Biology subjects

De Santis, F.

Publications and source records attributed to De Santis, F..

4 recordsLinked to original sources

bioRxiv2025

A New Approach to Modeling LGMDR1: Pyrvinium-Treated capn3b crispant Zebrafish

The lack of an accurate animal model for LGMDR1 is a major obstacle to therapeutic development. While murine models do not replicate the human gene expression profile, zebrafish offers a promising alternative. We generated a capn3b mutant zebrafish, which showed minimal phenotypic changes. However, when this model was treated with pyrvinium, a Wnt signaling inhibitor, its gene expression patterns mimic those observed in LGMDR1 patients, reinforcing the role of the Wnt pathway in LGMDR1 pathology. This pharmacologically enhanced model, despite lacking a clear phenotype in young larvae, could serve as a valuable tool for identifying potential therapeutic targets upon further investigation and validation.

molecular biology↗

bioRxiv2025

A human spiking computational model to explore sound localization

Sound localization relies on precise processing of binaural cues in medial (MSO) and lateral superior olive (LSO). However, key questions remain on how these two nuclei perform their specific computations depending on sound frequency, the relative contributions of interaural time differences (ITDs) and interaural level differences (ILDs), as well as the role of inhibitory timings. Experimental studies have struggled to address these issues because of technical challenges and a lack of methodological consistency. Here, we present a comprehensive computational model of auditory peripheral and brainstem neural populations to investigate how ITDs and ILDs are encoded by LSO and MSO. We developed a spiking neural network with realistic tonotopic organization and biologically consistent synaptic connections. We tested responses to pure tones and white noise from different locations under three cue conditions: human-recorded head-related transfer functions, isolated ITDs, and isolated ILDs. LSO neurons showed realistic ipsilateral-preferring responses across different stimuli, with cue dependency varying by tone frequency, while white noise responses were driven mostly by ILDs. MSO responses showed heterogeneous tuning, with contralateral preference for low-frequency tones, which got lost for higher-frequency ones, and white noise response driven by ITDs. We further validated two experimental findings: (1) removing MSO inhibition abolished contralateral tuning, and (2) varying the timing between excitation and inhibition produced large shifts in tuning, highlighting the importance of synaptic timing for ITD coding. This model serves as an in silico testbed for auditory research, offering new insights into the functioning of human spatial hearing.

neuroscience↗

bioRxiv2024

Spiking neural network models of sound localisation via a massively collaborative process

AbstractNeuroscientists are increasingly initiating large-scale collaborations which bring together tens to hundreds of researchers. However, while these projects represent a step-change in scale, they retain a traditional structure with centralised funding, participating laboratories and data sharing on publication. Inspired by an open-source project in pure mathematics, we set out to test the feasibility of an alternative structure by running a grassroots, massively collaborative project in computational neuroscience. To do so, we launched a public Git repository, with code for training spiking neural networks to solve a sound localisation task via surrogate gradient descent. We then invited anyone, anywhere to use this code as a springboard for exploring questions of interest to them, and encouraged participants to share their work both asynchro-nously through Git and synchronously at monthly online workshops. At a scientific level, our work investigated how a range of biologically-relevant parameters, from time delays to mem-brane time constants and levels of inhibition, could impact sound localisation in networks of spiking units. At a more macro-level, our project brought together 31 researchers from multiple countries, provided hands-on research experience to early career participants, and opportunities for supervision and teaching to later career participants. Looking ahead, our project provides a glimpse of what open, collaborative science could look like and provides a necessary, tentative step towards it.

neuroscience↗

bioRxiv2023

Meteorins regulate the formation of the left-right organizer and the establishment of vertebrate body asymmetry

While the exterior of vertebrate bodies appears bilaterally symmetrical, internal organ positioning and morphology frequently exhibit left-right (L-R) asymmetries. In several vertebrates, including human, mouse, frog and zebrafish, left-right symmetry-breaking during embryonic development is initiated by a ciliated organ called the Node or left-right organizer. Within the Node, a leftward flow of extraembryonic fluid named the Nodal flow mediates the asymmetric expressions of Nodal factors. Although downstream Nodal pathway components leading to the establishment of the embryonic left-right axis are well known, less is known about the development and formation of the embryonic Node itself. Here we reveal a novel role for the Meteorin protein family in the establishment of the left-right axis and in the formation of the Kupffers vesicle, the Node equivalent structure in zebrafish. We show that the genetic inactivation of each or all three members of the zebrafish Meteorin family (metrn, metrn-like a and metrn-like b) leads to defects in properties of the Kupffers vesicle, caused by impaired assembly and migration of the Kupffers vesicle forming dorsal forerunner cells. In addition, we demonstrate that Meteorins genetically interact with integrins ItgaV and Itg{beta}1b regulating the dorsal forerunner cell clustering and that meteorins loss-of-function results in disturbed Nodal factor expression and consequently in randomized or symmetric heart looping and jogging. These results identify a new role for the Meteorin protein family in the left-right asymmetry patterning during embryonic vertebrate development.

developmental biology↗