Biology subjects

Pallud, J.

Publications and source records attributed to Pallud, J..

4 recordsLinked to original sources

bioRxiv2026

Epileptogenesis dynamics driven by peritumoral circuit rewiring in gangliogliomas

Gangliogliomas (GGs) are emblematic low-grade epilepsy-associated tumors, yet the developmental mechanisms underlying their epileptogenicity remain unclear. Here, we investigated how tumor-network interactions evolve across postnatal maturation using an in-utero electroporated BRAFV600E-driven mouse model combining multiscale electrophysiology with histology, single-nucleus RNA sequencing, and complementary analyses in human GG tissue. We show that GGs induce early and evolutive modification of cortical organization and glioneuronal architecture. Despite glioneuronal preservation, seizure initiation shifted from distal cortical regions at postnatal stages to tumor-adjacent areas in adult networks. In both mouse and human, GG slices exhibited seizure activity localized to the peritumoral cortex. At the cellular level, neurons exhibited a developmental arrest of intrinsic electrophysiological maturation from postnatal to adult stages. Transcriptomic profiling identified stage-specific neuronal remodeling, with early alterations in inhibitory neurons and later changes affecting excitatory populations. Such developmental spatial seizure dynamics were associated with a pharmacological shift as NKCC1 inhibition with bumetanide selectively reduced seizure-like activity in neonatal but not mature tumor networks, indicating a restricted window of chloride-dependent epileptogenesis relevant to GABAergic maturation. Together, our results demonstrate that GG-associated epileptogenesis arises from developmentally regulated tumor-network interactions, highlighting distinct cellular and molecular mechanisms across maturation and revealing potential age-specific therapeutic targets.

neuroscience↗

bioRxiv2026

Human primary auditory cortex and insula encode perceptual decisions, not stimulus features

The traditional view of perceptual decision-making assumes a largely feedforward cortical hierarchy, in which sensory regions encode stimulus features that are progressively integrated with top-down signals in higher order associative areas to guide decisions. However, recent work has cast doubt on whether stimulus-and decision-related signals actually follow such a predicted spatiotemporal organization, especially in naturalistic situations where sensory cues are subtle and decisions more strongly driven by internal strategies. Leveraging the unique spatiotemporal precision of human intracerebral recordings, we map here how stimulus and decision variables are represented along the auditory cortical hierarchy as patients engage in a social voice decision task with realistic, low-salience cues. Contrary to feedforward predictions, we found no clear spatial or temporal gradient separating stimulus- and decision-related effects; rather, decision effects emerged early during stimulus exposure and, strikingly, flowed back all the way to the most primary regions of the superior temporal gyrus. In addition, the direction of these early and primary decision signals closely reflected the variability in patients specific decision criteria. Taken together, these results strongly challenge the traditional feedforward model, supporting a view in which the activity of early auditory regions does not reflect subtle stimulus categories but is instead dynamically configured by task-dependent priors and response strategies. Significant StatementThis work studies an ecological social-cognitive decision task based on subtle but natural vocal cues. Contrary to expectations, it shows that early and primary auditory activity in human intracerebral recordings does not reflect stimulus categories but instead patients decisions and decision criteria. These results are significant because they provide rare human intracerebral evidence that sensory regions are not static repositories of stimulus representations but rather dynamic, task-dependent filters that are configured by priors and decision criteria.

neuroscience↗

bioRxiv2025

Mapping glioblastoma spreading: connexin43 and glial dynamic in mouse and human glioblastoma microenvironment

High-grade gliomas (HGGs), including astrocytoma and glioblastoma (GBM), constitute the most prevalent primary tumors of the central nervous system (CNS). GBM cells demonstrate a notable ability to infiltrate the brain parenchyma, precluding complete surgical resection. Here we investigated the spreading of GBM cells and the response of the CNS microenvironment focusing on glial cells, which are essential interactors to GBM. We used acute and organotypic slices from the mouse brain and peritumoral cortex of patients with HGGs. We found that human peritumoral tissue from cortical resection was characterized by high levels of the astrocytic Connexin43 protein (Cx43) and discrete infiltration of microglia. In contrast, the tumor core exhibited high myeloid infiltration and an altered extracellular matrix (ECM) composition, which was poor in CD44. We tracked mouse and primary human-labeled-GBM cells in 2D cultures and in co-culture with organotypic slices generated from mouse brain and human peritumoral tissues. We found that the implanted GBM cells infiltrated the brain tissue, implying early glial modifications including an increase in Cx43 expression and distribution. Furthermore, the blockage of Cx43 hemichannels was accompanied by morphological changes and polarization of human GBM cells, typical for migration phenomena. The present study sheds light on the dynamics of GBM cells spreading in the living brain tissue, suggesting that the progression of the tumor correlates with changes within the host brain. Our findings identify the upregulation of Cx43 expression as a highly consistent modification in both mouse and human tissue that may be crucial for GBM infiltration.

neuroscience↗

bioRxiv2025

NKCC1 as a signaling hub regulating KCC2 stability, chloride homeostasis, and seizure susceptibility

Chloride homeostasis relies on the dynamic balance between the neuronal co-transporters NKCC1 and KCC2. We reveal an unexpected mechanism by which NKCC1 governs KCC2 membrane stability. NKCC1 clusters recruits SPAK and PP1 to dynamically trap KCC2, compensating for its lack of a direct SPAK-binding site. Single-particle tracking shows that these NKCC1-rich assemblies operate as signaling hubs, enabling either SPAK-driven KCC2 phosphorylation and its membrane destabilization or PP1-mediated dephosphorylation of SPAK and KCC2 membrane stabilization. Peptides that activate SPAK by engaging NKCC1s PP1-binding motif lower KCC2 surface levels and reduce chloride extrusion, whereas a SPAK-inhibiting peptide prevents SPAK recruitment to NKCC1, stabilizes KCC2 in membrane clusters, and enhances chloride extrusion. An optimized peptide analog preserves KCC2 clustering under hyperexcitable conditions, reduces seizure frequency and severity in PTZ-induced epilepsy, and suppresses ictal activity in human epileptic tissue. These findings identify NKCC1-KCC2 coupling as a central regulatory axis for inhibitory signaling, and position our peptides as promising therapeutic candidates to restore chloride homeostasis in epilepsy and other disorders marked by impaired KCC2 membrane stability.

neuroscience↗