Biology subjects

Stella, F.

Publications and source records attributed to Stella, F..

14 recordsLinked to original sources

bioRxiv2026

Taxon-in-context reveals ecological individuality in the human gut microbiome

Ecological theory holds that a microbe's role depends on its surrounding community. Yet abundance profiles and fixed ecological groupings leave its individual context implicit. We introduce taxon-in-context, a reproducible representation of each microbe's context within an individual's microbiome. Across 7,700 metagenomes, we show that common gut species occupy different contexts in different people. This flexibility peaked in early life and declined through adulthood, a pattern reproduced in a larger genus-level compendium. For selected species, context within each person's microbiome revealed age associations beyond species abundance and the person's context mixture. In an independent longitudinal urinary tract infection cohort, microbes switched contexts within individuals. Taxon-in-context enabled recurrence prediction where an abundance-based model performed near chance. Taxon-in-context and these findings expose a measurable, dynamic and individualized layer of microbiome organization, providing a basis for investigating why the same microbe or intervention may have different biological consequences across people.

systems biology↗

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

An ancestral haplotype of P2RX5 yields a B-cell surface marker and a promising multi-lineage immunotherapy target

While CD19- and BCMA-directed immunotherapies have improved outcomes for B-lymphoid and plasma cell malignancies, frequent relapses with antigen loss/downregulation highlight the need for new targets. Here, using transcriptomic datasets and newly-developed monoclonal antibodies, we show that P2RX5, long considered a pseudogene in humans, encodes a stable protein in 80% of individuals of African descent carrying the ancestral haplotype. Like CD19, P2RX5 displays B-cell lineage-restricted expression in normal tissues. Unlike CD19, P2RX5 is expressed not only in B-cell neoplasms, but also in T-cell leukemia (T-ALL) and multiple myeloma (MM). We developed P2RX5-directed bispecific T-cell engagers and CAR T cells, which killed T-ALL cells with no evidence of T-cell fratricide. These agents were non-inferior to FDA-approved CD19- and BCMA-directed immunotherapeutics in cell culture and xenograft models of Burkitt lymphoma and MM, while maintaining potency against CD19- and BCMA-negative variants. Hence, P2RX5 is a unique multi-lineage target for frontline or salvage immunotherapy.

cancer biology↗

bioRxiv2025

Harnessing the CD2 axis to broaden and enhance the efficacy of CAR T cell therapies

Patients with T-cell lymphomas and leukemias have overall poor outcomes due to the lack of targeted and effective treatments, particularly in the relapsed and refractory settings. Development of chimeric antigen receptor (CAR) T-cells against T-cell neoplasms is limited by a lack of discriminating T-cell antigens that allow for effective anti-tumor responses while preventing CAR T-cell fratricide. We hypothesized that targeting CD2, a pan-T-cell antigen, using anti-CD2 CAR T-cells engineered without CD2 expression (CART2), would support CAR T-cell manufacturability and preclinical efficacy. Optimized CD2-knockout CART2, generated using CRISPR-Cas9, eradicated primary patient-derived CD2+ hematological neoplasms in vitro and in vivo, secreted effector cytokines, and exhibited adequate proliferative capacity. Nevertheless, CD2 has a key costimulatory function, and its deletion could lead to CAR T-cell dysfunction. Therefore, we tested the role of the CD2:CD58 axis in CAR T-cells, using the anti-CD19 CART models. We demonstrate that CD2 loss attenuates CART19 efficacy by reducing avidity for tumor antigen, co-stimulation, and ultimately in vivo activity. Analogously, we show that tumor CD58 loss reduces CART19 efficacy. To overcome this issue, we developed a novel PD-1:CD2 switch receptor that rescues intracellular CD2 signaling, particularly when PD-L1 is engaged, resulting in improved in vivo outcomes. Collectively, we studied the role of CD2 both as a target for CAR T cell therapy and as a critical costimulatory protein, whose signaling can be rescued using the PD-1:CD2 switch receptor. This receptor can be incorporated into CAR T-cells and provides an effective strategy to overcome CD2-signaling deficiencies.

cancer biology↗

bioRxiv2024

Parallel maturation of hippocampal memory and CA1 task representations

Hippocampal-dependent memory is known to emerge late in ontogeny and its full development is protracted. Yet, the changes in hippocampal neuronal function that underlie this delayed and gradual maturation remain relatively unexplored. To address this gap, we recorded ensembles of CA1 neurons while charting the development of hippocampal-dependent spatial working memory (WM) in rat pups ([~]2-4weeks of age). We found a sharp transition in WM development, with age of inflection varying considerably between individual animals. In parallel with the sudden emergence of WM, hippocampal spatial representations became abruptly task specific, remapping between encoding and retrieval phases of the task. Further, we show how the development of task phase remapping could partly be explained by changes in place field size during this developmental period as well as the onset of precise temporal coordination of CA1 excitatory input. Together, these results suggest that a hallmark of hippocampal memory development may be the emergence of contextually specific CA1 representations driven by the maturation of CA1 micro-circuits.

neuroscience↗

bioRxiv2023

Sleep stages antagonistically modulate reactivation drift

Hippocampal reactivation of waking neuronal assemblies in sleep is a key initial step of systems consolidation. Nevertheless, it is unclear whether reactivated assemblies are static or whether they reorganize gradually over prolonged sleep. Here, we tracked reactivated CA1 assembly patterns over [~]20 hours of sleep/rest periods and related them to assemblies seen before or after in a spatial learning paradigm. We found that reactivated assembly patterns were gradually transformed and started to resemble those seen in the subsequent recall session. Periods of rapid eye movement (REM) sleep and non-REM (NREM) had antagonistic roles: while NREM accelerated the assembly drift, REM countered it. Moreover, only a subset of rate-changing pyramidal cells contributed to the drift, while stable firing rate cells maintained unaltered reactivation patterns. Our data suggest that prolonged sleep promotes the spontaneous reorganization of spatial assemblies, which can contribute to daily cognitive map changes or encoding new learning situations.

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

Hippocampal ripples coincide with ''up-state'' and cortical spindles in Retrosplenial Cortex

During NREM sleep hippocampal Sharp-wave ripples (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, Default Mode Network (DMN) areas interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in DMN areas are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the DMN and spindles, we combined cortical wide-field voltage imaging, ECoG, and hippocampal LFP recordings in anesthetized and sleeping mice. Here we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the Retrosplenial cortex. Furthermore, Retrosplenial transient activations and spindles predict Slow Gamma oscillations in CA1 during SWRs. Together, our results suggest that Retrosplenial-hippocampal interaction may be a central source of information exchange between cortex and hippocampus.

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↗

bioRxiv2022

Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep

Hippocampus-neocortex interactions during sleep are critical for memory processes: hippocampally-initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples are linked to generalized increases in neocortical cell activity and DOWN-UP state transitions. Yet, the spatial and temporal patterns of this exchange are unknown. With voltage imaging, electrocorticography, and laminarly-resolved hippocampal potentials, we characterized cortico-hippocampal interactions during anesthesia and NREM sleep. We observed neocortical activation transients spanning multiple spatial scales hinting at a quasi-critical regime. Transients were organized in a small number of functional networks matching known anatomical connectivity. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with the hippocampus. Interestingly, hippocampal slow gamma was the oscillation that best correlated with this neocortical network, outpacing ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bi-directional exchanges between hippocampus and neocortex.

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↗

bioRxiv2020

Schema-induced shifts in mice navigational strategies are unveiled by a minimal behavioral model of spatial exploration.

Shifts in spatial patterns produced during the execution of a navigational task can be used to track the effects of the accumulation of knowledge and the acquisition of structured information about the environment. Here we provide a quantitative analysis of mice behavior while performing a novel goal localization task in a large, modular arena, the HexMaze. To demonstrate the effects of different forms of previous knowledge we first obtain a precise statistical characterization of animals paths with sub-trial resolution and over different phases of learning. The emergence of a flexible representation of the task is accompanied by a progressive improvement of performance, mediated by multiple, multiplexed time scales. We then use a generative mathematical model of the animal behavior to isolate the specific contributions to the final navigational strategy. We find that animal behavior can be accurately reproduced by the combined effect of a goal-oriented component, becoming stronger with the progression of learning, and of a random walk component, producing choices unrelated to the task and only partially weakened in time.

neuroscience↗

bioRxiv2019

Partial coherence and frustration in self-organizing spherical grids

Nearby grid cells have been observed to express a remarkable degree of long-range order, which is often idealized as extending potentially to infinity. Yet their strict periodic firing and ensemble coherence are theoretically possible only in flat environments, much unlike the burrows which rodents usually live in. Are the symmetrical, coherent grid maps inferred in the lab relevant to chart their way in their natural habitat? We consider spheres as simple models of curved environments and, waiting for the appropriate experiments to be performed, we use our adaptation model to predict what grid maps would emerge in a network with the same recurrent connections, which on the plane produce coherence among the units. We find that on the sphere such connections distort the maps that single grid units would express on their own, and aggregate them into clusters. When remapping to a different spherical environment, units in each cluster maintain only partial coherence, similar to what is observed in disordered materials, such as spin glasses.

neuroscience↗

bioRxiv2017

How activity dependent feedback inhibition may maintain head direction signals in mouse presubiculum

Orientation in space is represented in specialized brain circuits. Persistent head direction signals are transmitted from anterior thalamus to the presubiculum, but the identity of the presubicular target neurons, their connectivity and function in local microcircuits are unknown. Here we examine how thalamic afferents recruit presubicular principal neurons and Martinotti interneurons and the ensuing synaptic interactions between these cells. Pyramidal neuron activation of Martinotti cells in superficial layers is strongly facilitating such that high frequency head directional stimulation efficiently unmutes synaptic excitation. Martinotti cell feedback plays a dual role: precisely timed spikes may not inhibit the firing of in-tune head direction cells, while exerting lateral inhibition. Autonomous attractor dynamics emerge from a modeled network implementing wiring motifs and timing sensitive synaptic interactions in the pyramidal - Martinotti cell feedback loop. This inhibitory microcircuit is therefore tuned to refine and maintain head direction information in the presubiculum.

neuroscience↗