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Vincent, P.

Publications and source records attributed to Vincent, P..

10 recordsLinked to original sources

Endothelial Cells retain inflammatory memory through chromatin remodeling

Sepsis survivors face a heightened risk of secondary infections and chronic vascular dysfunction despite clinical recovery, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein transient inflammatory exposure induces durable chromatin remodeling, priming endothelial cells for exaggerated responses to subsequent inflammatory insults. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by secondary Streptococcus pneumoniae (SP) infection, we reveal persistent transcriptional activation in endothelial cells (ECs), characterized by amplified expression of inflammatory cytokines, adhesion molecules (e.g., ICAM-1), complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq analyses demonstrated stable chromatin accessibility at key inflammatory loci, indicative of epigenetic priming. Mechanistically, we uncovered a critical role for the AP-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility and subsequent transcriptional amplification upon secondary challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections post-sepsis.

cell biology↗

Reassessment of body temperature and thermoregulation strategies in Mesozoic marine reptiles

Ichthyosauria, Plesiosauria and Metriorhynchidae were apex predators in Mesozoic oceanic trophic networks. Previous stable oxygen isotope studies suggested that several taxa belonging to these groups were endothermic and for some of them homeothermic organisms. However, these conclusions remain contentious owing to the associated uncertainties regarding the {delta}18O value and oxygen isotope fractionation relative to environmental sea water. Here, we present new hydroxylapatite phosphate {delta}18O values ({delta}18Op) of Ichthyosauria, Plesiosauria and Metriorhynchidae (Middle Jurassic to Early Cretaceous) recovered from mid- to high-paleolatitudes to better constrain their thermophysiology and investigate the presence of regional heterothermies. The intra-skeletal {delta}18Op variability failed to reveal distinct heterothermic patterns within any of the specimens, indicating either intra-body temperature homogeneity or an overriding diagenetic overprint of the original biological {delta}18Op bone record. Body temperature estimates have then been reassessed from new and published {delta}18Op values of well-preserved isolated teeth, recently revised Mesozoic latitudinal {delta}18O oceanic gradient and 18O-enrichment factor of fully aquatic air-breathing vertebrates. Our results confirm that Ichthyosauria were homeothermic endotherms (31{degrees}C to 41{degrees}C), while Plesiosauria were likely poikilothermic endotherms (27{degrees}C to 34{degrees}C). The new body temperature estimates of the Metriorhynchidae (25{degrees}C to 32{degrees}C) closely follow ambient temperatures and point to poikilothermic strategy with no or little endothermic abilities. These results improve our understanding of Mesozoic marine reptile thermoregulation and indicate that due to their limited body temperature variations, the {delta}18Op values from Ichthyosauria fossil remains could be used as valuable archives of Mesozoic oceans {delta}18Osw values that may help improve palaeoenvironmental and palaeoclimatic reconstructions. Non-technical abstractSome marine reptiles from the Mesozoic such as ichthyosaurs, plesiosaurs and metriorhynchids, were capable of reaching elevated body temperatures and for some of them to maintain it few degrees above that of their marine environment, a characteristic similar to that observed in modern cetaceans. Nevertheless, the estimation of their body temperature from the chemical oxygen signature of their fossil remains (bones and teeth) is accompanied by uncertainties associated with the chemical oxygen signature of the surrounding water and the mineralisation processes of the bones and teeth. In this study, new data were collected from four ichthyosaurs, three plesiosaurs and one metriorhynchid in order to gain a deeper understanding of the mechanisms by which these marine reptiles were able to maintain a body temperature higher than that of their environment. The chemical signatures of oxygen in the bones and teeth of the specimens did not exhibit any discernible patterns indicative of specific zones of heat production or loss, as observed in modern marine vertebrates. Concurrently, we reassessed the estimated body temperature of these marine reptiles, thereby corroborating the hypothesis that ichthyosaurs were homeothermic endotherms. Conversely, our novel estimates suggest that plesiosaurs were likely poikilothermic endotherms, whereas metriorhynchids were probably also poikilothermic endotherms but with a limited capacity for heat production. Finally, the narrow range of body temperatures maintained by ichthyosaurs indicates that the oxygen chemical signature of fossilised remains could serve as a valuable marker for reconstructing variations in the oxygen isotope composition of the Mesozoic oceans, paving the way to enhance our understanding of the environment and climate of this period in Earths history.

paleontology↗

Zapit: Open Source Random-Access Photostimulation For Neuroscience

Optogenetic tools are indispensable for understanding the causal neural mechanisms underlying animal behavior,providing millisecond-precision control over genetically defined neural populations. Random-access laser-scanning optogenetics is a powerful and underutilized method for transiently manipulating cortical activity in mice. Despite the utility of this technique, no general-purpose open-source implementation currently exists, and potential users need expertise across optics, real-time hardware control, and programming. This represents a major barrier to adoption, particularly for newly established research groups. Here we present 'Zapit', the first open-source general-purpose platform for random-access laser-scanning optogenetic experiments in head-fixed mice. Zapit is fully documented, has a user-friendly GUI, works in stereotaxic coordinates, and comes with easy to build hardware options that extend functionality beyond any published system. We validate Zapit's performance through electrophysiological recordings and cortical photoinhibition in behaving mice. Zapit is a novel and innovative tool with the potential to democratize laser-scanning optogenetics and significantly increase uptake throughout the scientific community.

neuroscience↗

Cross-pathway integration of cAMP signals through cGMP and calcium-regulated phosphodiesterases in mouse striatal cholinergic interneurons.

Acetylcholine plays a key role in striatal function, yet the intricate dynamics of cyclic nucleotide signaling which govern the firing properties of cholinergic interneurons (ChINs) have remained elusive. Since phosphodiesterases determine the dynamics of cyclic nucleotides, in this study, we used FRET biosensors and pharmacological compounds to examine phosphodiesterase activity in ChINs in mouse brain slices. Intriguingly, these neurons displayed strikingly low levels and slow cAMP responsiveness compared to medium-sized spiny neurons (MSNs). Our experiments revealed that PDE1, PDE3 and PDE4 are important regulators of cAMP level in ChINs. Notably, the induction of cGMP production by nitric oxide (NO) donors increases cAMP by inhibiting PDE3 - a mechanism hitherto unexplored in neuronal context. Furthermore, the activation of NMDA or metabotropic glutamate receptors increases intracellular calcium, consequently activating PDE1 and thereby decreasing both cAMP and cGMP. This interplay of phosphodiesterases enables the control of cAMP by the neuromodulatory influences of glutamate and NO. Remarkably, the NO/cGMP signal results in different effects: NO enhances cAMP in ChINs by inhibiting PDE3, whereas it reduces cAMP levels in MSNs by activating PDE2A. These findings underscore the specificity of intracellular signaling in ChINs compared to MSNs and show how the NO-cGMP pathway affects these various neuronal types differently. These observations have significant implications for understanding the regulation of the striatal network and the integration of dopaminergic signals and suggest innovative therapeutic strategies for addressing basal ganglia disorders with unmet medical need.

neuroscience↗

Humans, rats and mice show species-specific adaptations to sensory statistics in categorisation behaviour

Animals must exploit environmental regularities to make adaptive decisions, yet the learning algorithms that enabels this flexibility remain unclear. A central question across neuroscience, cognitive science, and machine learning, is whether learning relies on generative or discriminative strategies. Generative learners build internal models the sensory world itself, capturing its statistical structure; discriminative learners map stimuli directly onto choices, ignoring input statistics. These strategies rely on fundamentally different internal representations and entail distinct computational trade-offs: generative learning supports flexible generalisation and transfer, whereas discriminative learning is efficient but task-specific. We compared humans, rats, and mice performing the same auditory categorisation task, where category boundaries and rewards were fixed but sensory statistics varied. All species adapted their behaviour near-optimally, consistent with a normative observer constrained by sensory and decision noise. Yet their underlying algorithms diverged: humans predominantly relied on generative representations, mice on discriminative boundary-tracking, and rats spanned both regimes. Crucially, end-point performance concealed these differences--only learning trajectories and trial-to-trial updates revealed the divergence. These results show that similar near-optimal behaviour can mask fundamentally different internal representations, establishing a comparative framework for uncovering the hidden strategies that support statistical learning.

animal behavior and cognition↗

Machine learning and hypothesis driven optimization of bull semen cryopreservation media

Cryopreservation provides a critical tool for dairy herd genetics management. Due to widely varying inter- and within-bull post thaw fertility, recent research on cryoprotectant extender medium has not dramatically improved suboptimal post-thaw recovery in industry. This progress is stymied by the interactions between samples and the many components of extender media and is often compounded by industry irrelevant sample sizes. To address these challenges, here we demonstrate blank-slate optimization of bull sperm cryopreservation media by supervised machine learning. We considered two supervised learning models: artificial neural networks and Gaussian process regression (GPR). Eleven media components and initial concentrations were identified from publications in bull semen cryopreservation, and an initial 200 extender-post-thaw motility pairs were used to train and 32 extender-post-thaw motility pairs to test the machine learning algorithms. The median post-thaw motility after coupling differential evolution with GPR the increased from 52.6 {+/-} 6.9% to 68.3 {+/-} 6.0% at generations 7 and 17 respectively, with several media performing dramatically better than control media counterparts. This is the first study in which machine learning was used to determine the best combination of constituents to optimize bull sperm cryopreservation media, and provides a template for optimization in other cell types.

bioengineering↗

Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

Absence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

neuroscience↗

Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones.

Dopamine in the striatum plays a crucial role in reward processes and action selection. Dopamine signals are transduced by D1 and D2 dopamine receptors which trigger mirror effects through the cAMP/PKA signalling cascade in D1 and D2 medium-sized spiny neurones (MSNs). Phosphodiesterases (PDEs), which determine the profile of cAMP signals, are highly expressed in MSNs, but their respective roles in dopamine signal integration remain poorly understood. We used genetically-encoded FRET biosensors to monitor at the single cell level the functional contribution of PDE2A, PDE4 and PDE10A in the changes of the cAMP/PKA response to transient and continuous dopamine in mouse striatal brain slices. We found that PDE2A, PDE4 and PDE10A operate on the moderate to high cAMP levels elicited by D1 or A2A receptor stimulation. In contrast, only PDE10A is able to reduce cAMP down to baseline in both type of neurones, leading to the dephosphorylation of PKA substrates. PDE10A is therefore critically required for dopamine signal integration in both D1 and D2 MSNs.

neuroscience↗

Primary cilium cAMP regulates cyclic saltatory neuronal migration at the centrosome

The primary cilium (PC) is a small centrosome-assembled organelle, protruding from the surface of most eukaryotic cells. It plays a key role in cell migration, but the underlying mechanisms are unknown. Here, we show that the PC regulates neuronal migration via cAMP production activating centrosomal Protein Kinase A (PKA). Biosensor live-imaging revealed a periodic cAMP hotspot at the centrosome of embryonic, postnatal and adult migrating neurons. Genetic ablation of the PC, or knock-down of ciliary Adenylate Cyclase 3, caused hotspot disappearance and migratory defects, with defective centrosome/nucleus coupling and altered nucleokinesis. Delocalization of PKA from the centrosome phenocopied the migratory defects. Our results show that the PC and centrosome form a single cAMP-signaling unit dynamically regulating migration, further highlighting the centrosome as a signaling hub. The primary cilium regulates neuronal migration via cyclic AMP production activating Protein Kinase A at the centrosome

neuroscience↗

Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals

The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of a paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (AKAR3) to record PKA signals and by analyzing the distribution of D1R-and D2R/A2aR-SPNs in the TS, we characterized three evolutionary highly conserved subterritories: a D2R/A2aR-lacking area, a D1R/D2-SPNs-enriched and an D1R/D2R-intermingled area. The analysis of ERK phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate or learned avoidance responses, fasting, satiety or palatable signals. In contrast, D1R-SPNs of the intermingled and D2R/A2AR-lacking areas are strongly activated by both direct stimulation of D1R and psychostimulant drugs (d-amphetamine, cocaine, MDMA or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals.

neuroscience↗