Biology subjects

Kowalski, M.

Publications and source records attributed to Kowalski, M..

4 recordsLinked to original sources

bioRxiv2025

Developmental benzopyrene exposure alters stress hormones, neurotransmitters and behavioral responses of mice dependent on Cyp1 genotype

Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) produced during combustion processes and when grilling foods. Epidemiological studies indicate exposure to PAHs during pregnancy lead to learning and memory deficits as well as behavioral problems that persist into adolescence. Studies in rodents and zebrafish have frequently reported anxiolytic effects of BaP exposure in adult animals and in developmental studies. We conducted sequential experiments of Cyp1a1(-/-) and Cyp1b1(-/-) knockout mice compared with wild type C57BL/6J mice to determine if genotype changes the response to developmental BaP exposure. We treated pregnant dams from gestational day 10 to postnatal day 25 (P25) with BaP in corn oil-soaked cereal or the corn oil vehicle and tested one male and one female offspring beginning at P60. We found increased exploratory behavior in the elevated zero maze for Cyp1a1(-/-) knockout mice, but no significant differences in Cyp1b1(-/-) knockouts. In contrast, Cyp1b1(-/-) knockout mice buried fewer marbles in a second test of anxiety-like behavior. There were no significant differences when Cyp1a1(-/-) knockout mice were tested. BaP decreased immobility time in Cyp1a1(-/-) knockouts in the forced swim test, but increased immobility time in wild type and Cyp1b1(-/-) knockout mice. We measured plasma corticosterone levels at baseline and following the forced swim test and monoamine neurotransmitters at the end of behavioral testing. BaP treatment increased corticosterone in wild type mice, but decreased it in Cyp1a1(-/-) knockout mice. Both BaP-exposed and corn oil control Cyp1b1(-/-) knockout mice had higher corticosterone levels compared with wild type mice. Dopamine and serotonin signaling were altered in the hypothalamus dependent on genotype, treatment and sex. Together, these data suggest that both CYP1A1 and CYP1B1 have a normal role in brain functioning or development, and that CYP1 genotype alters the response to developmental BaP exposure in behavioral and biochemical tests related to stress, anxiety and depression. HighlightsO_LIBaP-exposed Cyp1a1(-/-) mice had lower corticosterone and decreased immobility in the forced swim test C_LIO_LIBaP exposure increased FST immobility in wild type and Cyp1b1(-/-) mice C_LIO_LICyp1a1(-/-) and Cyp1b1(-/-) knockout mice showed less anxiety-like behavior C_LIO_LIDevelopmental BaP exposure altered corticosterone levels dependent on Cyp1 genotype C_LIO_LIGenotype, treatment and sex all impacted neurotransmitter levels in the hypothalamus C_LIO_LIGenetic differences in CYP enzymes altered susceptibility to developmental BaP exposure C_LI

pharmacology and toxicology↗

bioRxiv2024

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine is an NMDA-receptor antagonist that produces sedation, analgesia and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1-4 Hz) at high doses. Ketamines primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and non-human primate local field potential recordings. We have discovered how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported, and provides important insights into ketamines mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

neuroscience↗

bioRxiv2022

Dictionary learning for integrative, multimodal, and scalable single-cell analysis

Mapping single-cell sequencing profiles to comprehensive reference datasets represents a powerful alternative to unsupervised analysis. Reference datasets, however, are predominantly constructed from single-cell RNA-seq data, and cannot be used to annotate datasets that do not measure gene expression. Here we introduce bridge integration, a method to harmonize singlecell datasets across modalities by leveraging a multi-omic dataset as a molecular bridge. Each cell in the multi-omic dataset comprises an element in a dictionary, which can be used to reconstruct unimodal datasets and transform them into a shared space. We demonstrate that our procedure can accurately harmonize transcriptomic data with independent single cell measurements of chromatin accessibility, histone modifications, DNA methylation, and protein levels. Moreover, we demonstrate how dictionary learning can be combined with sketching techniques to substantially improve computational scalability, and harmonize 8.6 million human immune cell profiles from sequencing and mass cytometry experiments. Our approach aims to broaden the utility of single-cell reference datasets and facilitate comparisons across diverse molecular modalities. AvailabilityInstallation instructions, documentations, and vignettes are available at http://www.satijalab.org/seurat

genomics↗

bioRxiv2017

Caenorhabditis elegans as an emerging model for studying the basic biology of anorectic effects of nicotine

Nicotine decreases food intake, and smokers often report that they smoke to control their weight. To see whether similar phenomena could be observed in the model organism Caenorhabditis elegans, we challenged drug-na{iota}ve nematodes with a chronic low (0.01 mM) and high (1 mM) nicotine concentration for 55 h (from hatching to adulthood). After that, we recorded changes in their behavior in a nicotine gradient, where they could choose a desired nicotine concentration. By using a combination of behavioral and morphometric methods, we found that both nicotine and food modulate worm behavior. In the presence of food the nematodes adapted to the low nicotine concentration, when placed in the gradient, chose a similar nicotine concentration like C. elegans adapted to the high nicotine concentration. However, in the absence of food, the nematodes adapted to the low nicotine concentration, when placed in the gradient of this alkaloid, chose a similar nicotine concentration like naive worms. The nematodes growing up in the presence of high concentrations of nicotine had a statistically smaller body size, compared to the control condition, and the presence of food did not cause any enhanced slowing movement. These results provide a platform for more detailed molecular and cellular studies of nicotine addiction and food intake in this model organism.

animal behavior and cognition↗