Biology subjects

Kiryk, A.

Publications and source records attributed to Kiryk, A..

4 recordsLinked to original sources

bioRxiv2025

The Role of TCF7L2 in Regulating Energy Metabolism in Thalamocortical Circuitry and its Broader Impact on Social Behavior

Psychiatric and metabolic disorders often co-occur. While shared genetic factors and cellular dysfunctions are implicated, the underlying molecular mechanisms remain poorly understood. TCF7L2, a risk gene for type 2 diabetes and autism spectrum disorder, is highly expressed in the thalamus--a brain region extensively interconnected with the cortex, playing a key role in sensory processing, motor control, and behavioral regulation. Given its known role as a transcription factor regulating systemic energy metabolism, we explored its potential contribution to brain metabolism and behavior. To this end, we used a conditional knockout model with postnatal TCF7L2 loss in the thalamus and partial deficiency in the pancreas. Tcf7l2 knockout mice exhibited social deficits and reduced motor habituation. In parallel, they also developed systemic glucose intolerance, modelling the psychiatric-metabolic comorbidity. Thalamic depletion of TCF7L2 resulted in elevated inhibitory phosphorylation of the pyruvate dehydrogenase --an enzymatic gatekeeper for pyruvate utilization in energy production--in the thalamus and cortex. This was accompanied by altered thalamic and cortical metabolism, characterized by reduced efficiency of pyruvate oxidation alongside enhanced oxidation of fatty acids and ketone bodies. Notably, a ketogenic diet alleviated metabolic dysregulation in the brain and normalized some social behaviors in knockout mice. These findings suggest that impaired energy metabolism in the thalamocortical circuitry may represent one of the pathogenic mechanisms underlying neuropsychiatric symptoms.

neuroscience↗

bioRxiv2024

Hormetic curve of dietary mono- and disaccharide content determines weight gain, gut microbiota composition and cognitive ability in mice

Hormesis is defined as dose response phenomenon characterized by low-dose stimulation and high-dose inhibition (Calabrese & Mattson, 2017). To date, low doses of several stressors (intermittent fasting, caloric restriction or selected phytochemicals) have been shown to exert beneficial effects on health (Martin et al., 2006). In the present study, we aimed to determine hormetic factors in a series of diets used in mice. We found that animals fed high-sugar diet (HSD) or high-fat diet (HFD) containing relatively high amounts of mono- and disaccharides become obese compared to animals fed standard diet (STAND) or ketogenic diet (KD) containing low doses of these compounds. Underlying the observed metabolic phenotype may be changes in the composition of the intestinal microbiota, showing u-shaped features in selected species. It is noteworthy that a short-term dietary regimen of several weeks resulted in difficulties in achieving effective scores on a complex cognitive test based on spatial procedural acquisition in the HSD and HFD groups. Our data identify dietary mono- and disaccharide content (commonly known as sugars) as a critical hormetic factor with beneficial/harmful effects at multiple levels of body function.

neuroscience↗

bioRxiv2024

Tracking changes in functionality and morphology of repopulated microglia in young and old mice

Microglia (MG) are myeloid cells of the central nervous system supporting its homeostasis and instigating neuroinflammation in pathologies. Single-cell RNA sequencing (scRNA-seq) revealed the functional heterogeneity of MG in mice brains. Inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling with inhibitors deplete microglia which rapidly repopulate. Functionalities of repopulated microglia are poorly known. We combined scRNA-seq, bulk RNA-seq, immunofluorescence and confocal imaging to study functionalities and morphology of repopulated microglia. CSRF1R inhibitor (BLZ-945) depleted MG in 21 days and their numbers were restored 7 days later as evidenced by TMEM119 staining and flow cytometry. ScRNA-seq and computational analyses demonstrate that repopulated MG originate from preexisting MG progenitors and reconstitute functional clusters but upregulate inflammatory genes. Percentages of proliferating, immature MG displaying inflammatory gene expression increase in aging mice. Morphometric analysis of MG cell body and branching shows distinct morphology of repopulated MG, particularly in old mouse brains. We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences microglia may contribute to the deterioration of microglia protective functions with age.

neuroscience↗

bioRxiv2023

Development and Application of Home Cage Monitoring in Laboratory Mice and Rats: a Systematic Review

Traditionally, in biomedical animal research, laboratory rodents are individually examined in test apparatuses outside their home cages at selected time points. However, the outcome of such tests can be influenced by the novel environment, the time of day, separation from the social group, or the presence of an experimenter. Moreover, valuable information may be missed when the animals are only monitored in short periods. These issues can be overcome by longitudinal monitoring mice and rats in their home cages. To shed light on the development of home cage monitoring (HCM) and the current state of the art, a systematic review was carried out on 521 publications retrieved through PubMed and Web of Science. Both the absolute ([~] x26) and relative ([~] x7) number of HCM-related publications increased from 1974 to 2020. In both mice and rats, there was a clear bias towards males and individually housed animals, but during the past decade (2011-2020), an increasing number of studies used both sexes and group housing. More than 70 % of the studies did not involve a disease model, but the percentage of studies using disease models increased since the 2000s. In most studies, animals were kept for short (up to 4 weeks) length periods in the HCM systems; intermediate length periods (4-12 weeks) increased in frequency in the years between 2011 and 2020. Before the 2000s, HCM techniques were predominantly applied for less than 12 hours, while 24-hour measurements have been more frequently since the 2000s. The systematic review demonstrated that manual monitoring is decreasing but still relevant. Until (and including) the 1990s, most techniques were applied manually but have been progressively replaced by automation since the 2000s. Independent of the publication year, the main behavioral parameters measured were locomotor activity, feeding, and social behaviors; the main physiological parameters were heart rate and electrocardiography. External appearance-related parameters were rarely examined in the home cages. Due to technological progress and application of artificial intelligence, more refined and detailed behavioral parameters could be investigated in the home cage in recent times. Over the period covered in this study, techniques for HCM of mice and rats has improved considerably. This development is ongoing and further progress and validation of HCM systems will extend the applications to allow for continuous, longitudinal, non-invasive monitoring of an increasing range of parameters in group-housed small rodents in their home cages.

animal behavior and cognition↗