Nejrohimiâ

In the article dedicated to the memory of Nikolay Nikolaevich Dygalo, the author recalls meetings with him at conferences and symposia over a 40-year scientific career in endocrinology and the study of stress. The first meeting took place in 1981 at the All-Union Symposium “Endocrine Mechanisms of Regulation of the Body’s Adaptation to Muscle Activity” in Tartu. The last meeting was on December 6, 2023, at the All-Russian Conference with international participation “Integrative Physiology-2023,” where Nikolay Nikolaevich gave an invited lecture. The long-lasting and friendly communication with Nikolay Nikolaevich was predestined by the kind and respectful relationship between their mentors – Evgeny Vladimirovich Naumenko and Anatoly Arkadyevich Filaretov – both of whom shared a common scientific interest in studying the key hormonal system of stress, the hypothalamic-pituitary-adrenocortical system. Nikolay Nikolaevich remains remembered as a person passionate about science, always vigorously striving for new achievements, retaining the enthusiasm of his youth, and with whom it was always joyful to communicate.

Striatal-enriched protein tyrosine phosphatase (STEP) is an intracellular protein involved in key signaling cascades of the nerve cell. By regulating the membrane localization of glutamate receptors and the activity of several signaling kinases, STEP can influence processes of neuroplasticity and synaptic function, and participate in the regulation of behavior, cognitition, and memory. STEP can act as an intermediary between the brain’s neurotrophic, dopaminergic, and glutamatergic systems. Dysregulation of STEP expression and function is observed in several neurodegenerative and psychiatric disorders, as well as in aging and traumatic brain injuries. In Alzheimer’s and Parkinson’s diseases, as well as in fragile X syndrome, there is an increase in STEP activity and expression in the brains of patients and in animal models of these diseases. There is evidence of this phosphatase’s involvement in the mechanisms of depression, autism spectrum disorders, schizophrenia, and anxiety; however, different model systems and experimental conditions yield contradictory results. STEP plays a modulatory role in the nervous system’s response to traumatic brain injuries, ischemic stroke, epileptic seizures, and stress exposure. Due to STEP’s involvement in the pathogenesis of numerous nervous system disorders, this phosphatase has been actively studied over the past decade. In this review, we comprehensively examine the existing data on the role of STEP phosphatase in the functioning of CNS and in the mechanisms of disease development and the response of nerve cells to damaging influences.

The formation of a conditional connection allows the organism to change its reactions to various environmental factors, combining and mobilizing the necessary internal adaptive processes. It is assumed that there are common mechanisms underlying the formation of adaptive processes – stress response and learning. To develop methods for non-invasive correction of nervous system pathologies at a model object of genetics – Drosophila, the relationship of adaptive mechanisms of the formation of a conditional connection and the development of a stressor reaction to the weakening of the Earth’s magnetic field in light: dark conditions was studied. The role of learning and lighting in overcoming stress in connection with the formation of long-term memory in the paradigm of conditioned courtship suppression was revealed. Within the framework of quantum dynamics of electronic and nuclear spins of transition states of radical molecules, the hypothesis of their participation in the formation of long-term memory is considered.

Domestication profoundly shapes the evolutionary trajectories of both humans and animals. Despite significant scientific interest, the genetic underpinnings of domestication, particularly those related to behavior, remain elusive. This paradox may be reconciled by considering that behavior-associated genes have already been identified but categorized exclusively to other functional groups. Our investigation into this hypothesis utilized goat genome and human brain transcriptome data, focusing on the pigmentation gene KITLG due to its frequent association with domestication. Through analysis of interpopulation covariation between KITLG and candidate genes in the domestic goat genome (Capra hircus), we identified eight genes evolutionarily linked with KITLG. These genes were divided into three functional categories: (i) regulation of the glucocorticoid (GC) signal, (ii) initiation, and (iii) control of structural neuroplasticity. In the human brain, the regional expression patterns of the corresponding transcripts were complementary and most pronounced in areas associated with social interaction. We propose that a mutation in KITLG may decrease the activation threshold for GC-mediated neuroplasticity in these regions, enhancing the processing of social stimuli. The association of this allele with spotted coat patterns likely facilitated its selection, with the uniqueness of the pattern promoting selective social contacts. Consequently, the genomes of domesticated animals is probably more profoundly influenced by behavioral functions than previously believed. Further research could unveil novel functional attributes of the nervous systems in both animals and humans.

Glucagon-like peptide-1 (GLP-1) is the main incretin that ensures insulin secretion and normalization of postprandial glycemia. GLP-1 mimetics are used for treatment of type 2 diabetes mellitus and obesity. Besides the insulinotropic effect, GLP-1 and its mimetics have been shown to affect on the functions of the cardiovascular and endocrine systems, the central mechanisms of appetite and metabolism regulation, the ion-regulatory and osmoregulatory renal functions, and a paradoxical hyperglycemic effect of incretin mimetics was also discovered. In current work the mechanisms by which the sympathoadrenal system is involved in the development of hyperglycemic and natriuretic effects of the GLP-1 mimetic exenatide in rats were studied. Experiments with healthy rats revealed that GLP-1 and its mimetic exenatide augmented the renal sodium excretion. Exenatide at doses of 0.15-5 nmol/kg, but not GLP-1 (1.5 nmol/kg), showed a hyperglycemic effect (blood glucose increased to 7.2–9.1 mM during the first hour). It has been shown that the rise of blood glucose level in rats administrated with incretin mimetic was associated with increase in renal excretion of catecholamine metabolites, was delayed by preliminary injection of a ganglionic blocker (pentamine 30 mg/kg) and was considerably leveled by non-selective β- and selective β2-adrenergic blockers (propranolol 5 mg/kg, ICI-118551 1 mg/kg). A significant modulation of natriuresis was revealed in response to the administration of exenatide during blockade of various adrenergic receptors subtypes. α1- and α2-blockers appreciably reduced (by 80%), and β1- and β2-blockers increased (by 150%) exenatide-stimulated renal sodium excretion. Thus, the data obtained indicate on the exenatide-induced activation of the sympathoadrenal system, which modulates the direction and severity of the incretin mimetic effects on blood glucose level and renal sodium excretion in healthy animals. The potential action on the sympathoadrenal system is important to consider when assessing the risk of adverse side effects during incretin mimetic therapy.

Ischemic stroke (IS) is one of the leading causes of long-term disability worldwide. At the same time, there is still no unequivocal understanding of the reasons for the varying degrees and speed of recovery of patients after IS. Recovery from IS is due to the highly organized interaction of brain structures and cells with other organs and tissues and involves a number of pathophysiological processes occurring both inside and outside the brain. Exosomes are involved in modulating pathophysiological processes after IS by mediating cell-tissue communication, primarily by delivering cargo such as proteins and microRNAs. A comparative quantitative analysis of the protein profiles of serum exosomes of patients examined at different stages after IS was carried out. Protein levels are associated with immune system functioning and coagulation in the serum exosomes of patients examined 1.5–2 years after IS was significantly higher compared to the parameters of patients examined in the earlier post-stroke period. The results indicate an increased level of immune system activation in the long post-stroke period compared to the early post-stroke period and the involvement of exosomes in this process. Further study of the molecular and biochemical parameters of exosomes in the long-term post-stroke period will allow us to assess the risks of functional outcomes of more fully IS and find potential targets for their reduction.

Physical activity is well known to have a beneficial effect on whole body functions, whereas a sedentary lifestyle contributes to the development of metabolic and other diseases and can lead to cognitive decline and increased risk of dementia. The hippocampus mainly controls cognitive performance and the hippocampal neurodegeneration is directly correlated with dementia progression. Hindlimb unloading (HU) is a widely used method to simulate microgravity in rodents and can be used as a model of mobility restriction since one of the main factors of HU is muscle disuse. Additionally, rodents show impaired learning and memory after long-term HU. Here, we explored whether HU would affect the survival or death of the hippocampal cells. Our data demonstrated that after 3-day HU, both apoptosis and autophagy were activated in the hippocampus, as evidenced by the activation of caspase 3 and 9 and an increase in the number of Cathepsin D and LC3b double-positive cells correspondently. Our data indicated that HU has no deleterious effects leading to neurodegeneration for up to 14 days. Moreover, our results also showed that the activation of autophagy during short-term HU had a protective effect, as we did not observe any cell loss or damage.

This is a story about the resurrection of genetics after the notorious Session in 1948, the contribution of both Leningrad and Novosibirsk. They have made acquainted their young geneticists because of this the author of the article can say about them, especially of Nikolay Dygalo, with Pushkin’s verse: “My first friend, so priceless”.