Vol 109, No 11 (2023)

Circadian rhythms are cyclic fluctuations in the intensity of biological processes associated with the change of day and night, to which many organisms have adapted during the evolution. Disturbances in circadian rhythms are triggered by both environmental factors (e.g., altering the time zone or the length of day/night) and disrupted internal regulation of cycles (e.g., mutations of key clock genes). These changes can lead to the pathogenesis of various diseases, including psychopathologies. Since the mechanisms underlying circadian regulation are rather evolutionarily conservative, experimental animal models are actively used to probe these processes and their relationship with psychopathologies. Here, we discuss the regulation of circadian rhythms, as well as their cross-taxon similarities and differences between mammals and teleost fish (zebrafish, Danio rerio). We also discuss recent findings on molecular genetic mechanisms underlying the regulation of circadian rhythms and their link to pathogenesis of mental disorders in humans and model organisms.

Lysosomal storage diseases are characterized by enzyme deficiency in the lysosomal appar-atus of the cell, triggering a pathological accumulation of undigested cellular material (proteins, lipids or carbohydrates) and tissue damage. Clinically and etiologically dive-rse, this group includes over 70 presently recognized hereditary conditions with no known effective therapy. Thus, the search for therapeutic strategies directed at these disorders represents an urgent unmet biomedical task, also necessitating the use of appropriate and valid experimental (animal) models. Here, we discuss the existing models of lysosomal storage diseases and the applicability of rodent and zebrafish as model organisms for probing these diseases.

Synaptopathies include a heterogeneous group of severely debilitating neurological diseases characterized by structural and functional deficits of neuronal synapses. Common synaptopathies include epilepsy, schizophrenia, prion diseases, autism spectrum disorders, various autoimmune diseases and cochlear synaptopathies. Their pathogenesis is caused by both genetic and environmental factors. However, the relationship between the cause and clinical manifestations of each particular synaptopathy, and their therapy, remain poorly understood. Here, we discuss animal models of synaptopathies, with a specific emphasis on zebrafish (Danio rerio), as well as outline several lines of future research in this field. Overall, zebrafish emerge as a promising organism to mimic a wide range of synaptopahies, paralleling and complementing their existing models in rodents.

It is known that insufficient sleep or diurnal rhythm disturbances of sleep and wakefulness exert a detrimental effect on cognitive functions. It was thought for a long period that memory consolidation is the most vulnerable link, i.e., information transfer from short-term/working memory to long-term memory. However, there is a progressive number of studies indicating that the most negative consequences of sleep loss are observed in working memory. In our study, we undertook an effort to assess possible disturbances in working memory and long-term memory following sleep loss impact with different protocols in acute and chronic experiment in rats. Sleep in Wistar rats was deprived/restricted by swinging platform technique according to the following protocols: 1 – total sleep deprivation for 18 h; 2 – partial sleep restriction for 24 h (3 h of sleep deprivation alternated with 1 h of sleep opportunity – totally 18 h of sleep deprivation); 3 – chronic partial sleep restriction (conditions 2 for five consistent days). Total sleep deprivation in Y-maze test was shown to result in a significant decrease in spontaneous alternations of maze arms that indicates working memory impairment. This impact in Barnes test did not exert an effect on long-term memory – time spent for seeking a shelter did not change in this task. Acute and chronic sleep restriction induced no changes in working memory and long-term memory. The results obtained allow us to come to conclusion that working memory (in contrast to long-term memory) is a vulnerable component of cognitive function under total sleep deprivation conditions. This negative effect was abolished if periods of sleep deprivation alternated with short periods of sleep opportunities that indicate protective significance of short sleep periods for cognitive functions during sleep deficit. Hence, short-term sleep is helpful for cognitive health and protects working memory, whereas continuous long-term wakefulness impairs it.

Pharmacoencephalography (pharmaco-EEG) is a prominent instrument for the pharmacological screening new psychoactive molecules. This experimental approach has not remained a vestige of neurobiological studies, and can be used successfully to complete today’s research objectives. The development and rise to universal use of machine learning techniques opens up novel prospects for the use of pharmaco-EEG data to solve the problems of classification and prognosis. We have previously shown that naïve Bayes classifier (NBC) combined with the principal component analysis (PCA) can be used to differentiate between antipsychotic and sedative drug effects as well as to distinguish among the antipsychotics’ effects. In the present study, we evaluated the possibility to employ this method to assess the dose-dependency of antipsychotic effects. The experiments were carried out in white outbred male rats with chronically implanted electrocorticographic electrodes. As the agents of interest, we chose two drugs with antipsychotic activity, chlorpromazine and promethazine, in three doses each (0.1, 1, 10 mg/kg and 0.5, 5 and 20 mg/kg, respectively). The training set, used as a reference to determine the pharmacological effects of the agents of interest, included the D₂-dopamine receptor blocker haloperidol, M-cholinergic receptor blocker tropicamide, H₁-histamine receptor blocker chloropyramine, the sedative dexmedetomidine, and the anxiolytic phenazepam. We have shown that the lowest chlorpromazine dose (0.1 mg/kg) can be characterized as antipsychotic with a marked histaminolytic effect, while the highest one (10 mg/kg) exhibits predominantly antipsychotic activity with a cataleptogenic effect. All the doses demonstrated anticholinergic activity, which increased with the dose. For promethazine, we observed a clear dose-dependent transition from antipsychotic action to cataleptogenic, alongside a notable antimuscarinic effect of all doses. None of promethazine doses showed any resemblance to chloropyramine, which probably indicates its anti-dopaminergic and antimuscarinic effects being able to mask its H₁-antihistamine effect in the used dose range. In summary, our results demonstrate that NBC coupled with PCA can be used to determine the dose-dependency of antipsychotic agents’ effects based on their impact on electrocorticogram parameters. Further development of this method as well as expansion of psychotropic agent electropharmacogram library would allow for more precise prognosis of pharmacological activity of the agents of interest.

Traumatic brain injury (TBI) is a serious biomedical problem with high prevalence and mortality risks. Understanding TBI in traditional (e.g., rodent) animal models often presents challenges due to the complexity of their brain and its limited regenerative capabilities. Here, we present novel data obtained using the zebrafish TBI model based on a stab wound of telencephalon, aiming to investigate behavioral and molecular consequences of TBI in zebrafish. Four days following the injury, adult zebrafish displayed hypolocomotion in the novel seen tank test and impaired working memory in the Y-maze test, paralleling behavioral deficits in rodent models and human TBI patients. Molecular analyses of key genes involved in the inflammatory response and cell death pathways revealed a remarkable upregulation of the interferon-stimulated gene 15 (isg15) in the injured telencephalon, a general biomarker for neuronal damage. Furthermore, noradrenaline (but not dopamine or serotonin) levels in whole-brain tissue declined following TBI, likely contributing to the observed cognitive deficits and implicating neurotransmitter dysregulation in TBI pathogenesis.