Research into genetic and physiological mechanisms of widespread disorders such as arterial hypertension as well as neuropsychiatric and other human diseases is urgently needed in academic and practical medicine and in the field of biology. Nevertheless, such studies have many limitations and pose difficulties that can be overcome by using animal models. To date, for the purposes of creating animal models of human pathologies, several approaches have been used: pharmacological/chemical intervention; surgical procedures; genetic technologies for creating transgenic animals, knockouts, or knockdowns; and breeding. Although some of these approaches are good for certain research aims, they have many drawbacks, the greatest being a strong perturbation (in a biological system) that, along with the expected effect, exerts side effects in the study. Therefore, for investigating the pathogenesis of a disease, models obtained using genetic selection for a target trait are of high value as this approach allows for the creation of a model with a “natural” manifestation of the pathology. In this review, three rat models are described: ISIAH rats (arterial hypertension), GC rats (catatonia), and PM rats (audiogenic epilepsy), which are developed by breeding in the Laboratory of Evolutionary Genetics at the Institute of Cytology and Genetics (the Siberian Branch of the Russian Academy of Sciences).

Emotional stress is one of the health risk factors in the modern human lifestyle. Stress exposure can provoke the manifestation of various pathological conditions, one of which is a sharp increase in the blood pressure level. In the present study, we analyzed changes in the transcriptome profiles of the hypothalamus of hypertensive ISIAH and normotensive WAG rats exposed to a single short-term restraint stress (the rat was placed in a tight wire-mesh cage for 2 h). This type of stress can be considered emotional stress. The functional annotation of differentially expressed genes allowed us to identify the most significantly altered biological processes in the hypothalamus of hypertensive and normotensive rats. The study made it possible to identify a group of genes that describe a general response to stress, independent of the rat genotype, as well as a hypothalamic response to stress specific to each strain. The alternatively changing expression of the Npas4 (neuronal PAS domain protein 4) gene, which is downregulated in the hypothalamus of the control WAG rats and induced in the hypothalamus of hypertensive ISIAH rats, is suggested to be the key event for understanding inter-strain differences in the hypothalamic response to stress. The stress-dependent ISIAH strain-specific induction of Fos and Jun gene transcription may play a crucial role in neuronal activation in this rat strain. The data obtained can be potentially useful in the selection of molecular targets for the development of pharmacological approaches to the correction of stress-induced pathologies related to neuronal excitability, taking into account the hypertensive status of the patients.

Stress can play a significant role in arterial hypertension and many other complications of cardiovascular diseases. Considerable attention is paid to the study of the molecular mechanisms involved in the body response to stressful influences, but there are still many blank spots in understanding the details. ISIAH rats model the stress-sensitive form of arterial hypertension. ISIAH rats are characterized by genetically determined enhanced activities of the hypothalamic–pituitary–adrenocortical and sympathetic–adrenomedullary systems, suggesting a functional state of increased stress reactivity. For the first time, the temporal expression patterns of Fos and several related genes were studied in the hypothalamus of adult male hypertensive ISIAH rats after a single exposure to restraint stress for 30, 60, or 120 min. Fos transcription was activated and peaked 1 h after the start of restraint stress. The time course of Fos activation coincided with that of blood pressure increase after stress. Activation of hypothalamic neurons also alters the transcription levels of several transcription factor genes (Jun, Nr4a3, Jdp2, and Ppargc1a), which are associated with the development of cardiovascular diseases. Because Fos induction is a marker of brain neuron activation, activation of hypothalamic neurons and an increase in blood pressure were concluded to accompany increased stress reactivity of the hypothalamic–pituitary–adrenocortical and sympathoadrenal systems in hypertensive ISIAH rats during short-term restraint.

Normotensive and hypertensive organisms respond differently to stress factors; however, the features of the central molecular genetic mechanisms underlying the reaction of the hypertensive organism to stress have not been fully established. In this study, we examined the transcriptome profiles of the hypothalamus of hypertensive ISIAH rats, modeling a stress-sensitive form of arterial hypertension, and normotensive WAG rats at rest and after exposure to a single short-term restraint stress. It was shown that oxidative phosphorylation is the most significantly enriched process among metabolic changes in the hypothalamus of rats of both strains when exposed to a single short-term restraint stress. The analysis revealed DEGs representing both a common response to oxidative stress for both rat strains and a strain-specific response to oxidative stress for hypertensive ISIAH rats. Among the genes of the common response to oxidative stress, the most significant changes in the transcription level were observed in Nos1, Ppargc1a, Abcc1, Srxn1, Cryab, Hspb1, and Fosl1, among which Abcc1 and Nos1 are associated with hypertension, and Fosl1 and Ppargc1a encode transcription factors. The response to oxidative stress specific to hypertensive rats is associated with the activation of the Fos gene. The DEG’s promoter region enrichment analysis allowed us to hypothesize that the response to oxidative stress may be mediated by the participation of the transcription factor CREB1 (Cyclic AMP-responsive element-binding protein 1) and the glucocorticoid receptor (NR3C1) under restraint stress in the hypothalamus of both rat strains. The results of the study revealed common and strain-specific features in the molecular mechanisms associated with oxidative phosphorylation and oxidative stress response in the hypothalamus of hypertensive ISIAH and normotensive WAG rats following a single short-term restraint stress. The obtained results expand the understanding of the most significant molecular targets for further research aimed at developing new therapeutic strategies for the prevention of the consequences of acute emotional stress, taking into account the hypertensive state of the patient.

Since the work of Nobel Prize winner Thomas Morgan in 1909, the fruit fly Drosophila melanogaster has been one of the most popular model animals in genetics. Research using this fly was honored with the Nobel Prize many times: in 1946 (Muller, X-ray mutagenesis), in 1995 (Lewis, Nüsslein-Volhard, Wieschaus, genetic control of embryogenesis), in 2004 (Axel and Buck, the olfactory system), in 2011 (Steinman, dendritic cells in adaptive immunity; Beutler and Hoffman, activation of innate immunity), and in 2017 (Hall, Rosbash and Young, the molecular mechanism of the circadian rhythm). The prominent role of Drosophila in genetics is due to its key features: short life cycle, frequent generational turnover, ease of maintenance, high fertility, small size, transparent embryos, simple larval structure, the possibility to observe visually chromosomal rearrangements due to the presence of polytene chromosomes, and accessibility to molecular genetic manipulation. Furthermore, the highly conserved nature of several signaling pathways and gene networks in Drosophila and their similarity to those of mammals and humans, taken together with the development of high-throughput genomic sequencing, motivated the use of D. melanogaster as a model organism in biomedical fields of inquiry: pharmacology, toxicology, cardiology, oncology, immunology, gerontology, and radiobiology. These studies add to the understanding of the genetic and epigenetic basis of the pathogenesis of human diseases. This paper describes our curated knowledge base, FlyDEGdb (https://www.sysbio.ru/FlyDEGdb), which stores information on differentially expressed genes (DEGs) in Drosophila. This information was extracted from 50 scientific articles containing experimental data on changes in the expression of 20,058 genes (80 %) out of the 25,079 Drosophila genes stored in the NCBI Gene database. The changes were induced by 52 stress factors, including heat and cold exposure, dehydration, heavy metals, radiation, starvation, household chemicals, drugs, fertilizers, insecticides, pesticides, herbicides, and other toxicants. The FlyDEGdb knowledge base is illustrated using the example of the dysf (dysfusion) Drosophila gene, which had been identified as a DEG under cold shock and in toxicity tests of the herbicide paraquat, the solvent toluene, the drug menadione, and the food additive E923. FlyDEGdb stores information on changes in the expression of the dysf gene and its homologues: (a) the Clk, cyc, and per genes in Drosophila, and (b) the NPAS4, CLOCK, BMAL1, PER1, and PER2 genes in humans. These data are supplemented with information on the biological processes in which these genes are involved: oocyte maturation (oogenesis), regulation of stress response and circadian rhythm, carcinogenesis, aging, etc. Therefore, FlyDEGdb, containing information on the widely used model organism, Drosophila, can be helpful for researchers working in the molecular biology and genetics of humans and animals, physiology, translational medicine, pharmacology, dietetics, agricultural chemistry, radiobiology, toxicology, and bioinformatics.

Hypertension is among the major risk factors of many cardiovascular diseases. Chronic psychoemotional stress is one of its key causes. Studies of molecular mechanisms of human hypertension development are conducted in animals, including artificial rat strains that model various forms of the disease. The RatDEGdb database, used in our work, includes 144 hypothalamic genes that represent the common response to single short-term restraint stress in hypertensive ISIAH and normotensive WAG rats. These rat genes were annotated with changes in the expression of the human orthologs using data on 17,458 differentially expressed genes (DEGs) from patients with hypertension compared to normotensive subjects. We applied principal component analysis to orthologous pairs of DEGs identified in hypertensive patients and rat hypothalamic DEGs upon single short-term restraint stress. Two principal components, corresponding to a linear combination of log2 expression changes associated with the similarity (PC1) and difference (PC2) in the response to psychoemotional stress in two rat strains, on the one hand, and different forms of human hypertension, on the other, explained 64 % and 33 % of the variance in differential gene expression, respectively. The significant correlation revealed between PC1 and PC2 values for the group of DEGs with stress-induced downregulation indicates that psychoemotional stress and hypertension share a common molecular mechanism. Functional annotation suggests that stress-induced downregulation of genes involved in the plasma membrane function and, simultaneously, interactions with the extracellular matrix is the most likely contribution of psychoemotional stress to the development of the hypertensive status inpatients, and the SMARCA4 transcription factor is the most likely mediator in the epigenetic modification affecting gene expression under chronic stress. Peripheral blood markers for the diagnosis of psychoemotional stress are proposed.