Biology subjects

Thiberge, S.

Publications and source records attributed to Thiberge, S..

8 recordsLinked to original sources

bioRxiv2025

High-speed whole-brain imaging in Drosophila

Recent advances in brain-wide recordings of small animals such as worms, fish, and flies have revealed complex activity involving large populations of neurons. In the Drosophila brain, with about 140,000 neurons, brain-wide recordings have been critical to uncovering widespread sensory and motor activity. However, current limitations in volumetric imaging rates hinder the accurate capture of fast neural dynamics. To improve the speed of volumetric imaging in Drosophila, we leverage the recently introduced light beads microscopy (LBM) method. We built a microscope and a LBM module tailored to fly brain experiments and used it to record brain-wide calcium signals in adult behaving flies at either 28 volumes per second or at 60 volumes per second (when selecting the central brain alone). We uncover fast-timescale auditory responses that are missed with standard volumetric imaging. We also demonstrate how temporal super-resolution can be combined with LBM data to uncover responses to single Drosophila courtship song pulses. This establishes LBM as a viable tool for capturing whole-brain activity at high spatial and temporal resolution in the fly.

neuroscience↗

bioRxiv2025

Plasmodium falciparum PP1 phosphatase is a key regulator of malaria parasite transmission

For the successful transmission of malaria parasites from humans to mosquitoes, Plasmodium falciparum gametocytes must remain in the bloodstream long enough to be taken up by a mosquito. Once ingested, they are then activated into gametes to continue the parasite life cycle in the mosquito midgut. Both persistence of gametocytes in the blood and their activation into gametes are tightly regulated by phospho-signaling. While the serine-threonine phosphatase PfPP1 is an essential enzyme for parasite asexual proliferation, its role during transmission of sexual stages remains elusive. Here, we employed a conditional depletion strategy to conduct a functional analysis of PfPP1 during gametocyte development, gamete activation and transmission to mosquitoes. We show that PfPP1 regulates the deformability and the permeability of mature gametocyte-infected erythrocytes through the dephosphorylation of PKA substrates, thus highlighting a key role for PfPP1 in modulating the host cell mechanical properties, which are crucial for gametocyte persistence in the bloodstream. We also provide evidence that PfPP1 controls crucial steps of gamete activation via stimulation of the cGMP/ PKG pathway. Collectively, these results underscore the pivotal role of PfPP1 in the transmission of P. falciparum to the mosquito during both sexual development and gamete activation. AUTHOR SUMMARYThe protein phosphatase PP1 is a major contributor to total cellular phosphatase activity in eukaryotes and plays a critical role during various cellular processes. Here, we have unraveled novel mechanisms regulated by the phosphatase PfPP1 in the human malaria parasite Plasmodium falciparum. While PfPP1 is known to be essential for the parasite asexual proliferation, in the present study we demonstrate that PfPP1 is also required during the sexual parasite stages, called gametocytes, that ensure parasite transmission from humans to mosquitoes. PfPP1 is involved in regulating the mechanical properties of the gametocyte-infected host cell, a process necessary for the persistence of gametocytes in blood circulation. Moreover, PfPP1 also contributes to the activation of gametocytes into gametes, the stages able to pursue the parasite life cycle in mosquitoes. In addition to providing insights into novel mechanisms involved in parasite transmission, this study also highlights the possibility of interfering with PfPP1 signaling pathway for blocking malarial parasite transmission.

microbiology↗

bioRxiv2023

Overlapping representations of food and social stimuli in VTA dopamine neurons

Dopamine neurons of the ventral tegmental area (VTADA) respond to food and social stimuli and contribute to both forms of motivation. However, it is unclear if the same or different VTADA neurons encode these different stimuli. To address this question, we performed 2-photon calcium imaging in mice presented with food and conspecifics, and found statistically significant overlap in the populations responsive to both stimuli. Both hunger and opposite-sex social experience further increased the proportion of neurons that respond to both stimuli, implying that modifying motivation for one stimulus affects responses to both stimuli. In addition, single-nucleus RNA sequencing revealed significant co-expression of feeding- and social-hormone related genes in individual VTADA neurons. Taken together, our functional and transcriptional data suggest overlapping VTADA populations underlie food and social motivation.

neuroscience↗

bioRxiv2022

Hemisynthetic derivatives of the natural alkaloid trilobine are fast-acting antimalarial compounds with sustained activity in multi-drug resistant P. falciparum isolates

Malaria eradication requires the development of new drugs to combat drug-resistant parasites. The search for new chemical scaffolds that target novel pathways of the human malaria parasite Plasmodium falciparum is of highest priority. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed us to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Efforts were made to obtain compounds with significantly improved preclinical properties. Out of those, compound 125 delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays) and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down strategy to identify potential protein targets of this chemical family. Mass spectrometry analysis identified the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms.

pathology↗

bioRxiv2022

Humanized mice for sustained Plasmodium vivax blood-stage infection and transmission

Plasmodium vivax is the most widespread human malaria parasite 1. The presence of extravascular reservoirs 2, the early circulation of infective stages (gametocytes), and relapsing infections arising from dormant liver stages 3 render this parasite particularly difficult to control and eliminate 4. Experimental research is limited by the lack of a continuous culture in vitro system that fulfills the parasites needs,5 namely its tropism for immature CD71+ red blood cells (RBCs). 5 Here, we report a humanized mice model, which upon engraftment of human hematopoietic progenitor and stem cells (HPSCs), exhibits efficient human erythropoiesis. Humanized HIS-HEry mice inoculated with cryopreserved P. vivax samples sustain long-lasting asexual parasite multiplication within CD71+ human RBCs and differentiation into mature gametocytes that can be efficiently transmitted to Anopheles mosquitoes, leading to formation salivary-gland sporozoites. Blood stages can be sequentially transferred to uninfected humanized mice by injection of fresh or frozen infected bone marrow cells, providing a unique murine model for the long-term maintenance of P. vivax isolates. This work offers a novel experimental platform to investigate the biology of RBC invasion and intraerythrocytic P. vivax development in vivo and evaluate new interventions against this elusive human parasite.

microbiology↗

bioRxiv2020

Chemical signatures of human odour generate a unique neural code in the brain of Aedes aegypti mosquitoes

A globally invasive form of the mosquito Aedes aegypti specializes in biting humans, making it an efficient vector of dengue, yellow fever, Zika, and chikungunya viruses. Host-seeking females strongly prefer human odour over the odour of non-human animals, but exactly how they distinguish the two is not known. Vertebrate odours are complex blends of volatile chemicals with many shared components, making discrimination an interesting sensory coding challenge. Here we show that human and animal odour blends evoke activity in unique combinations of olfactory glomeruli within the Aedes aegypti antennal lobe. Human blends consistently activate a universal glomerulus, which is equally responsive to diverse animal and nectar-related blends, and a more selective human-sensitive glomerulus. This dual signal robustly distinguishes humans from animals across concentrations, individual humans, and diverse animal species. Remarkably, the human-sensitive glomerulus is narrowly tuned to the long-chain aldehydes decanal and undecanal, which we show are consistently enriched in (though not specific to) human odour and which likely originate from unique human skin lipids. We propose a model of host-odour coding wherein normalization of activity in the human-sensitive glomerulus by that in the broadly-tuned universal glomerulus generates a robust discriminatory signal of the relative concentration of long-chain aldehydes in a host odour blend. Our work demonstrates how animal brains may distil complex odour stimuli of innate biological relevance into simple neural codes and reveals novel targets for the design of next-generation mosquito-control strategies.

neuroscience↗

bioRxiv2019

Auditory Activity is Diverse and Widespread Throughout the Central Brain of Drosophila

Sensory pathways are typically studied by starting at receptor neurons and following postsynaptic neurons into the brain. However, this leads to a bias in analysis of activity towards the earliest layers of processing. Here, we present new methods for volumetric neural imaging with precise across-brain registration, to characterize auditory activity throughout the entire central brain of Drosophila and make comparisons across trials, individuals, and sexes. We discover that auditory activity is present in most central brain regions and in neurons known to carry responses to other modalities. Auditory responses are temporally diverse, but the majority of activity, regardless of brain region, is tuned to aspects of courtship song. We find that auditory responses are stereotyped across trials and animals in early mechanosensory regions, becoming more variable at higher layers of the putative pathway, and that this variability is largely independent of spontaneous movements. This study highlights the power of using an unbiased, brain-wide approach for mapping the functional organization of sensory activity.

neuroscience↗

bioRxiv2018

Specialized and spatially organized coding of sensory, motor, and cognitive variables in midbrain dopamine neurons

There is increased appreciation that dopamine (DA) neurons in the midbrain respond not only to reward 1,2 and reward-predicting cues 1,3,4, but also to other variables such as distance to reward 5, movements 6-11 and behavioral choices 12-15. Based on these findings, a major open question is how the responses to these diverse variables are organized across the population of DA neurons. In other words, do individual DA neurons multiplex multiple variables, or are subsets of neurons specialized in encoding specific behavioral variables? The reason that this fundamental question has been difficult to resolve is that recordings from large populations of individual DA neurons have not been performed in a behavioral task with sufficient complexity to examine these diverse variables simultaneously. To address this gap, we used 2-photon calcium imaging through an implanted lens to record activity of >300 midbrain DA neurons in the VTA during a complex decision-making task. As mice navigated in a virtual reality (VR) environment, DA neurons encoded an array of sensory, motor, and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioral variables, in addition to encoding reward. These functional clusters were spatially organized, such that neighboring neurons were more likely to be part of the same cluster. Taken together with the topography between DA neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by DA neurons.

neuroscience↗