Biology subjects

Mercier, M.

Publications and source records attributed to Mercier, M..

10 recordsLinked to original sources

bioRxiv2026

Surprise gates two distinct mechanisms to support memorability in music

Music is a uniquely memorable human creation that, when skillfully composed, can persist in individual memory (as in e.g., earworms) and cultural transmission (e.g. global hits or anthems). While both acoustic and statistical properties are known to influence a songs memorability, the neural mechanisms that facilitate the engramming of certain musical sequences remain unclear. Current theories suggest that memory systems function as predictive internal models, enhancing learning when expectations are violated. Yet expected stimuli, by aligning with and reinforcing prior knowledge, also enhance memorability. How these two opposing processes arise from the brains sensitivity to statistical regularities, especially in naturalistic sequences, is not well understood. Here, we leveraged musics intrinsic balance between expectancy and surprise, and examined the neural correlates of minutes-scale memorability using intracranial EEG recordings from nine patients with epilepsy performing a musical memory task. Quantifying the statistical surprise of each musical excerpt with PolyRNN, a polyphonic model of musical expectations, we uncovered a U-shaped relationship between musical surprise and memory performance: both highly expected and highly surprising melodies led to greater memorability. While neural pattern similarity between song repetitions was enhanced for low-surprise stimuli, high-surprise stimuli enhanced neural pattern separability in medial temporal regions, each mediating memorability in distinguishable ways. These findings reveal complementary neural mechanisms through which statistical structure shapes musical sequence memory, clarifying how the brain encodes complex, ecologically valid stimuli.

neuroscience↗

bioRxiv2025

Coupled rhythms in early auditory cortex mirror speech acoustics

Theta and gamma neural dynamics dominate the human auditory cortex during speech perception and have been proposed to track syllable boundaries and encode phonemic information, respectively. To what extent these rhythms are intrinsically generated or imposed by speech acoustics remains unsolved. Applying analytic methods from neuroscience to speech audio corpora from 17 languages, we found that canonical brain features --theta, gamma, and their phase-amplitude coupling-- are a robust and specific acoustic signature of speech envelope across languages. They represent syllabic rate (2-6 Hz), vocalic features (30-50 Hz), and fundamental frequency (100-150 Hz). Intracerebral (sEEG) recordings from the auditory cortex of 18 epilepsy patients revealed that theta-gamma dynamics and their coupling are absent at rest. They emerge during speech perception and are linearly driven by the acoustic envelope, consistent with an evoked origin. Nevertheless, these responses originate from distinct yet functionally interconnected neural populations, indicating that the early auditory cortex demultiplexes speech timescales. Thus, early auditory cortex mirrors theta-gamma speech rhythms across segregated neural populations. IN BRIEFEarly auditory cortex demultiplexes speech: stimulus-locked gamma activity aligns theta phase with the nested acoustic structure, functionally organising speech timescales

neuroscience↗

bioRxiv2025

Interplay of synaptic and backpropagating signals in neurogliaform dendrites

Inhibitory interneurons are conventionally thought to support precise timing of neural activity and regulation of circuit excitability, whilst principal neurons are the main locus of synaptic plasticity. Recent evidence for long-term potentiation (LTP) at glutamatergic synapses on GABAergic interneurons calls for close attention to the sub-cellular phenomena that underlie the induction of plasticity in aspiny dendrites. Neurogliaform interneurons, in particular, exhibit large NMDA receptor-mediated currents, robust Hebbian LTP and pronounced supralinear summation of glutamatergic signals converging on dendritic compartments. Unlike pyramidal neurons, however, dendritic supralinearity in interneurons operates independently of sodium channels. Here we investigate the principles governing supralinear synaptic integration and how it interacts with backpropagating action potentials in the context of synaptic plasticity. We developed a biophysically realistic, multi-compartmental model of a murine hippocampal neurogliaform interneuron, with dendritic architecture and ion channel densities tuned to match ex vivo recordings. The interaction of synaptic inputs and action potential were validated with patch-clamp electrophysiology and two-photon imaging of dendritic calcium-dependent fluorescence transients. We show that, whether simulated glutamatergic excitatory postsynaptic potentials are clustered on a dendritic fragment or dispersed across the entire arbor, they summate supralinearly as assessed from the calculated somatic voltage response. Clustered inputs however induce more pronounced local depolarizations and calcium transients than dispersed inputs. Action potentials generated at the soma backpropagate throughout the dendritic arbor but are attenuated at branch points. Coincident synaptic input and backpropagating action potentials relieve this attenuation, further enhance dendritic depolarizations, and greatly potentiate calcium influx via NMDA receptors. Despite differences in dendritic anatomy and in the roles of sodium channels, the interplay of orthodromic and antidromic voltage propagation and resultant calcium signal amplification exhibits remarkable similarities between neurogliaform interneurons and principal cells. Author summaryLearning and memory are believed to rely in large part on the brains ability to strengthen excitatory connections among principal cells. Potentiation of excitation must however be balanced by inhibition. Our study focuses on a key player in this balancing act: the neurogliaform interneuron, which exerts a powerful inhibition of the apical dendrites of principal neurons in the cortex and hippocampus. Recent work has revealed that both principal neurons and neurogliaform interneurons amplify coincident excitatory signals in their extensively branching dendrites. Key to the induction of synaptic potentiation is the coincidence of orthodromic depolarization arising from synapses and action potentials generated at or near the cell body. We asked how these electrical signals interact, using a blend of computer simulations and experimental manipulations. Unlike principal neurons, neurogliaform interneurons are devoid of dendritic spines, and voltage-gated sodium channels are dispensable for boosting of synaptic depolarization. Nevertheless, the core principle that coincident orthodromic and antidromic signals leads to widespread depolarization spreading throughout the dendritic arbor is conserved between these neurons. The conclusions of this work shed light not only on healthy brain function but also on common disorders such as epilepsy and schizophrenia, which abnormal dendritic function has been implicated.

neuroscience↗

bioRxiv2025

A2AR-mediated inhibition of B cell maturation: a novel mechanism of immune suppression in cancer

High levels of extracellular adenosine, highly abundant in the tumor microenvironment, promote immune suppression mainly through the A2AR expressed by tumor-infiltrating immune cells. Here we show that plasma cells are the most negatively affected by adenosine among the immune cells present in the tumor microenvironment. Furthermore, both tonsillar and tumor-associated B cells, including germinal center (GC)-like B cells, plasma cells and plasma blasts (PCs and PBs, respectively, and collectively referred to as antibody-secreting cells (ASCs), express high levels of A2AR. Given the importance of tumor-infiltrating B and PCs in antitumor responses, we investigated how adenosine impairs their numbers and function. Triggering of A2AR inhibited B cell maturation into ASCs and immunoglobulin production in vitro, and impaired upregulation of PC genes upon stimulation. These effects were restored by inupadenant (EOS100850), a potent and highly selective small molecule A2AR antagonist. Spatial transcriptomics analysis of tumor biopsies from patients treated with inupadenant revealed that ASCs specifically increased in tertiary lymphoid structures. Altogether, these data demonstrate that A2AR plays a key role in adenosine-mediated inhibition of B cell maturation toward ASCs through a B cell-intrinsic mechanism, and that this effect is fully reverted by inupadenant.

immunology↗

bioRxiv2024

Multi-stream predictions in human auditory cortex during natural music listening

Musical expectations shape how we perceive and process music, yet current computational models are limited to monophonic or simplified stimuli. The study of the neural processes underlying musical expectations in real-world music therefore requires significant advances in our statistical modeling of these stimuli. We present PolyRNN, a recurrent neural network designed to model expectations in naturalistic, polyphonic music. We recorded neurophysiological activity non invasively (MEG) and within the human brain (intracranial EEG) while participants listened to naturally expressive piano recordings. The musical expectations estimated by the model are encoded in evoked P2- and P3-like components in auditory regions. Comparing PolyRNN to a state-of-the-art generative music model, we show that piano roll representations are best suited to represent expectations in polyphonic contexts. Overall, our approach provides a new way to capture the musical expectations emerging from natural music listening, and enables the study of predictive processes in more ecologically valid settings.

neuroscience↗

bioRxiv2024

Frequency coding of multisensory integration in the local field potentials of the medial pulvinar

The pulvinar is a posterior thalamic nucleus, with a heterogeneous anatomo-functional organization. It is divided into four parts, including the medial pulvinar, which is densely connected with primary unisensory and multisensory cortical regions, and subcortical structures, including the superior colliculus. Based on this connectivity, the medial pulvinar may play an important role in sensory processing and multisensory integration. However, its contribution to multisensory integration has rarely been directly investigated. To fill this knowledge gap, two macaque monkeys were trained on a fixation task, during which auditory, visual and audiovisual stimuli were presented. We characterize local field potentials of the medial pulvinar associated with these stimuli. In the temporal domain, we describe an early and a late period showing multisensory integration, both dominated by sub-additive processes (the audiovisual response is inferior to the sum of the unisensory responses). In the frequency domain, multisensory integration, mostly sub-additive, is predominant in the lower frequencies (90% of recorded signals in 4.5-8.5Hz and 96% in 8.5-20Hz). Prevalence largely decreases in high frequencies (54% in 35-60Hz, 37% in 60-120Hz). This suggests that the medial pulvinar is a multisensory hub, integrating visual and auditory information in different frequency bands and contributing to cortico-pulvino-cortical multisensory computational loops.

neuroscience↗

bioRxiv2024

Constitutive sodium permeability in a C. elegans two-pore domain potassium channel

Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematode C. elegans has one of the largest K2P families, with 47 subunit-coding genes. This remarkable expansion has been accompanied by the evolution of atypical selectivity filter sequences that diverge from the canonical TxGYG motif. Whether and how this sequence variation may impact the function of K2P channels has not been investigated so far. Here we show that the UNC-58 K2P channel is constitutively permeable to sodium ions and that a cysteine residue in its selectivity filter is responsible for this atypical behavior. Indeed, by performing in vivo electrophysiological recordings and Ca2+ imaging experiments, we demonstrate that UNC-58 has a depolarizing effect in muscles and sensory neurons. Consistently, unc-58 gain-of-function mutants are hypercontracted, unlike the relaxed phenotype observed in hyperactive mutants of many neuromuscular K2P channels. Finally, by combining molecular dynamics simulations with functional studies in Xenopus laevis oocytes, we show that the atypical cysteine residue plays a key role in the unconventional sodium permeability of UNC-58. As predicting the consequences of selectivity filter sequence variations in silico remains a major challenge, our study illustrates how functional experiments are essential to determine the contribution of such unusual potassium channels to the electrical profile of excitable cells. SIGNIFICANCEPotassium channels play a central role in modulating cellular excitability, particularly of neuronal cells. Their unique structure determines their ability to let ions pass selectively through cell membranes. The impact of pathological or evolutionary variations in this selectivity filter remains difficult to predict. Here, we reveal that UNC-58, a member of the two-pore domain potassium channel family of C. elegans, exhibits an unusual sodium permeability due to a unique cysteine residue in its selectivity filter. Our findings underscore the importance of functional studies to determine how sequence variation in potassium channel selectivity filters can shape the electrical profiles of excitable cells.

physiology↗

bioRxiv2023

Enhanced neuroimaging with a calcium sensor in the live adult Drosophila Melanogaster brain using closed-loop adaptive optics light-sheet microscopy

AO_SCPLOWBSTRACTC_SCPLOWWe report on an Adaptive Optics (AO) Light-Sheet Fluorescence Microscope compatible with neuroimaging, based on direct wavefront sensing without the requirement of a guide star. We demonstrate fast AO correction, typically within 500ms, of in-depth aberrations of the live adult Drosophila brain, enabling to double the contrast when imaging with structural or calcium sensors. We quantify the gain in terms of image quality on multiply neuronal structures part of the sleep network in the Drosophila brain, at various depths, and discuss the optimization of key parameters driving AO such as the number of corrected modes and the photon budget. We present a first design of a compact AO add-on that is compatible with integration into most of reported Light-Sheet setups and neuroimaging.

biophysics↗

bioRxiv2022

Speech and music recruit frequency-specific distributed and overlapping cortical networks

To what extent does speech and music processing rely on domain-specific and domain-general neural networks? Using whole-brain intracranial EEG recordings in 18 epilepsy patients listening to natural, continuous speech or music, we investigated the presence of frequency-specific and network-level brain activity. We combined it with a statistical approach in which a clear operational distinction is made between shared, preferred, and domain-selective neural responses. We show that the majority of focal and network-level neural activity is shared between speech and music processing. Our data also reveal an absence of anatomical regional selectivity. Instead, domain-selective neural responses are restricted to distributed and frequency-specific coherent oscillations, typical of spectral fingerprints. Our work highlights the importance of considering natural stimuli and brain dynamics in their full complexity to map cognitive and brain functions.

neuroscience↗

bioRxiv2017

Reliable CRISPR/Cas9 genome engineering in Caenorhabiditis elegans using a single efficient sgRNA and an easily selectable phenotype

CRISPR/Cas9 genome engineering strategies allow the directed modification of the C. elegans genome to introduce point mutations, generate knock-out mutants and insert coding sequences for epitope or fluorescent tags. Three practical aspects however complicate such experiments. First, the efficiency and specificity of single-guide RNAs (sgRNA) cannot be reliably predicted. Second, the detection of animals carrying genome edits can be challenging in the absence of clearly visible or selectable phenotypes. Third, the sgRNA target site must be inactivated after editing to avoid further double-strand break events. We describe here a strategy that addresses these complications by transplanting the protospacer of a highly efficient sgRNA into a gene of interest to render it amenable to genome engineering. This sgRNA targeting the dpy-10 gene generates genome edits at comparatively high frequency. We demonstrate that the transplanted protospacer is cleaved at the same time as the dpy-10 gene. Our strategy generates scarless genome edits because it no longer requires the introduction of mutations in endogenous sgRNA target sites. Modified progeny can be easily identified in the F1 generation, which drastically reduces the number of animals to be tested by PCR or phenotypic analysis. Using this strategy, we reliably generated precise deletion mutants, transcriptional reporters, and translational fusions with epitope tags and fluorescent reporter genes. In particular, we report here the first use of the new red fluorescent protein mScarlet in a multicellular organism. wrmScarlet, a C. elegans-optimized version, dramatically surpassed TagRFP-T by showing an 8-fold increase in fluorescence in a direct comparison.

genetics↗