Biology subjects

Charlot, B.

Publications and source records attributed to Charlot, B..

3 recordsLinked to original sources

bioRxiv2024

Biologically grounded brain-on-chip model identifies selective topographic reorganization within hyperexcitable neural networks

Connectomics has revolutionized our understanding of brain function by emphasizing the importance of neural networks and their topographical organization. Corticostriatal circuits, which play a critical role in cognition and emotion, follow a precise topographic architecture essential for integrating and processing cortical information within the basal ganglia. Disruptions to this connectivity are often implicated in neurodevelopmental and psychiatric disorders such as obsessive compulsive disorders, schizophrenia, epilepsy, and autism spectrum disorders. However, studying network disruptions in vivo presents significant challenges due to their intricate architecture and early developmental onset. To address this, we employed a brain-on-chip microfluidic platform to recreate a biologically relevant model of topographically organized corticostriatal networks. By mimicking the directional control of neuronal projections using Tesla valve-inspired microchannels, we demonstrate that genetic perturbations affecting neuronal excitability during development lead to selective alterations of local versus long-range network topology, resulting in the formation of new convergent nodes. This model offers critical insights into how early perturbations contribute to circuit-specific pathologies, providing a valuable tool for understanding neurodevelopmental disorders and advancing therapeutic strategies.

neuroscience↗

bioRxiv2024

Influence of asymmetric microchannels in the structure and function of engineered neuronal circuits

Understanding the intricate structure-function relationships of neuronal circuits is crucial for unraveling how the brain sustains efficient information transfer. In specific brain regions, like the hippocampus, neurons are organized in layers and form unidirectional connectivity, which is thought to help ensure controlled signal flow and information processing. In recent years, researchers have tried emulating these structural principles by providing cultured neurons with asymmetric environmental cues, namely microfluidics microchannels that promote directed axonal growth. Even though a few reports have claimed achieving unidirectional connectivity of in vitro neuronal circuits, given the lack of functional characterization, whether this structural connectivity correlates with functional connectivity remains unknown. We have replicated and tested the performance of asymmetric microchannel designs previously reported in the literature to be successful in the promotion of directed axonal growth, as well as other custom variations. A new variation of "Arrowhead", termed "Rams", was the best-performing motif with a [~]76% probability per microchannel of allowing strictly unidirectional connections at 14 days in vitro. Importantly, we assessed the functional implications of these different asymmetric microchannel designs. For this purpose, we combined custom microfluidics with microelectrode array (MEA) technology to record the electrophysiological activity of two segregated populations of hippocampal neurons ("Source" and "Target"). This functional characterization revealed that up to [~]94% of the spiking activity recorded along microchannels with the "Rams" motif propagates towards the "Target" population. Moreover, our results indicate that these engineered circuits also tended to exhibit network-level synchronizations with defined directionality. Overall, this characterization of the structure-function relationships promoted by asymmetric microchannels has the potential to provide insights into how neuronal circuits use specific network architectures for effective computations. Moreover, the here-developed devices and approaches may be used in a wide range of applications, such as disease modeling or preclinical drug screening.

neuroscience↗

bioRxiv2022

Trans-synaptic dwelling of SARS-CoV-2 particles perturbs neural synapse organization and function

SARS-CoV-2 infection is associated with short- and long-term neurological and psychiatric complications, referred to as neuroCOVID. These symptoms are relatively heterogenous and fluctuating, hampering the discovery of molecular mechanisms underlying viro-induced brain perturbations. Here, we show that the human cerebral cortex poorly supports SARS-CoV-2 dissemination using post-mortem COVID-19 patient samples, ex vivo organotypic cultures of human brain explants and stem cell-derived cortical organoids. Despite restricted infection, the sole exposure of neural cells to SARS-CoV-2 particles is sufficient to induce significant perturbations on neural synapse organization associated to electrical activity dysfunction. Single-organoid proteomics revealed that exposure to SARS-CoV-2 is associated to trans-synaptic proteins upregulation and unveiled that incoming virions dwell at LPHN3/FLRT3-containing synapses. Our study provides new mechanistic insights on the origin of SARS-CoV-2-induced neurological disorders. One-Sentence SummarySARS-CoV-2 modulates neural plasticity and electrical activity as viral particles lodge at the trans-synaptic interface.

microbiology↗