Kartezio: Evolutionary Design of Explainable Pipelines for Biomedical Image Analysis

An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. Crucially however, these frameworks require large human-annotated datasets for training and the resulting models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming based computational strategy that generates transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets, a feature which confers tremendous flexibility, speed, and functionality to this approach. We also deployed Kartezio to solve semantic and instance segmentation problems in four real-world Use Cases, and showcase its utility in imaging contexts ranging from high-resolution microscopy to clinical pathology. By successfully implementing Kartezio on a portfolio of images ranging from subcellular structures to tumoral tissue, we demonstrated the flexibility, robustness and practical utility of this fully explicable evolutionary designer for semantic and instance segmentation.Comment: 36 pages, 6 main Figures. The Extended Data Movie is available at the following link: https://www.youtube.com/watch?v=r74gdzb6hdA. The source code is available on Github: https://github.com/KevinCortacero/Kartezi

Caractérisation des propriétés motivationnelles du sevrage des opiacés - analyse comparative des substrats neurobiologiques des effets inconditionnés et conditionnés

Mr Bernard Bioulac - Université Bordeaux 2, Bordeaux - Président. Me Brigitte Kieffer - CNRS UMR 7104, Strasbourg - Rapporteur. Mr Georges Di Scala - CNRS UMR 5106, Bordeaux - Rapporteur. Mr Rafael Maldonado - Université pompeu Fabra, Barcelone - Examinateur. Mlle Martine Cador - CNRS UMR 5541, Bordeaux - Examinateur. Mlle Catherine Le Moine - CNRS UMR 5541, Bordeaux - Directrice de thèseAddictive behaviors are pathological states characterized by a loss of control over drug consumption and by a persistent vulnerability to relapse following abstinence from repeated drug use. Addiction involves motivational and emotional processes as well as associative-learning and affective memory. In former opiate addicts, re-exposure to environmental situations previously paired with withdrawal is able to induce strong craving episodes, and it has been proposed that these conditioned stimuli could be strongly involved in precipitating relapse in drug-taking behavior by re-activating the neurobiological networks which is engaged in an unconditioned manner by the withdrawal state itself. In this context, we have focused on the characterization of the motivational component of morphine withdrawal, by using behavioral models (naloxone-precipitated withdrawal using low doses in morphine-dependent rats, re-exposure to morphine withdrawal-paired environmental stimuli in a conditioned place aversion paradigm), which allow to assess the aversive and motivational properties of opiate withdrawal, both in the unconditioned and conditioned situations. Using these models, we have investigated the neuronal correlates of these processes, using extensive mapping of the neurobiological substrates recruited, in terms of localization and neuronal population, with an anatomical and functional approach using the detection of c-fos as a marker of neuronal reactivity, by in situ hybridization. On the whole, our results show that the neurobiological substrates underlying the motivational component of opiate withdrawal – which include in particular the structures of the extended amygdala (nucleus accumbens medial shell part, bed nucleus of the stria terminalis and central nucleus of the amygdala) and its associated limbic territories (basolateral nucleus of the amygdala, hippocampus, lateral septal nucleus and ventral tegmental area) – can be dissociated from a number of other cerebral structures, which, in contrast, are involved in the expression of the overt somatic symptoms of withdrawal. Within the ventral tegmental area (VTA), our phenotypical analysis of the neuronal populations which are recruited following naloxone-precipitated morphine withdrawal (unconditioned situation) and after re-exposure to withdrawal-paired environmental stimuli (conditioned situation) show an intense induction of the majority of GABAergic interneurons. Although such GABAergic activity should lead to dopaminergic neurons inhibition, we also demonstrate that a subset of the VTA dopaminergic neurons (about 15%) is activated in both the unconditioned and conditioned situations. Within the amygdala, our results show an anatomical and functional double-dissociation in the global response of the central (CeA) and basolateral (BlA) nuclei of the amygdala in terms of c-fos mRNA expression between the unconditioned and conditioned situations. In the BlA, although acute naloxone-precipitated withdrawal decreased c-fos expression in the majority of glutamatergic efferent neurons, a subpopulation of these neurons exhibited decreased c-fos mRNA expression. In contrast, re-exposure to withdrawal-conditioned stimuli enhanced c-fos expression in a large number of BlA glutamatergic efferents. Within GABAergic neurons of the CeA, c-fos responses were opposite to the global responses measured in the BlA, as c-fos mRNA expression in these neurons is increased in the unconditioned situation, whereas it is decreased in the conditioned situation. Altogether, our results emphasize that the pattern of c-fos mRNA expression that we detect within all these interconnected limbic structures could reflect 1/ the onset of associative-learning processes aimed to encode the incentive-value of morphine withdrawal-associated environmental stimuli, in the unconditioned situation, and 2/ the retrieval and expression of learned-associations, in the conditioned situation (withdrawal memories). Therefore, on the basis of our results, and together with a number of data in the literature, we propose a functional model for the acquisition and the retrieval of morphine withdrawal memories.L'addiction correspond à un désordre psychobiologique caractérisé par une tendance chronique à la rechute, et implique des processus d'ordre motivationnels et émotionnels qui mettent en jeu des phénomènes d'apprentissage et de mémoire affective. Chez le toxicomane abstinent, la présentation de situations environnementales précédemment associées à l'expérience du sevrage des opiacés est capable d'induire un intense désir pour la drogue (craving), et il a été proposé que ces stimuli conditionnés pourraient précipiter la rechute en réactivant les circuits neuronaux qui sont mis en jeu de manière inconditionnée par le sevrage. Dans ce contexte, nous avons entrepris la caractérisation de la composante motivationnelle du sevrage des opiacés en utilisant des modèles comportementaux (sevrage précipité par des faibles doses de naloxone chez le rat morphino-dépendant, réexposition à des stimuli environnementaux précédemment associés au sevrage dans un modèle d'aversion de place conditionnée) qui permettent d'évaluer les propriétés aversives et motivationnelles du sevrage, aussi bien sur le versant inconditionné que conditionné. Nous avons ainsi recherché les substrats neurobiologiques impliqués dans ces phénomènes en traçant de manière extensive les circuits neuronaux recrutés, en terme de localisation et de populations neuronales, par une approche de neuroanatomie fonctionnelle utilisant la détection du marqueur de réactivité neuronale c-fos par hybridation in situ. D'une manière générale, nos résultats montrent que les substrats neuronaux sous-jacents à la composante motivationnelle du sevrage – qui incluent en particulier les structures de l'extended amygdala (noyau accumbens partie médiale shell, noyau du lit de la strie terminale et noyau central de l'amygdale) et les régions limbiques qui lui sont associées (noyau basolatéral de l'amygdale, hippocampe, septum latéral et aire tegmentale ventrale) – peuvent être dissociés d'un ensemble d'autres régions cérébrales qui sont en revanche impliquées dans l'expression de la symptomatologie somatique du sevrage. Au niveau de l'aire tegmentale ventrale (VTA), notre analyse phénotypique des neurones recrutés au cours du sevrage précipité par la naloxone (situation inconditionnée) et lors de la présentation de stimuli environnementaux associés au sevrage (situation conditionnée) montre une induction massive dans la population des interneurones GABAergiques. Bien qu'une telle activité GABAergique est supposée être capable d'inhiber en grande partie les neurones dopaminergiques, nous montrons également qu'une sous-population de neurones dopaminergiques de la VTA (environ 15%) est activée dans ces deux situations. Au niveau de l'amygdale, nos résultats montrent l'existence d'une double dissociation anatomique et fonctionnelle dans la réponse globale des noyaux central (CeA) et basolatéral (BlA) en terme d'expression de c-fos entre les situations inconditionnée et conditionnée. Dans le BlA, bien que le sevrage précipité par la naloxone induise une diminution de l'activité de la majorité des neurones efférents glutamatergiques, une sous-population de ces neurones montre une intense induction de l'ARNm c-fos. La réexposition aux stimuli conditionnés au sevrage provoque quant à elle une intense activation dans de nombreux neurones glutamatergiques du BlA. Dans les neurones GABAergiques du CeA, les réponses c-fos sont opposées aux réponses globales du BlA, puisque l'expression de c-fos dans ces neurones est augmentée dans la situation inconditionnée, alors qu'elle est diminuée dans la situation conditionnée. Nous proposons que le pattern d'expression de c-fos que nous détectons dans l'ensemble de ces structures limbiques pourrait refléter 1/ la mise en place de processus d'apprentissage associatif permettant d'encoder la valeur affective et motivationnelle des stimuli environnementaux associés au sevrage de la morphine, dans la situation inconditionnée, et 2/ le rappel et l'expression des associations mémorisées au cours du conditionnement, dans la situation conditionnée (mémoire du sevrage). Ainsi, sur la base de l'ensemble de nos résultats et de nombreuses données de la littérature, nous proposons un modèle fonctionnel pour la formation et le rappel de la mémoire du sevrage des opiacés

Caractérisation des propriétés motivationnelles du sevrage des opiacés (analyse comparative des substrats neurobiologiques des effets inconditionnés et conditionnés)

Chez le toxicomane, la présentation de situations environnementales précédemment associées au sevrage des opiacés induit un intense désir pour la drogue. Ces stimuli conditionnés pourraient précipiter la rechute en réactivant les circuits neuronaux activés de manière inconditionnée par le sevrage. Nous avons ainsi entrepris, chez l'animal, la caractérisation anatomique et fonctionnelle de ces processus motivationnels qui impliquent la mémoire affective, en utilisant le marqueur de réactivité neuronale c-fos. Nous montrons que les substrats neuronaux sous-jacents à la composante motivationnelle du sevrage des opiacés (qui incluent des structures limbiques) sont dissociés d'un ensemble d'autres régions qui sont en revanche impliquées dans l'expression de la composante somatique du sevrage. Sur la base de l'ensemble de nos résultats, nous proposons un modèle fonctionnel pour la formation et le rappel de la "mémoire du sevrage des opiacés".In former opiate addicts re-exposure to environmental situations previously paired with withdrawal is able to induce strong craving episodes. These conditioned stimuli could precipitate relapse in drug-taking behaviour by re-activating the neurobiological networks engaged in an unconditionned manner by the withdrawal state itself. Thus, we have focused, in animals, on the anatomical characterization of these motivational processes which involve affective memory, by using c-fos as a marker of neuronal reactivity. We show that the neurobiological substrates underlying the motivational component of opiate withdrawal (which include limbic structures) can be dissociated from a number of other structures, which in contrast are involved in the expression of the overt somatic symptoms of withdrawal. On the basis of our results, we propose a functional model for the acquisition and the retrieval of morphine withdrawal memories.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Pentoxifylline and insulin-like growth factor-I -IGF-I) abrogate kainic acid-induced cognitive impairment in mice

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Chronic brain indoleamine 2,3-dioxygenase activation based on Bacille Calmette-Guerin infection affects central 5-HT neurotransmission: a murine model of depressive-like behavior

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Multigenerational Effects of a Complex Human-Relevant Exposure during Folliculogenesis and Preimplantation Embryo Development: The FEDEXPO Study

International audienceAnimal toxicological studies often fail to mimic the complexity of the human exposome, associating low doses, combined molecules and long-term exposure. Since the reproductive potential of a woman begins in the fetal ovary, the literature regarding the disruption of its reproductive health by environmental toxicants remains limited. Studies draw attention to follicle development, a major determinant for the quality of the oocyte, and the preimplantation embryo, as both of them are targets for epigenetic reprogramming. The “Folliculogenesis and Embryo Development EXPOsure to a mixture of toxicants: evaluation in the rabbit model” (FEDEXPO) project emerged from consideration of these limitations and aims to evaluate in the rabbit model the impacts of an exposure to a mixture of known and suspected endocrine disrupting chemicals (EDCs) during two specific windows, including folliculogenesis and preimplantation embryo development. The mixture combines eight environmental toxicants, namely perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), 2,2′4,4′-tetrabromodiphenyl ether (BDE-47), di(2-ethylhexyl) phthalate (DEHP) and bisphenol S (BPS), at relevant exposure levels for reproductive-aged women based on biomonitoring data. The project will be organized in order to assess the consequences of this exposure on the ovarian function of the directly exposed F0 females and monitor the development and health of the F1 offspring from the preimplantation stage. Emphasis will be made on the reproductive health of the offspring. Lastly, this multigenerational study will also tackle potential mechanisms for the inheritance of health disruption via the oocyte or the preimplantation embryo

Pre- and Postnatal Dietary Exposure to a Pesticide Cocktail Disrupts Ovarian Functions in 8-Week-Old Female Mice

International audienceFemale infertility has a multifactorial origin, and exposure to contaminants, including pesticides, with endocrine-disrupting properties is considered to be involved in this reproductive disorder, especially when it occurs during early life. Pesticides are present in various facets of the environment, and consumers are exposed to a combination of multiple pesticide residues through food intake. The consequences of such exposure with respect to female fertility are not well known. Therefore, we aimed to assess the impact of pre- and postnatal dietary exposure to a pesticide mixture on folliculogenesis, a crucial process in female reproduction. Mice were exposed to the acceptable daily intake levels of six pesticides in a mixture (boscalid, captan, chlorpyrifos, thiacloprid, thiophanate and ziram) from foetal development until 8 weeks old. Female offspring presented with decreased body weight at weaning, which was maintained at 8 weeks old. This was accompanied by an abnormal ovarian ultrastructure, a drastic decrease in the number of corpora lutea and progesterone levels and an increase in ovary cell proliferation. In conclusion, this study shows that this pesticide mixture that can be commonly found in fruits in Europe, causing endocrine disruption in female mice with pre- and postnatal exposure by disturbing folliculogenesis, mainly in the luteinisation process

Evolutionary design of explainable algorithms for biomedical image segmentation

International audienceAn unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks require large human-annotated datasets for training and the resulting “black box” models are difficult to interpret. In this study, we introduce Kartezio , a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches

Evolutionary design of explainable algorithms for biomedical image segmentation

An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks require large human-annotated datasets for training and the resulting “black box” models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches