Drawbacks and Unexpected Advantages of the Response to Modeling Posttraumatic Stress Disorder in Old Wistar Rats.

In modeling post-traumatic stress disorder (PTSD), old Wistar rats exhibit the same general signs of a PTSD-like condition as young rats do. The ratio of testosterone to corticosterone levels was assessed as a new index and proved to provide a guideline for dividing the rat population into low- and high-anxiety groups when modeling PTSD. Several features were observed in behavior, psycho-emotional manifestations, hormone levels, and myocardial state in old rats. A sharp rise in circulating testosterone was for the first time shown to occur in old, but not young, rats in stress, contributing to a more rapid decision as to where to move in the labyrinth space. Priority data were obtained on dysfunctional accumulation of mitochondria in the myocardium in intact and stressed old rats. The information obtained may be useful in developing drugs against harmful consequences of PTSD and senile changes in the myocardium.

Role of Neurohumoral Imbalance at Post-Traumatic Stress Disorder in the Antitumor Immune Response. Experimental Study.

The aim of the study is to investigate the growth and development of B16 melanoma in mature male C57Black/6 mice with a post-traumatic stress disorder (PTSD) model. Behavioral, immunohistochemical, morphometric methods, enzyme immunoassay were used. A forced decrease in the level of corticosterone, which is characteristic for PTSD, was established, followed by intensification of the production of increased concentrations of pro-inflammatory interleukins by the cells of the immune system and, at the same time, a decrease in the secretion of anti-inflammatory cytokines. Priority data were obtained: the neurohumoral imbalance that develops in PTSD is a limiting factor to the growth of B16 melanoma, at least at the initial stages of the oncological process.

The Search for Diagnostic Criteria to Divide the Wistar Rat Population into Phenotypes during Modeling of Post-Traumatic Stress Disorder.

The levels of circulating hormones (corticosterone, testosterone, and leptin) and interleukins were studied in sexually mature male Wistar rats against the background of post-traumatic stress disorder (predator threat stress). It was found that in addition to the previously used anxiety index determined by animal behavior, the population of stressed individuals can be divided into stress-resistant and stress-sensitive phenotypes by the level of leptin and the index of anabolism (testosterone/corticosterone ratio). For the first time, it was determined that in stress-resistant rats, the levels of leptin and the testosterone/corticosterone index exceeds the control values, while in stress-sensitive individuals, these indicators are much lower.

Phenotypically Determined Liver Dysfunction in a Wistar Rat Model of Post-Traumatic Stress Disorder.

The extraordinary situation of the 2019-2022 pandemic caused a dramatic jump in the incidence of post-traumatic stress disorder (PTSD). PTSD is currently regarded not only as a neuropsychiatric disorder, but also as a comorbidity accompanied by cardiovascular diseases, circulatory disorders, liver dysfunction, etc. The relationship between behavioral disorders and the degree of morphofunctional changes in the liver remains obscure. In this study, PTSD was modeled in sexually mature male Wistar rats using predatory stress induced by a prey's fear for a predator. Testing in an elevated plus maze allowed the rat population to be divided into animals with low-anxiety (LAP) and high-anxiety (HAP) phenotypes. It was found that morphofunctional analysis of the liver, in contrast to its biochemical profiling, provides a clearer evidence that predatory stress induces liver dysfunction in rats of both phenotypes. This may indicate a decrease in the range of compensatory adaptive reactions in stressed animals. However, in HAP rats, the level of morphofunctional abnormalities in the mechanisms responsible for carbohydrate-fat, water-electrolyte and protein metabolism in the liver testified the prenosological state of the organ, while further functional loading and resulting tension of the regulatory systems could lead to homeostatic downregulation. Meanwhile, the liver of LAP animals was only characterized by insignificant diffuse changes. Thus, we demonstrate here a link between behavioral changes and the degree of morphofunctional transformation of the liver.

Risk Factors and Mechanisms of Cardiovascular Diseases in Posttraumatic Stress Disorder Model in Wistar Rats as Dependent on Stress Resistance and Age.

The article focuses on the pathogenetic mechanisms of posttraumatic stress disorder (PTSD), which is associated with psychological stress because of the coronavirus pandemic. The molecular mechanisms responsible for disease susceptibility in some individuals and stress resistance in others are amongst crucial research interests of experimental and clinical medicine. Priority data were obtained to indicate that distortions of synthesis and metabolism and, most significantly, a switch between two energy transport forms, glucose and lipids, underlie myocardial dysfunction in young and old stress-sensitive Wistar rats in a PTSD model. Histochemistry and polarization microscopy showed energy deficit in cardiomyocytes and signs of ischemic and hypoxic areas emerging in the myocardium as a result of an accumulation of NADH and NADPH, which initiate excessive production of reactive oxygen species.

Horizons of Heparin Therapy in COVID-19 and Pandemic-Related Diseases.

The disease caused by the coronavirus SARS-CoV-2, named COVID-19, has been spread around the world at a high transmission rate. It was initially considered to be an acute respiratory distress syndrome. Recent clinical data has highlighted that COVID-19 is characterized by a vascular dysfunction and thrombosis, which are not typical for many other acute respiratory diseases. Thrombotic complications are markers of severe COVID-19 and are associated with multiple organ failure and increased mortality. The application of unfractionated and/or low-molecular-weight heparins as anticoagulant medications, significantly reduced the severity of the disease and COVID-19-induced mortality, since heparin is a multifunctional agent. The goal of this review is to summarize the literature data on the pathogenic mechanisms of SARS-CoV-2 and to characterize the properties of heparin, which allow inhibiting these mechanisms at any stage of pathogenesis. We proposed a vicious circle hypothesis of SARS-CoV-2 pathogenesis, as well as an original approach to low-dose heparin therapy beyond its anticoagulant properties. The analysis of a wide range of effects and mechanisms of action of heparin will help create an idea of current possibilities and future potential of applying this drug.

Indicators of Hypoxia Tolerance as Determined by Cellular Elements of Rat Blood.

Although hypoxia tolerance is mainly determined genetically, it is important to study individual variability of animal organisms in order to identify the factors that underlie their tolerance to hypoxic exposure. We investigated blood cell counts and coagulograms in Wistar rats as predictors allowing the animal population to be split into hypoxia-tolerant and hypoxia-intolerant individuals. The validity of the specific predictors' choice was proved by a coincidence between the population split in accordance with the detected individual parameters and the results of testing animals in a decompression chamber at a rarefaction corresponding to the "rise to an altitude" of 11500 m above sea level. Circulating blood cells were quantitatively assessed by eighteen indicators before and after hypoxic exposure. The differences between animals low-tolerant (LT), high-tolerant (HT), and medium-tolerant (MT) to hypoxia were determined by five indicators: white blood cell count (WBC), granulocyte count (Gran#), red blood cell count (RBC), reticulocyte count/percent (RTC), and mean corpuscular hemoglobin (MCH). The RBC, RTC, and MCH values in HT rats were significantly higher than in LT animals (by 1.4, 1.9, and 1.1 times, respectively). The WBC and Gran# values in HT rats were lower than in LT individuals. The hypoxia tolerance indices (HTI) were calculated using the original formula. It was established that in LT rats, the HTI ≤ 0.203, in HT rats ≥ 0.335, and in MT rats < 0.335 but > 0.203. After testing in a decompression chamber, the activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT) decreased, but the fibrinogen level increased. LT rats were characterized by the lowest APTT, TT, and PT values and the highest values of the fibrinogen level. Our results indicate that one of the most important mechanisms underlying a high hypoxia tolerance in rats consists in sustaining reciprocal relationships between the complex of RBC indicators, which tend to increase under hypoxia, and Gran# indicators, which tend to decrease after hypoxic exposure.

New Morphofunctional Criteria for Resistance Profile in Post-Traumatic Stress Disorder Models as Adrenal Dysfunction Trigger.

For the first time in modeling posttraumatic stress disorder (PTSD), we have described the morphofunctional state of adrenal glands in Wistar rats resistant and sensitive to predator stress (rodent fear of the predator). Despite the evident signs of adrenal dysfunction in both phenotypes, we have discovered the thickening of undifferentiated cell zone and high indices of functional activity of stem cells in resistant animals, suggesting ample adaptation. The most important data demonstrate the direct relationship between the reduction of corticosterone and testosterone levels and adrenal dysfunction in PTSD models. The study results allow considering the adrenal stem cells as potential therapeutic targets.

Comparison of the Adaptive Capacity in Old and Young Wistar Rats to Stress Exposure and Acute Hypoxic Hypoxia.

We compared behavioral and psychoemotional manifestations of young and old male Wistar rats in elevated plus-maze, the levels of corticosterone and testosterone, as well as the resistance to acute hypoxic hypoxia before and after stress exposure (10-min swimming sessions over 10 days). The behavioral characteristics, responses of the main stress hormone corticosterone, and resistance to acute hypoxic hypoxia were identical in both age groups before and after stress. A distinguishing feature was pronounced flattening of the psychoemotional manifestations in old animals. The main adaptive differences between young and old rats were revealed in the response of circulating testosterone to stress.

The Role of the Hippocampus in the Neuroendocrine Response to Neurobiological Stimuli in Experiment.

We compared the levels of functional activity of cells in each adrenal zone with blood levels of corticosterone, testosterone, and neuropeptide Y in control and hippocampectomized F1(C57BL/6×DBA/2) mice during modeling of metabolic, motivational, and cognitive tension. The morphofunctional state of the adrenal glands was studied using a new morphometric approach. It was found that hippocampectomy changed the testosterone response to neurobiological stimuli; similar changes were observed in the zona reticularis of the adrenal cortex producing dehydroepiandrosterone that is involved in the regulation of testosterone secretion. At the same time, hippocampectomy enhanced the response of the peptide hormone; the index of functional activity of chromaffin cells producing this hormone also increased. These findings allow us to put forward a hypothesis that the hippocampus is involved in the regulation of mutual influences of the studied hormones and that it modulates the sensitivity of testosterone and NPY to metabolic and cognitive factors.

The Cost of Adaptation to Information Loading in Mice with Various Genetic Profiles.

It was found that male BALB/c and F1(C57BL/6×DBA/2) mice are able to recognize the structure of a complex food-gathering task, when modeling the information loading similar to intellectual work in humans. There were significant differences between linear and hybrid animals in the pattern of learning process formation and prevailing psychoemotional reactions that accompany information load. Factors of information loading (uncertainty of maze environment and solution of the food-gathering task) had a specific influence on the CNS and manifested in individual non-specific features. The presented experimental conditions (changes in the metabolic and functional state) revealed pronounced intergroup differences in the reaction of the functional zones of the adrenal cortex. In hybrid mice, information loading induced a significant decrease in testosterone level and thickness of the zona reticularis producing precursor hormones. This is probably due to disruption of interactions in the adrenal-thyroid system in hybrid mice, whereas in BALB/c mice, these interactions fully protect from suppression of testosterone production, the main anabolic hormone. The individual characteristics of the response to information loading can be formed as a result of unequal involvement of the psychophysiological, psychological, and autonomic systems responsible for adaptation to environmental factors.

"Behavior" of the Hormonal Ensemble through the Prism of Cluster Analysis.

The serum hormone concentrations were studied in a group of male F1 (C57BL/6×DBA/2) mice in different states of food activity (satiety, 24-h food deprivation, and cognitive load against the background of food deprivation). The hormonal response depended on food activity: the content of leptin, triiodothyronine, and testosterone decreased in hungry animals, while during cognitive load (learning), we observed a decrease in the concentrations of ghrelin, leptin, thyroxine, and testosterone. The exceptions were neuropeptide Y (its concentration increased in hungry animals) and corticosterone (its level remained unchanged). The use of hierarchical cluster analysis allowed identifying functional organization of the relationships within the hormonal ensemble that underwent plastic changes depending on the state of the organism. It was shown that the hormonal ensemble was system-organized in the form of a "core" that determines stability of the system and the "field", within which functional interactions of the hormones are preserved.

Specific Behavioral Patterns Enhancing Hypoxia Resistance in Wistar Rats Subjected to Moderate Swimming Exercise.

Enhanced resistance to acute hypoxic hypoxia was observed in male Wistar rats exposed to daily moderate exercise (swimming in water of comfortable temperature). It was found that moderate physical exercise was associated with the development of tolerant behavior reflecting the prevalence of inhibitory processes in the CNS over excitatory processes. The observed relationships between the peculiarities of tolerant behavioral pattern and development of hypoxia resistance can be used in specific physical training of people professionally exposed to factors inducing hypoxia.

Heparin Modulates the Main Properties of the Central Nervous System in Experimental Post-Traumatic Stress Disorder: A New Concept of the Mechanisms of Pathogenesis and Treatment.

Elevated plus-maze test was used to reveal the role of excitation and inhibition mechanisms in the CNS in the organization of the behavior of male Wistar rats under normal conditions and during modeling experimental post-traumatic stress disorder (with or without administration of low doses of high-molecular-weight heparin). The data about insufficiency in the system of excitation mechanisms and pronounced excess in the system of inhibition mechanisms in post-traumatic stress disorder are prioritized. Heparin seems to be a promising and effective preparation to cope with extreme psychotraumatic abnormalities in CNS.

Physical Fatigue and Morphofunctional State of the Myocardium in Experimental Chronic Stress.

The relationship between the development of skeletal muscle fatigue of a specific type in male Wistar rats and morphofunctional alterations in the myocardium in the posttraumatic stress disorder (PTSD) model has been investigated for the first time. The aggravation of oxidative stress in the cardiomyocytes and the related transformation of the cell structural components and the depletion of energy reserves in PTSD has been identified as one of the main factors that accelerate the onset of musculoskeletal fatigue.

[Psychophysiological signs of aging in mice F1 (C57BL/6×DBA/2).]

The psychophysiological effects of aging in mice of the line F1 (C57BL/6×DBA/2) at the age of 3, 7, and 14 months were investigated. It was found that the cognitive abilities, memory and spatial orientation in all animals did not depend on age, they were able to form a 4-link food-getting habit. The instability of behavior found in all mice at the stereotyped stage of in the form of periodic reproduction of false and irrational realizations was determined by the peculiarities of the basic nervous processes - increased excitability and weakness of inhibition. It was possible to establish that the consistent reduction of the excitation phase during the aging process caused the instability of the dominant state and motivational activity, negatively affecting the attention stable and, consequently, the ability to consistently reproduce the optimal variant of habit.

Experimental Evaluation of the Effects of Low-Dose Heparin on the Behavior and Morphofunctional Status of the Liver in Wistar Rats with Posttraumatic Stress Disorders.

Posttraumatic stress disorders were induced in Wistar rats by modeling predatory stress. Animals tested in elevated plus-maze demonstrated signs of high anxiety and difficulties in space orientation. Behavioral disorders were paralleled by degenerative changes in hepatocytes. A course of low-dose high-molecular heparin after stress exposure promoted effective adaptation and normalization of behavioral and morphofunctional disorders. Analysis of the results indicated good prospects of heparin as an effective drug under conditions of exposure to extreme factors of psychotraumatic type.

[CYTOKINES SECRETION BY SPLENOCY-TES IN RESPONSE TO MICE F1 (C57BL/6XDBA/2) BEHAVIOR IN ENVIRONMENTS OF VARYING COMPLEXITY].

We study the dependence of the mitogen-induced cytokine secretion by splenocytes from the character of the behavior of F1 (C57BL/6XDBA/2) mice in environments with different degrees of spatial complexity: simple in the form of home box, enriched box and maze. Suppression of in-terleukins IL-2, IL-4, IL-6 and IL-10 expression, regardless of their structural and functional properties, was observed only in an enriched environment when aggressive and neurotic manifestations were increased. The opposite effect in the form of significant increase of the productions in all studied cytokines was observed in the case of the stereotypical goal-directed behavior in a maze. It was supposed that cytokines of the splenocytes are involved in the realization of highly 307 differentiated adaptive response of the organism due to the influence of social and cognitive factors, the expression of which depends on the specific physiological and biochemical systems.

Systemic Effects of Testosterone: Hormonal and Behavioral Mechanisms.

We studied the effects of food deprivation, spatial complexity of environment, and cognitive strain on blood level of testosterone in male (C57Bl/6×DBA/2)F1 mice. Hormone concentration decreased after exposure to any factor and this decrease depended on combined impact to the factors. Testosterone concentration was most sensitive to cognitive strain against the background of food deprivation. The total response of testosterone under conditions of enriched environment and activation of social interactions in the form of neurotic and aggressive behavior provoked by food deprivation was not equal to the sum of individual effects of these factors. Testosterone response to combined exposure to external and internal factors reflected systemic effect.

Behavioral characteristics of ovariectomied Wistar rats trained in a maze. Effect of mental stress and castration for infradian rhythms.

Four psychotypes differing by cognitive activity and psychoemotional reactions were distinguished in a population of orchiectomied Wistar rats and in a population of intact animals on the model of a complex cognitive test combined with the free choice method. With similar parameters of cognitive activity, the psychotypes of castrated rats were inferior to those of intact animals by the number of psychoemotional reactions and levels of locomotor activity. Infradian rhythms of spontaneous locomotor activity with a 4-day period were detected in intact and castrated rats. These rhythms did not change under the effect of mental stress, associated with food-getting behavior training, and did not depend on testosterone level.