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Caenorhabditis elegans nematodes produce and maintain imprints of attractive chemosensory cues to which they are exposed early in life. Early odor-exposure increases adult chemo-attraction to the same cues. Imprinting is transiently or stably inherited, depending on the number of exposed generations. We show here that the Alanine tRNA (UGC) plays a central role in regulating C. elegans chemo-attraction. Naive worms fed on tRNA Ala (UGC) purified from odor-experienced worms, acquire odor-specific imprints. Chemo-attractive responses require the tRNA-modifying Elongator complex sub-units 1 ( elpc-1 ) and 3 ( elpc-3 ) genes. elpc-3 deletions impair chemo-attraction, which is fully restored by wild-type tRNA Ala (UGC) feeding. A stably inherited decrease of odor-specific responses ensues from early odor-exposition of elpc-1 deletion mutants. tRNA Ala (UGC) may adopt various chemical forms to mediate the cross-talk between innately-programmed and environment-directed chemo-attractive behavior., (Copyright © 2020 Fernandes De Abreu, Salinas-Giegé, Drouard and Remy.)

Social environment modulates learning through unknown mechanisms. Here, we report that a pheromone mixture that signals overcrowding inhibits C. elegans from learning to avoid pathogenic bacteria. We find that learning depends on the balanced signaling of two insulin-like peptides (ILPs), INS-16 and INS-4, which act respectively in the pheromone-sensing neuron ADL and the bacteria-sensing neuron AWA. Pheromone exposure inhibits learning by disrupting this balance: it activates ADL and increases expression of ins-16, and this cellular effect reduces AWA activity and AWA-expressed ins-4. The activities of the sensory neurons are required for learning and the expression of the ILPs. Interestingly, pheromones also promote the ingestion of pathogenic bacteria while increasing resistance to the pathogen. Thus, the balance of the ILP signals integrates social information into the learning process as part of a coordinated adaptive response that allows consumption of harmful food during times of high population density., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Quantitative imaging has become a vital technique in biological discovery and clinical diagnostics; a plethora of tools have recently been developed to enable new and accelerated forms of biological investigation. Increasingly, the capacity for high-throughput experimentation provided by new imaging modalities, contrast techniques, microscopy tools, microfluidics and computer controlled systems shifts the experimental bottleneck from the level of physical manipulation and raw data collection to automated recognition and data processing. Yet, despite their broad importance, image analysis solutions to address these needs have been narrowly tailored. Here, we present a generalizable formulation for autonomous identification of specific biological structures that is applicable for many problems. The process flow architecture we present here utilizes standard image processing techniques and the multi-tiered application of classification models such as support vector machines (SVM). These low-level functions are readily available in a large array of image processing software packages and programming languages. Our framework is thus both easy to implement at the modular level and provides specific high-level architecture to guide the solution of more complicated image-processing problems. We demonstrate the utility of the classification routine by developing two specific classifiers as a toolset for automation and cell identification in the model organism Caenorhabditis elegans. To serve a common need for automated high-resolution imaging and behavior applications in the C. elegans research community, we contribute a ready-to-use classifier for the identification of the head of the animal under bright field imaging. Furthermore, we extend our framework to address the pervasive problem of cell-specific identification under fluorescent imaging, which is critical for biological investigation in multicellular organisms or tissues. Using these examples as a guide, we envision the broad utility of the framework for diverse problems across different length scales and imaging methods.

Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

In a previous study, we demonstrated that mouse adult F(1) offspring, exposed to a vitamin D deficiency during pregnancy, developed a less severe and delayed Experimental Autoimmune Encephalomyelitis (EAE), when compared with control offspring. We then wondered whether a similar response was observed in the subsequent generation. To answer this question, we assessed F(2) females whose F(1) parents (males or females) were vitamin D-deprived when developing in the uterus of F(0) females. Unexpectedly, we observed that the vitamin D deficiency affecting the F(0) pregnant mice induced a precocious and more severe EAE in the F(2) generation. This paradoxical finding led us to assess its implications for the epidemiology of Multiple Sclerosis (MS) in humans. Using the REFGENSEP database for MS trios (the patient and his/her parents), we collected the parents' dates of birth and assessed a potential season of birth effect that could potentially be indicative of the vitamin D status of the pregnant grandmothers. A trend for a reduced number of births in the Fall for the parents of MS patients was observed but statistical significance was not reached. Further well powered studies are warranted to validate the latter finding.

There is now strong evidence linking vitamin D, the steroid hormone of sunlight, and Multiple Sclerosis (MS). Two of the most intriguing findings are the season of birth and childhood sun exposure effects. They both suggest that a vitamin D deficiency during these critical imprinting periods is a risk factor for MS. After having confirmed that people born in November are at lower risk of developing MS, we devised a mouse model of prenatal vitamin D deficiency. We observed that adult offspring born to vitamin D deficient mothers, when compared to control offspring, developed a striking milder and delayed experimental autoimmune encephalomyelitis (EAE) and permanently overexpressed the vitamin D receptor. This unexpected finding led us to conjecture that the newborns, after having known an in utero vitamin D-deficient environment, were highly sensitive ex utero to cholecalciferol-containing diet and interpreted the postnatal food as a vitamin D enriched environment. To validate this hypothesis, we devised a mouse model of postnatal vitamin D supplementation. Interestingly, using the same EAE model, we demonstrated that a delayed onset and less severe symptoms were displayed by postnatally vitamin D-supplemented mice. The latter finding is in accordance with previous animal studies demonstrating that a postnatal vitamin D deficiency induced an earlier onset and an increased symptom severity of EAE and epidemiological reports describing the importance of an adequate supply of vitamin D during early life., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Accumulating data indicate that vitamin D, a sun-induced hormone, plays a key role in multiple sclerosis (MS) etiology. Notably, it has been shown that there is a remarkable season of birth effect in MS. We surmised that gestational vitamin D deficiency is a risk factor for MS. To test this hypothesis, a vitamin D deficiency was induced in C57BL/6 female mice 6 weeks prior to conception and prolonged until offspring birth. Contrary to our prediction, we show here that adult offspring exposed to developmental vitamin D deficiency (DVD) developed a striking milder and delayed experimental autoimmune encephalomyelitis (EAE), when compared to control offspring. Using reverse transcription and quantitative real-time PCR, we measured the expression level of 22 candidate transcripts in the spleen, the cerebrum and the spinal cord, at Day0 and Day30 post-immunization. We report here that, at Day30 post-immunization, TNF, osteopontin, H2-Eb were over-expressed and IFN was under-expressed in the spinal cord of control mice and not in DVD mice. Another discrepancy between nervous and immune systems was observed: expression of IL4 was dysregulated exclusively in the spleen. Reduced symptom severity in DVD mice can partially be explained by a nervous system-restricted over-expression of vitamin D receptor (VDR), two heat shock proteins (HSP90, HSPa8) and FK506 binding protein 1a (FKBP1a), at Day0. Our clinical test and molecular findings converge to indicate that maternal hypovitaminosis D imprints the foetus and alters the susceptibility of the offspring to EAE. We propose a new hypothesis to explain our unexpected observations., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Epidemiological studies have highlighted a season of birth effect in multiple sclerosis and schizophrenia. As a result, low prenatal vitamin D has been proposed as a candidate risk factor for these brain diseases, with cognitive impairments. In order to further investigate the long-term consequences of a transient gestational hypovitaminosis D, we used a mouse developmental vitamin D (DVD) deficiency model. Female C57Bl/6J mice were fed a vitamin D-free diet for 6 weeks prior to conception and during gestation. At birth, dams and their offspring were fed a normal vitamin D-containing diet. The adult offspring underwent a learning test based on olfactory cues, at 30 weeks and 60 weeks of age. In addition, using magnetic resonance imaging (MRI), volumes of cerebrum, hippocampus and lateral ventricles were measured at 30 weeks and 70 weeks of age. We found that DVD-deficient mice, when compared to control animals at Week 30, displayed impaired learning and smaller lateral ventricles. At Weeks 60-70, both groups deteriorated when compared to young mice and no significant difference was observed between groups. This study confirms that transient prenatal vitamin D deficiency alters brain development and functioning and induces cognitive impairments in the young adult offspring., (Copyright 2010 Elsevier B.V. All rights reserved.)

It has been known for more than 20 years that vitamin D exerts marked effects on immune and neural cells. These non-classical actions of vitamin D have recently gained a renewed attention since it has been shown that diminished levels of vitamin D induce immune-mediated symptoms in animal models of autoimmune diseases and is a risk factor for various brain diseases. For example, it has been demonstrated that vitamin D (i) modulates the production of several neurotrophins, (ii) up-regulates Interleukin-4 and (iii) inhibits the differentiation and survival of dendritic cells, resulting in impaired allo-reactive T cell activation. Not surprisingly, vitamin D has been found to be a strong candidate risk-modifying factor for Multiple Sclerosis (MS), the most prevalent neurological and inflammatory disease in the young adult population. Vitamin D is a seco-steroid hormone, produced photochemically in the animal epidermis. The action of ultraviolet light (UVB) on 7-dehydrocholesterol results in the production of pre-vitamin D which, after thermo-conversion and two separate hydroxylations, gives rise to the active 1,25-dihydroxyvitamin D. Vitamin D acts through two types of receptors: (i) the vitamin D receptor (VDR), a member of the steroid/thyroid hormone superfamily of transcription factors, and (ii) the MARRS (membrane associated, rapid response steroid binding) receptor, also known as Erp57/Grp58. In this article, we review some of the mechanisms that may underlie the role of vitamin D in various brain diseases. We then assess how vitamin D imbalance may lay the foundation for a range of adult disorders, including brain pathologies (Parkinson's disease, epilepsy, depression) and immune-mediated disorders (rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosus or inflammatory bowel diseases). Multidisciplinary scientific collaborations are now required to fully appreciate the complex role of vitamin D in mammal metabolism.

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.