Biology subjects

Schneider, N.

Publications and source records attributed to Schneider, N..

6 recordsLinked to original sources

bioRxiv2023

Superovulation and aging perturb oocyte-granulosa cell communication

In vitro fertilization has been developed to overcome reduced fertility, which is increasingly due to a decline in reproductive cell quality during aging. Here, we quantitatively investigated the interplay between superovulation and aging in mouse oocytes and their paired granulosa cells using newly adapted isolation techniques. We tested the hypothesis that superovulation disrupts oocyte maturation, revealing the key intercellular communication pathways dysregulated by forced hormonal stimulation. We further demonstrated that granulosa cell transcriptional markers can prospectively predict an associated oocytes early developmental potential. By using naturally ovulated old mice as a non-stimulated reference, we showed that aging and superovulation dysregulate similar genes and interact with each other. By comparing mice and human transcriptional responses of granulosa cells, we found that age-related dysregulation of hormonal responses and cell cycle pathways was shared, though substantial divergence exists in other pathways. HighlightsO_LISuperovulation perturbs cumulus-oocyte communication C_LIO_LIGranulosa cell transcription predicts superovulated oocyte quality C_LIO_LISuperovulation and aging non-additively perturb similar sets of genes C_LI

developmental biology↗

bioRxiv2023

ADBP-1 regulates ADR-2 nuclear localization to control editing substrate selection

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is a prevalent and conserved RNA modification. While A-to-I RNA editing is essential in mammals, in Caenorhabditis elegans, it is not, making them invaluable for RNA editing research. In C. elegans, ADR-2 is the sole catalytic A-to-I editing enzyme, and ADR-1 is an RNA editing regulator. ADAR localization is well-studied in humans but not well-established in C. elegans. In this study, we examine the cellular and tissue-specific localization of ADR-2. We show that while ADR-2 is present in most cells in the embryo, at later developmental stages, its expression is both tissue- and cell-type-specific. Additionally, both ADARs are mainly in the nucleus. ADR-2 is adjacent to the chromosomes during the cell cycle. We show that the nuclear localization of endogenous ADR-2 depends on ADBP-1, not ADR-1. In adbp-1 mutant worms, ADR-2 is mislocalized, while ADR-1 is not, leading to decreased editing levels and de-novo editing, mostly in exons, suggesting that ADR-2 is also functional in the cytoplasm. Besides, mutated ADBP-1 affects gene expression. Furthermore, we show that ADR-2 targets adenosines with different surrounding nucleotides in exons and introns. Our findings indicate that ADR-2 cellular localization is highly regulated and affects its function.

cell biology↗

bioRxiv2022

The function and decline of the female reproductive tract at single-cell resolution

The female reproductive tract (FRT) undergoes extensive remodeling during each reproductive cycle, regulated by systemic changes in sex hormones. Whether this recurrent remodeling influences a specific organs aging trajectory is unknown. To address this, we systematically characterized at single-cell resolution the morphological and transcriptional changes that occur in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrus cycle, during decidualization, and into aging. Transcriptional and cell-to-cell communication networks in estrus cycle and aging are enriched for ECM reorganization and inflammation, two essential components of FRT remodeling. We directly link the organ-specific level of these two processes over reproductive lifespan with the gradual, age-related development of fibrosis and chronic inflammation. Our data represent a comprehensive atlas of the FRT lifespan, revealing pathological consequences of incomplete resolution of recurrent inflammation and tissue repair.

genomics↗

bioRxiv2022

A scalable screening platform for phenotypic subtyping of ALS patient-derived fibroblasts

A major challenge for understanding and treating Amyotrophic Lateral Sclerosis (ALS) is that most patients have no known genetic cause. Even within defined genetic subtypes, patients display considerable clinical heterogeneity. It is unclear how to identify subsets of ALS patients that share common molecular dysregulation or could respond similarly to treatment. Here, we developed a scalable microscopy and machine learning platform to phenotypically subtype readily available, primary patient-derived fibroblasts. Application of our platform identified robust signatures for the genetic subtype FUS-ALS, allowing cell lines to be scored along a spectrum from FUS-ALS to non-ALS. Our FUS-ALS phenotypic score negatively correlates with age of diagnosis and provides information that is distinct from transcript profiling. Interestingly, the FUS-ALS phenotypic score can be used to identify sporadic patient fibroblasts that have consistent pathway dysregulation with FUS-ALS. Further, we showcase how the score can be used to evaluate the effects of ASO treatment on patient fibroblasts. Our platform provides an approach to move from genetic to phenotypic subtyping and a first step towards rational selection of patient subpopulations for targeted therapies.

systems biology↗

bioRxiv2020

Single-dose ethanol intoxication causes acute and lasting neuronal changes in the brain

Alcohol intoxication at early ages is a risk factor for development of addictive behavior. To uncover neuronal molecular correlates of acute ethanol intoxication, we used stable-isotope labeled mice combined with quantitative mass spectrometry to screen over 2000 hippocampal proteins of which 72 changed synaptic abundance up to two-fold after ethanol exposure. Among those were mitochondrial proteins and proteins important for neuronal morphology, including MAP6 and Ankyrin-G. Based on these candidate proteins, we found acute and lasting molecular, cellular, and behavioral changes following a single intoxication in alcohol-naive mice. Immunofluorescence analysis revealed a shortening of axon initial segments. Longitudinal two-photon in vivo imaging showed increased synaptic dynamics and mitochondrial trafficking in axons. Knockdown of mitochondrial trafficking in dopaminergic neurons abolished conditioned alcohol preference in Drosophila. This introduces mitochondrial trafficking as a process implicated in reward learning, and highlights the potential of high-resolution proteomics to identify cellular mechanisms relevant for addictive behavior.

neuroscience↗

bioRxiv2019

Mice optimize switching decisions through cost-benefit evaluation

In the classical view of economic choices, subjects make rational decisions evaluating the costs and benefits of options in order to maximize their overall income. Nonetheless, subjects often fail to reach optimal outcomes. The overt value of an option drives the direction of decisions, but covert factors such as emotion and sunk cost are thought to drive the observed deviations from optimality. Many questions remain to be answered as to 1) which contexts contribute the most to deviation from an optimal solution; and 2) the extent of these effects. In order to tackle these questions, we devised a decision-making task for mice, in which cost and benefit parameters could be independently and flexibly adjusted and for which a tractable optimal solution was known. Comparing mouse behavior with this optimal solution across parameter settings revealed that the factor most strongly contributing to suboptimality was the cost parameter. The quantification of sunk cost, a covert factor implicated in our task design, revealed it as another contributor to suboptimality. In one condition where the large reward option was particularly unattractive and the small reward cost was low, the sunk cost effect and the cost-led suboptimality almost vanished. In this regime and this regime only, mice could be viewed as close to rational. Taken together, our findings support a model whereby parallel neural circuits independently activate and modulate multiple valuation algorithms, and suggest that "rationality" is a task-specific construct even in mice. Significant StatementIrrational factors in economic decision-making often cause significant deviation from optimal outcomes. By devising a flexible economic choice behavior for mice and comparing their behavior with an optimal solution, we investigated overt and covert factors that contributed to suboptimal outcomes and quantified the deviation from optimality. This investigation identified regimes where mice could be viewed as rational or irrational depending upon the parameters in the same task. These findings may provide a platform to investigate biological substrates underlying rational and irrational decision factors.

neuroscience↗