Effect of Chronic Unpredictable Mild Stress on TAAR2 Knockout Mice E. V. Efimova, T. S. Shemiakova, D. D. Maslennikova, A. N. Vaganova, A. A. Markina, et al. Cell and Tissue Biology, 2025 Abstract Objective: Trace amine-associated receptor 2 (TAAR2) is a member of the TAAR family, which was long considered to function primarily as an olfactory receptor. However, recent studies have demonstrated that TAAR2 is also expressed in the brain and may play a role in regulating monoamine systems and behavior. Previous research has shown that TAAR2 knockout (TAAR2-KO) mice exhibit decreased immobilization in the forced swim test, which may indicate reduced depression-like behavior, increased level of dopamine in striatum and increased adult neurogenesis. In the present study, we first investigated expression levels of mRNA of proteins, known to increase in chronic stress in TAAR2-KO mice. Also we studied the effects of chronic unpredictable mild stress (CUMS), a widely used model of depression, on TAAR2-KO mice. Methods: Expression levels of mRNA were assessed using qPCR. Also, to study effects of CUMS TAAR2-KO and wild-type (WT) mice were exposed to mild stressors for four weeks. After four weeks of stress exposure, we assessed basal body temperature and behavior in comparison with intact (unstressed) knockout and wild-type mice. Results and Discussion: Following four weeks of CUMS, neither TAAR2-KO nor WT mice showed significant changes in locomotor activity in the open field test. Stressed animals, both WT and TAAR2-KO exhibited increased grooming frequency. Although increased grooming can be indicative of heightened anxiety, performance in the elevated plus maze showed no differences in time spent in the open arms between groups. In a forced swimming test TAAR2-KO mice shown to be more susceptible to stress, with increased immobilization time. Chronic mild stress is known to affect not only behavior but also body temperature, as prolonged stress exposure can lead to hyperthermia. In our study, stressed animals exhibited increased body temperature. However, while the increase was statistically significant in WT mice, it was much less pronounced in TAAR2-KO mice. Conclusions: Taken together, our findings suggest that, despite previous reports of reduced depression-like behavior in TAAR2-KO mice, the absence of TAAR2 has only a minor effect on the physiological and behavioral responses to chronic unpredictable mild stress.
Adaptation of the Transformer Maze to Assess the Cognitive Abilities of Mice A. A. Markina, N. A. Trubnikova, A. B. Volnova, R. R. Gainetdinov, E. V. Filatova Cell and Tissue Biology, 2025 Abstract Objective: The Transformer maze was developed to evaluate the effectiveness of spatial navigation, learning, and memory. The modular design of the maze allows to create different routes inside the maze, varying the color of the walls and the presence of passages in them. Previously, this modification of the maze was used only for training rats. In this article, we demonstrate the possibilities of a Transformer maze for studying mouse behavior. Methods: The study was conducted on 15 male mice, divided into two groups: trained and untrained one. Previously, all animals were subjected to mild food deprivation, handling and getting used to the maze space. For trained group the experiment consisted of 4 days of maze training and 1 day of testing. Unlike trained mice, which underwent both training and testing phases, untrained mice underwent only the testing phase. Results and Discussion: In the experiment, we highlighted a number of parameters that allow us to assess the efficacy of learning of mice: the length of the path traveled, the number of visits to cul-de-sac sectors, the latency of entry into the finish sector and others. Our experiments have shown that trained mice perform the task better than untrained animals. Conclusions: The experiments demonstrated the potential of using a transforming maze to study spatial memory and learning characteristics in mice. This method is of translational significance, as it could potentially be used to identify cognitive impairments in transgenic mice or when studying pharmacological models of neuropsychiatric disorders.
TAAR8 in the Brain: Implications for Dopaminergic Function, Neurogenesis, and Behavior Taisiia S. Shemiakova, Alisa A. Markina, Evgeniya V. Efimova, Ramilya Z. Murtazina, Anna B. Volnova, Aleksandr A. Veshchitskii, Elena I. Leonova, Raul R. Gainetdinov Biomedicines, 2025 Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation.
Dopamine Receptors and TAAR1 Functional Interaction Patterns in the Duodenum Are Impaired in Gastrointestinal Disorders Anastasia N. Vaganova, Alisa A. Markina, Aleksandr M. Belousov, Karina V. Lenskaia, Raul R. Gainetdinov Biomedicines, 2024 Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients’ samples and a loss of these genes’ functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation.
Neurophotonic methods in approach to in vivo animal epileptic models: Advantages and limitations Vassiliy Tsytsarev, Julia V. Sopova, Elena I. Leonova, Mikhail Inyushin, Alisa A. Markina, Angelina V. Chirinskaite, Anna B. Volnova Epilepsia, 2024 Neurophotonic technology is a rapidly growing group of techniques that are based on the interactions of light with natural or genetically modified cells of the neural system. New optical technologies make it possible to considerably extend the tools of neurophysiological research, from the visualization of functional activity changes to control of brain tissue excitability. This opens new perspectives for studying the mechanisms underlying the development of human neurological diseases. Epilepsy is one of the most common brain disorders; it is characterized by recurrent seizures and affects >1% of the world's population. However, how seizures occur, spread, and terminate in a healthy brain is still unclear. Therefore, it is extremely important to develop appropriate models to accurately explore the causal relationship of epileptic activity. The use of neurophotonic technologies in epilepsy research falls into two broad categories: the visualization of neural epileptic activity, and the direct optical influence on neurons to induce or suppress epileptic activity. An optogenetic variant of the classical kindling model of epileptic seizures, in which activatable cells are genetically defined, is called optokindling. Research is also underway concerning the application of neurophotonic techniques for suppressing epileptic activity, aiming to bring these methods into clinical practice. This review aims to systematize and describe new approaches that use combinations of different neurophotonic methods to work with in vivo models of epilepsy. These approaches overcome many of the shortcomings associated with classical animal models of epilepsy and thus increase the effectiveness of developing new diagnostic methods and antiepileptic therapy.
Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies Alisa A. Markina, Rogneda B. Kazanskaya, Julia A. Timoshina, Vladislav A. Zavialov, Denis A. Abaimov, Anna B. Volnova, Tatiana N. Fedorova, Raul R. Gainetdinov, Alexander V. Lopachev Biomedicines, 2023 In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na+,K+-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na+,K+-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na+,K+-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na+,K+-ATPase in dopaminergic system pathologies—both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson’s disease, we extend our discussion to the role of Na+,K+-ATPase and cardiotonic steroids in neurodegenerative diseases as well.
