Biology subjects

Marcos, E.

Publications and source records attributed to Marcos, E..

8 recordsLinked to original sources

bioRxiv2025

A sensitivity-consistency trade-off in memory formation regulated by dentate gyrus inhibition

A core computational challenge for memory systems is the need to balance two opposing demands: (1) sensitivity to subtle input differences for flexible encoding, and (2) consistency to preserve stable, interference-resistant representations. How the brain dynamically regulates this trade-off remains unclear. Here, we show that modulating parvalbumin-expressing (PV+) interneurons in the dentate gyrus regulates this balance by shifting hippocampal computation between sensitivity and consistency regimes. Combining cell-type-specific pharmacogenetics, behavioral assays, and computational modeling, we found that reducing PV+-mediated inhibition during encoding enhanced the subsequent discrimination of similar inputs but it increased vulnerability to interference. In contrast, increased inhibition stabilized memory representations at the cost of discriminability. Together, the results establish PV+ interneurons as key modulators of hippocampal memory processing, enabling the system to prioritize either flexible updating or robust retention based on inhibitory tone at the time of encoding. This sensitivity-consistency continuum may reflect a fundamental organizing principle of memory computation.

neuroscience↗

bioRxiv2024

Influence of temporal information gaps on decision making: describing the dynamics of working memory

Decision making involves evaluating options and predicting their likely outcomes. Traditional laboratory studies of decision making often employ tasks involving the discrimination of perceptual evidence, where sensory information is constant and presented continuously. However, during natural behavior, decision making usually involves intermittent information streams, punctuated by periods with no input. To investigate decision making under such conditions, we designed a perceptual task where participants observed tokens sequentially jumping from a central circle to one of two peripheral targets, disappearing shortly after. Participants were required to report which target they believed would have received most tokens by the trials end. Half of the trials included a temporal gap, during which no information was displayed. To better understand decision-making dynamics, we introduced specific patterns of token jumps. We found that participants made choices with less available information and disproportionally weighted the information presented immediately after the gap more heavily than they did when no gap was present. Traditional computational models, which assume uniform or gradual decay or increase of weighting of information over time, could not account for this effect. A control task with randomly presented information further confirmed that the disproportionate weighting of post-gap information is a robust feature of the decision-making process. These findings highlight the importance of studying decision making in environments with intermittent information and temporal gaps, where the timing and structure of inputs critically shape behavior. Significance statementDecision making in real-world environments often involves intermittent information, where key evidence might be separated by temporal gaps. Our study demonstrate that people disproportionately rely on information received immediately after such gaps, weighting the same information more heavily than when no gap is present. Traditional decision-making models do not account for this effect, as they lack mechanisms to capture how temporal disruptions shape evidence weighting. By understanding how gaps influence decision making, this research provides insights into how people adapt their decisions in fluctuating environments, with implications for fields ranging from neuroscience to artificial intelligence.

neuroscience↗

bioRxiv2023

The structural landscape of the immunoglobulin fold by large-scale de novo design

De novo designing immunoglobulin-like frameworks that allow for functional loop diversification shows great potential for crafting antibody-like scaffolds with fully customizable structures and functions. In this work, we combined de novo parametric design with deep-learning methods for protein structure prediction and design to explore the structural landscape of 7-stranded immunoglobulin domains. After screening folding of nearly 4 million designs, we have assembled a structurally diverse library of [~]50,000 immunoglobulin domains with high-confidence AlphaFold2 predictions and structures diverging from naturally occurring ones. The designed dataset enabled us to identify structural requirements for the correct folding of immunoglobulin domains, shed light on {beta}-sheet-{beta}-sheet rotational preferences and how these are linked to functional properties. Our approach eliminates the need for preset loop conformations and opens the route to large-scale de novo design of immunoglobulin-like frameworks.

bioinformatics↗

bioRxiv2023

Antibodies halting motility in Mycoplasma pneumoniae reveal the dynamic nature of the adhesion complex

Mycoplasma pneumoniae is a bacterial wall-less human pathogen and the etiological agent of atypical pneumonia and tracheobronchitis in both adults and children. M. pneumoniae infectivity, gliding motility and adherence to host target respiratory epithelial cells are mediated by adhesin proteins P1 and P40/P90 forming a transmembrane complex that binds to sialylated oligosaccharides human cell ligands. Here we report the cryo-EM structure of P1 bound to the Fab fragment of monoclonal antibody P1/MCA4, which stops gliding and induces detachment of motile M. pneumoniae cells. On the contrary, polyclonal antibodies generated against the N-domain of P1 or against the whole ectodomain of P40/P90 have little or no effects on adhesion or motility. The epitope of P1/MCA4, centred on loop Thr1426-Asp1438 in the small C-terminal domain of P1, is inaccessible to antibodies in the "open" conformation of the adhesion complex, when ready for attachment to sialylated oligosaccharides. Mutations in the highly conserved Engelman motifs found in the transmembrane helix of P40/P90 also alter adhesion and motility. During the attachment/detachment cycle of the adhesion complex, the C-terminal domain of P1 experiences large conformational rearrangements that are hindered by the antibodies against the domain. Interfering with the gliding of mycoplasma cells suggests new ways to confront M. pneumoniae infections.

molecular biology↗

bioRxiv2022

Design of extended metal-binding β-sandwiches from de novo immunoglobulin domains

The antigen binding sites of antibodies, and derivatives such as scFvs, consist of an immunoglobulin structural framework that anchors hypervariable loops, and that is arranged as a dimer of {beta}-sandwiches (from the heavy and light chains) packing face-to-face. Yet, the naturally occurring dimer orientation of antibodies is not well suited for engineering rigid single-chain formats of increased stability and solubility, which are two key limitations of engineered antibodies. In this work, we computationally designed an extended 12-stranded {beta}-sandwich as a rigid single-chain dimer of de novo immunoglobulin domains interacting through an alternative edge-to-edge arrangement. The extended {beta}-sandwich was found to be hyperstable and structurally accurate as confirmed through X-ray crystallography. We functionalized this design by inserting a long EF-hand calcium-binding motif into the {beta}-hairpin bridge between both domains, showing high metal-binding affinity while remaining soluble and stable in solution. Finally, we propose a few designs with two EF-hand motifs in either or the same side of the scaffold with high-confidence structure predictions; altogether suggesting the robustness and versatility of our scaffold to harbor long functional loops. Our extended {beta}-sandwiches are structurally divergent to natural antibodies and open new avenues for incorporating multiple loop binding sites either for increased or bispecific activities.

biochemistry↗

bioRxiv2021

De Novo Design of Immunoglobulin-like Domains

Antibodies and antibody derivatives such as nanobodies contain immunoglobulin-like (Ig) {beta}-sandwich scaffolds which anchor the hypervariable antigen-binding loops and constitute the largest growing class of drugs. Current engineering strategies for this class of compounds rely on naturally existing Ig frameworks, which can be hard to modify and have limitations in manufacturability, designability and range of action. Here we develop design rules for the central feature of the Ig fold architecture - the non-local cross-{beta} structure connecting the two {beta}-sheets - and use these to de novo design highly stable seven-stranded Ig domains, confirm their structures through X-ray crystallography, and show they can correctly scaffold functional loops. Our approach opens the door to the design of a new class of antibody-like scaffolds with tailored structures and superior biophysical properties.

biochemistry↗

bioRxiv2019

d-Lysergic acid diethylamide has major potential as a cognitive enhancer

Psychedelic agonists of serotonin receptors induce neural plasticity and synaptogenesis, but their potential to enhance learning remains uncharted. Here we show that a single dose of d-LSD, a potent serotonergic agonist, increased novel object preference in young and adult rats several days after treatment. d-LSD alone did not increase preference in old animals, but could rescue it to young levels when followed by a 6-day exposure to enriched environment (EE). Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions, with alterations of long-range synapses. Better pattern separation within EE explained its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.

neuroscience↗

bioRxiv2018

Delay activity dynamics: task dependent time encoding and low dimensional trajectories

Our decisions often depend on multiple sensory experiences separated by time delays. The brain can remember these experiences and, simultaneously, estimate the timing between events. To understand the mechanisms underlying working memory and time encoding we analyze neural activity recorded during delays in four experiments on non-human primates. To disambiguate potential mechanisms, we propose two analyses, namely, decoding the passage of time from neural data, and computing the cumulative dimensionality of the neural trajectory over time. Time can be decoded with high precision in tasks where timing information is relevant and with lower precision when irrelevant for performing the task. Neural trajectories are always observed to be low dimensional. These constraints rule out working memory models that rely on constant, sustained activity, and neural networks with high dimensional trajectories, like reservoir networks. Instead, recurrent networks trained with backpropagation capture the time encoding properties and the dimensionality observed in the data.

neuroscience↗