

neuroscience↗

bioRxiv2021

The Hybrid Drive: a chronic implant device combining tetrode arrays with silicon probes for layer-resolved ensemble electrophysiology in freely moving mice

Understanding the function of brain cortices requires simultaneous investigation at multiple spatial and temporal scales and to link neural activity to an animals behavior. A major challenge is to measure within- and across-layer information in actively behaving animals, in particular in mice that have become a major species in neuroscience due to an extensive genetic toolkit. Here we describe the Hybrid Drive, a new chronic implant for mice that combines tetrode arrays to record within-layer information with silicon probes to simultaneously measure across-layer information. The design of our device combines up to 14 tetrodes and 2 silicon probes, that can be arranged in custom arrays to generate unique areas-specific (and multi-area) layouts. We show that large numbers of neurons and layer-resolved local field potentials can be recorded from the same brain region across weeks without loss in electrophysiological signal quality. The drives lightweight structure ({approx} 3.5 g) leaves animal behavior largely unchanged during a variety of experimental paradigms. We demonstrate how the data collected with the Hybrid Drive allow state-of-the-art analysis in a series of experiments linking the spiking activity of CA1 pyramidal layer neurons to the oscillatory activity across hippocampal layers. Our new device fits a gap in the existing technology and increases the range and precision of questions that can be addressed about neural computations in freely behaving mice.

neuroscience↗

bioRxiv2018

The Hex-Maze: A previous knowledge task for mice

New information is rarely learned in isolation, instead most of what we experience can be incorporated into or uses previous knowledge networks in some form. However, most rodent laboratory tasks assume the animal to be naive with no previous experience influencing the results. Previous knowledge in form of a schema can facilitate knowledge acquisition and accelerate systems consolidation: memories become more rapidly hippocampal independent and instead rely more on the prefrontal cortex. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze - the HexMaze. Analysing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge accelerating both online learning and performance increases over offline periods. Importantly, we are the first to show that schema build-up is dependent on how much time passes, not how often the animal is trained.

animal behavior and cognition↗