Modern concepts hold that intellectual problems in neurological brain damage are based on active forgetting, which is regulated by actin remodeling signal cascades dependent on small GTPases Rac and Rho. The key enzyme in these cascades is LIM kinase 1 (LIMK1). Changes in limk1 gene expression lead to neurocognitive pathologies. There is a need to create and validate simple animal models for rapid screening and testing of targeted therapeutic agents altering the protein–protein interactions of GTPases and components of signal cascades. One opportunity for this is provided by Drosophila, mutant strains of which allow the key points of the intersections of biochemical and neural networks which accompany active forgetting to be identifi ed.

Courtship suppression is a behavioral adaptation of the fruit fly. When majority of the females in a fly population are fertilized and non-receptive for mating, a male, after a series of failed attempts, decreases its courtship activity towards all females, saving its energy and reproductive resources. The time of courtship decrease depends on both duration of unsuccessful courtship and genetically determined features of the male nervous system. Thereby, courtship suppression paradigm can be used for studying molecular mechanisms of learning and memory. p-Cofilin, a component of the actin remodeling signaling cascade and product of LIM-kinase 1 (LIMK1), regulates Drosophila melanogaster forgetting in olfactory learning paradigm. Previously, we have shown that limk1 suppression in the specific types of nervous cells differently affects fly courtship memory. Here, we used Gal4 > UAS system to induce limk1 overexpression in the same types of neurons. limk1 activation in the mushroom body, glia, and fruitless neurons decreased learning index compared to the control strain or the strain with limk1 knockdown. In cholinergic and dopaminergic/serotoninergic neurons, both overexpression and knockdown of limk1 impaired Drosophila short-term memory. Thus, proper balance of the limk1 activity is crucial for normal cognitive activity of the fruit fly.

The signal pathway of actin remodeling, including LIM-kinase 1 (LIMK1) and its substrate cofilin, regulates multiple processes in neurons of vertebrates and invertebrates. Drosophila melanogaster is widely used as a model object for studying mechanisms of memory formation, storage, retrieval and forgetting. Previously, active forgetting in Drosophila was investigated in the standard Pavlovian olfactory conditioning paradigm. The role of specific dopaminergic neurons (DAN) and components of the actin remodeling pathway in different forms of forgetting was shown. In our research, we investigated the role of LIMK1 in Drosophila memory and forgetting in the conditioned courtship suppression paradigm (CCSP). In the Drosophila brain, LIMK1 and p-cofilin levels appeared to be low in specific neuropil structures, including the mushroom body (MB) lobes and the central complex. At the same time, LIMK1 was observed in cell bodies, such as DAN clusters regulating memory formation in CCSP. We applied GAL4 × UAS binary system to induce limk1 RNA interference in different types of neurons. The hybrid strain with limk1 interference in MB lobes and glia showed an increase in 3-h short-term memory (STM), without significant effects on long-term memory. limk1 interference in cholinergic neurons (CHN) impaired STM, while its interference in DAN and serotoninergic neurons (SRN) also dramatically impaired the flies’ learning ability. By contrast, limk1 interference in fruitless neurons (FRN) resulted in increased 15–60 min STM, indicating a possible LIMK1 role in active forgetting. Males with limk1 interference in CHN and FRN also showed the opposite trends of courtship song parameters changes. Thus, LIMK1 effects on the Drosophila male memory and courtship song appeared to depend on the neuronal type or brain structure.

The Earth’s magnetic field is subject to continuous changes. It has also been shown to induce effect on the vital activities of all living organisms. These factors make the study of magneto-biological effects important and highly relevant. From the biological point of view, weak magnetic fields, especially weak static magnetic fields, are among the most poorly understood, however, they have a noticeable effect on living organisms, including humans. The use of such fields is on the rise, which requires a comprehensive understanding of mechanisms behind their effect on living things. The article investigates the effect of weak static magnetic fields amplified and weakened relative to the Earth’s magnetic field on cellular tissue regeneration. It has been shown that one of the main cellular processes—proliferation—increases when the cells are exposed to enhanced or depressed static magnetic fields. The greatest effect of such exposure is observed in mesodermal tissue, i. e., the myocardium, vessels, and muscles. The effect of tissue-specific oligopeptides on cellular proliferation is comparable to that of static magnetic fields: the stimulation of cellular regeneration occurs primarily in the myocardium, muscles, and vessels. A special focus is given to the therapeutic potential of weak magnetic fields and their interaction with clinical drugs in various pathologies.

Непрерывно меняющееся магнитное поле Земли и его постоянное воздействие на жизнедеятельность всех живых организмов обусловливает важность и востребованность исследования магнитобиологических эффектов. Однако с биологической точки зрения слабые магнитные поля, в особенности слабые статические магнитные поля, являются одними из самых плохо изученных, хотя они способны оказывать заметное воздействие на живые организмы, в том числе и на человека. Сфера применения таких полей в настоящее время неуклонно расширяется, что делает необходимым детальное осмысление механизмов их действия на живые объекты. В работе рассмотрено воздействие слабых статических магнитных полей, усиленных и ослабленных относительно магнитного поля Земли, на клеточную регенерацию тканей. Показано, что один из основных клеточных процессов — пролиферация — усиливается при воздействии как усиленных, так и ослабленных статических магнитных полей. Наибольший эффект воздействия наблюдается в тканях мезодермального генеза — миокарда, сосудов и мышц. Влияние тканеспецифических олигопептидов на клеточную пролиферацию сопоставимо с действием на ткани статических магнитных полей: стимуляция клеточной регенерации происходила прежде всего в тканях миокарда, мышц и сосудов. Отдельное внимание уделено терапевтическому потенциалу слабых магнитных полей и вопросам их взаимодействия с лекарственными препаратами для клинического использования при различных патологиях.

The paper continues the cycle of studies on the evolutionary link between the mechanisms of stress response formation and cognitive functions started in 1959 by M.E. Lobashev and V.B. Savvateev. We explore the role of a key neuroplasticity factor LIM kinase 1 (LIMK1) expressed in dopaminergic and serotonergic neurons in Drosophila genome stability, as well as learning and memory, both in standard conditions and when an organism exhibits a stress response to Earth's weakened static magnetic field (WSMF). We demonstrate that a low LIMK1 level promotes learning acquisition, but not the formation of intermediate-term memory; at the same time, stress exposure restores the learning ability and memory formation in the Drosophila strain with an increased LIMK1 content. We identify inter-strain differences in the frequency of DNA double-strand breaks (DSBs) and show an increase in DSBs after the exposure to WSMF. The data obtained reveal the role of dopaminergic and serotonergic neurons not only in cognitive functions, but also as WSMF targets in the development of a stress response.

M.E. Lobashev and V.В. Savvateev in 1959 obtained unique data on the expansion of the adaptive capabilities of the organism when training the properties of higher nervous activity by the formation of conditioned food reflexes to stimuli that exhaust the nervous system. Apparently, the formation of a conditioned connection help to overcoming stressful effects, adaptation to restrictive conditions, and changes in the functioning of the nervous system. To test this assumption, the influence of stressful influences hypoxia on learning and memory of Drosophila in the paradigm of conditioned reflex suppression of courtship was studied. The results were obtained on the enhancement of the ability to learn under hypoxic exposure. These experimental conditions did not affect memory formation. The effect of hypoxia on chromosomes through the formation of double-stranded breaks was revealed. The data are discussed in light of the relationship between neuroplasticity processes and mechanisms of adaptation to stressors.

В настоящее время нейродегенеративные заболевания (НДЗ) имеют весьма широкое распространение. По данным Всемирной организации здравоохранения (ВОЗ) в 2015 году деменция затронула 47 млн человек во всем мире, и, по прогнозам, эта цифра к 2030 году достигнет 75 млн, а к 2050 году — 132 млн. Нейрофизиологи во всем мире стремятся познать этиологию и патогенез НДЗ. Известно, что одной из причин возникновения нейрокогнитивных патологий является нарушение экспрессии гена limk1. Кроме того, согласно современным представлениям, основу интеллектуальных проблем при нейрологических повреждениях мозга составляет активное забывание, регулируемое сигнальным каскадом ремоделирования актина, ключевым звеном которого является фермент LIMK1. В работе проведен анализ формирования и динамики изменения краткосрочной и среднесрочной памяти у линий Drosophila melanogaster, полиморфных по гену limk1 (Canton-S, Oregon-R и agnts3). Полиморфизм по гену limk1 дрозофилы сказывается на содержании его продукта (мутант agnts3 характеризуется 2,5-кратным повышением содержания LIMK1 по сравнению с CS) и приводит к нарушениям поведения ухаживания и обучения. Результаты настоящего исследования двух линий дикого типа и мутанта agnts3 с измененной структурой гена limk1 показывают, что нарушения структуры данного гена могут являться причиной нарушения процессов обучения и забывания.

Stress effects are factors that provoke a wide range of socially significant diseases. We studied the effect of two such factors - weak static magnetic field (WSMF) with induction value of 200 mcT and a number of epigenetic regulators, oligopeptides. One of the main cellular processes - proliferation - is shown to occur when WSMF is acting in tissues of various genesis with different intensity. The greatest effect of WSMF exposure is observed in ectodermal genesis tissue - the cerebral cortex. The results of experiments with tissue-specific oligopeptides were comparable to those of WSMF. Analysis of the results of experiments to study cognitive behavior leads to the conclusion of beneficial effects on medium-term memory formation using oligopeptides Ala-Glu-Asp-Pro and Lys-Glu-Asp-Ala. Similarity in the outcome of WSMF and bioregulatory peptides impact in different species of animals on the proliferative cell activity in nervous tissue culture and cognitive behaviour suggests the existence of a common ancient mechanism for regulating the activity of organisms. It is noted that the efficiency of external WSMF influence on biological objects is caused by its high penetration ability.

Metabolism disorders of L-kynurenine, which is an intermediate product of the decomposition of genetically encoded L-tryptophan amino acid, is a component in the development of a number of neuropathological processes. The effect of tryptophan and kynurenine on cell proliferation has been studied in the organotypic culture of cerebral cortex tissue in young and old rats. Tryptophan at an effective concentration (0.05 ng/mL) oppressed cell proliferation in the cerebral cortex in young and old rats by 35 and 18%, respectively. However, cell proliferation was stimulated under the action of kynurenine (1 ng/mL), and it was more pronounced in cerebral cortex explants in old rats (by 22% as compared with the control group). The obtained data on kynurenine properties for the stimulation of cell proliferation in the cerebral cortex in old animals is promising for the creation of new medicinal nootropic drugs in age-associated diseases of the nervous system.

In an organotypic culture, an investigation was conducted into combined effects of cyclophosphamide DNA as synthesis inhibitor used to model a resorptive action of mustard gas, and cortexin polypeptide or each of 20 encoded amino acids on the development of cell proliferation in cerebral cortex explants of the rat. The combined administration of cyclophosphamide together with cortexin or with each of the 20 encoded amino acids, except glycine, showed suppression of the cytostatic agent inhibitory effect. Thus, cortexin and amino acids have a protective effect on cell proliferation in the tissue culture of the central nervous system under the action of mustardlike substances.

Effect of carboxylic acids - structurally related to amino acids, on the proliferation activity of the cells in organotypic cultures of rat spleen was first studied. It was found that almost all aliphatic carboxylic acids have stimulating effects on proliferative activity of cells in young and old rats. In contrast only 3 from 14 active amino acids in young rats were able stimulate proliferation, but 11 amino acids inhibited it. In the old rats a number of the active amino acids was decreased until 4, an inhibiting effect was observed in 3 of them. Thus, the carboxylic acids are able to stimulate the regeneration processes in the immune tissue both in the young and old organisms. This fact can be a base for the research of new medical substances for the stimulation of the immunogenesis by the aging.