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Volume 111, Nº 10 (2025)
EXPERIMENTAL ARTICLES
Maturation of neonatal reflexes and behavioral features in 5xFAD mice, a model of Alzheimer’s disease
Resumo
Alzheimer’s disease (AD) is a progressive age-related neurodegenerative pathology leading to dementia. Genetic models of AD in mice have been established aimed to elucidate the mechanisms of this pathology and to find possible ways of its correction. Transgenic mice of the 5xFAD strain with two human transgenes App and Psen1 and five mutations represent the popular model for investigating AD. The aim of this work was to evaluate the maturation of neonatal reflexes and the body mass increase during early postnatal ontogenesis in 5xFAD mice, as well as behavioral features of these mice at the age of three months. Wild type (WT) mice of the same sex and age from the same litters were used as controls. The results obtained indicate that 5xFAD mice do not differ from their WT sibs in body mass increase and the rate of neonatal reflexes maturation during weaning period. At the age of three months, 5xFAD males showed sex differences in behavior: males exhibited lower overall locomotor activity than females and showed signs of beginning to develop depressive-like behavior. Lower anxiety level in males as well as higher exploratory activity in females were revealed in the three-mo.-old 5xFAD mice compared to WT siblings of the same sex. As a result of this study, behavioral features of young 5xFAD mice were characterized at the age of three months. The maturation of neonatal reflexes during the weaning period was studied for the first time in this transgenic model of AD.
Russian Journal of Physiology. 2025;111(10):1581-1600
1581-1600
The abundance of H3K27me3 histone modification in the mouse colon under chronic inflammation
Resumo
The prevalence of inflammatory bowel diseases (IBD) has increased globally over recent decades. Following industrialization, the incidence of IBD has been rising not only in European and North American countries but also in Asian nations, including China and India. Despite its widespread occurrence and extensive research efforts, the etiopathogenesis of IBD remains incompletely understood. Epigenetic mechanisms, such as DNA methylation and post-translational modifications of histones, play a crucial role in its pathogenesis. Histone modifications influence chromatin structure and can serve as markers for transcriptionally active or inactive regions. Given the global alterations in gene expression profiles observed in the intestines of IBD patients, it is plausible to hypothesize comprehensive structural changes in chromatin activity and accessibility during intestinal inflammatory processes, affecting both mucosal immune cells and epithelial cells. Particularly, studies utilizing colonic tissue samples from patients with enterocolitis have demonstrated a reduction in the overall levels of trimethylation of histone H3 at lysine 27 (H3K27me3) within epithelial cells. Concurrently, targeting the H3K27me3 modification presents a promising therapeutic approach for IBD through the regulation of transcription in immune cells. This research investigated the presence of this histone modification in epithelial cell nuclei and in colonic tissue as a whole within two mouse models of chronic colitis. Our findings indicate that the overall level of H3K27me3 increases in the nuclei of enterocytes in a chronic colitis model with Muc2 gene knockout. This result suggests that the H3K27me3 modification significantly influences the pathogenesis of IBD, not only in immune cells but also in colonic epithelial cells.
Russian Journal of Physiology. 2025;111(10):1601-1614
1601-1614
Short-Term Synaptic Plasticity of Hippocampal Neural Networks Under Experimentally Induced Blood–Brain Barrier Dysfunction
Resumo
Impaired synaptic plasticity is a hallmark of a number of neurological disorders successfully reproduced in animal models. Short-term forms of plasticity provide dynamic regulation of synaptic efficacy in response to various patterns of neuronal activity and largely depend on maintaining optimal conditions of the neuronal microenvironment, the key regulator of which is the blood-brain barrier (BBB). In recent years, the BBB has been considered an active participant in central nervous system homeostasis, and its dysfunction is recognized as a trigger for many neurological pathologies. We have developed an in vitro protocol that mimics the early consequences of BBB dysfunction by adapting the ionic composition of the incubation solution to blood plasma with the addition of thrombin. In the present study, we analyzed short-term synaptic plasticity in the hippocampal CA3-to-CA1 networks during the early phase following modeled BBB breakdown. Data obtained reveals significant alterations in short-term synaptic plasticity in the hippocampus under conditions of BBB dysfunction. We observed enhanced paired-pulse facilitation (PPF) at interstimulus intervals of 25 and 50 ms, suggesting a presynaptic locus for the changes in neurotransmitter release. Furthermore, a significant increase in the amplitude of post-tetanic potentiation (PTP) was recorded, indicating an increased reactivity of the CA3-to-CA1 neural networks. The selective enhancement of the early, activity-dependent phase of plasticity following high-frequency stimulation, in the absence of changes in the overall temporal dynamics, suggests a specific modulation of pattern-dependent short-term plasticity in BBB pathology. Induction of seizure-like activity of hippocampal neural networks has previously been demonstrated under identical conditions. Therefore, the present study characterizes specific alterations in synaptic properties due pathological condition formation that may ultimately lead to long-term consequences.
Russian Journal of Physiology. 2025;111(10):1615-1626
1615-1626
Disorder of myelinization in the spinal cord of transgenic mSOD1 mice as one of the mechanisms pathogenesis of amyotrophic lateral sclerosis
Resumo
Amyotrophic lateral sclerosis (ALS) is a disease characterized by progressive muscle weakness, atrophy, spasticity, paralysis caused by degeneration and death of motor neurons in the brain and spinal cord, leading to death. Model animals such as SOD1-G93A mice expressing a human mutation of the gene encoding the antioxidant enzyme superoxide dismutase 1 are widely used to study the pathogenesis of ALS and its treatment. Transgenic mice exhibit disease phenotypes similar to ALS patients, expressed in motor function impairment, motor neuron degeneration in the spinal cord, brainstem, and cortex, leading to paralysis of the hind limbs and death. In the present work, the areas of transverse serial sections of the lumbar enlargement of the spinal cord, as well as the areas occupied by white and gray matter in these sections were estimated using light microscopy in wild-type WT mice and transgenic mSOD1 mice at different stages of ALS development. The revealed reduction in the volume of the lumbar enlargement of the spinal cord in transgenic mice is detected already at the early presymptomatic stage of the disease and is due to a decrease in the volumes of both gray and white matter. A decrease in the number of neurons in the gray matter of the spinal cord, a characteristic sign of ALS caused by the death of these cells, was detected in transgenic mice only at the symptomatic stage of the disease. Using fluorescence microscopy, a decrease in the fluorescence intensity of fluoromyelin, a specific myelin dye, in the white matter of the lumbar enlargement of the spinal cord in transgenic mice was established starting from the early presymptomatic stage. The revealed morphological changes in the lumbar spinal cord of transgenic mSOD1 mice allow us to conclude that already at the early pre-symptomatic stage of ALS, demyelination processes develop, most likely arising as a result of disruption of the functioning of myelin-forming cells.
Russian Journal of Physiology. 2025;111(10):1627-1641
1627-1641
Taar1 modulates neuronal and glial density in the neocortex following spinal cord injury
Resumo
Spinal cord injury (SCI) initiates a complex cascade of secondary pathological processes, including chronic neuroinflammation and neuroplastic remodeling both at the lesion site and in distant regions, such as the cerebral cortex. This study explores the role of trace amine-associated receptor 1 (TAAR1) in modulating neuroinflammatory responses in the somatosensory cortex following lateral spinal cord hemisection in wild-type mice and TAAR1-knockout (TAAR1-KO). Behavioral tests revealed no significant differences in sensorimotor recovery, suggesting a limited impact of TAAR1 on functional recovery. However, immunohistochemical analysis uncovered substantial alterations in glial reactivity. Specifically, TAAR1-KO mice exhibited a marked increase in GFAP⁺ astrocyte density within the granular and pyramidal cortical layers, indicating enhanced astrogliosis. At the same time, the number of pro-inflammatory S100β⁺ astrocytes remained unchanged, which emphasizes the selective effect of TAAR1 on distinct astrocyte subpopulations. Additionally, TAAR1-KO mice showed a reduction in the density of Iba-1⁺ microglial cells. Furthermore, a decline in pyramidal neuron counts was noted, potentially indicative of impaired survival. Crucially, these differences emerged only post-injury, as genotypes were indistinguishable under baseline conditions. The obtained data demonstrate the key role of TAAR1 in modulating the glial response and expand our understanding of the molecular mechanisms of neuroinflammation in SCI, opening new avenues for the development of TAAR1-targeted neuroprotective strategies.
Russian Journal of Physiology. 2025;111(10):1642-1658
1642-1658
Aquaporin-4 Knockdown in the Substantia Nigra Exacerbates α-Synuclein Pathology, Neurodegeneration, and Motor Dysfunction in a Rat Model of Parkinson's Disease
Resumo
The water channel aquaporin-4 (AQP4) is a key participant in the molecular and cellular mechanisms that provide the removal of various metabolites and amyloid proteins from brain tissue. It is assumed that AQP4 dysfunction can provoke the development of Parkinson's disease (PD) and lead to its aggravation. The aim of this study was to investigate whether decreased AQP4 expression in the substantia nigra pars compacta (SNpc) affects the development of α-synuclein pathology, neurodegeneration, and motor impairment in a rat model of clinical stage PD. Experiments were performed on male Wistar rats (6-7 months). To suppress AQP4 expression in the SNpc, a lentiviral construct containing a nucleotide sequence encoding hairpin RNA (shRNA) to AQP4 mRNA (AQP4-LVC) was injected. To reproduce the clinical stage of PD, the proteasome inhibitor lactacystin (LC) was bilaterally injected into the SNpc 4 weeks after AQP4-LVC administration. To solve the scientific task, behavioral tests, the immunohistochemical method, and immunoblotting were applied. The AQP4-LVC caused a 42% decrease in the AQP4 protein content in the SNpc 4 weeks later. The LC model of PD was characterized by the appearance of motor disorders, the death of 57% of dopamine (DA)-ergic neurons in the SNpc and 56% of their axons in the striatum, weakening of compensatory processes aimed at maintaining DA level in the nigrostriatal system, and an increase in the content of the total water-soluble form of α-synuclein and its aggregated and phosphorylated (Ser129) forms. Decreased expression of AQP4 in the LC model of PD caused aggravation of motor impairment and the appearance of signs of dystrophy, indicating the development of the terminal phase of the clinical stage of PD. The rapid increase in parkinsonism symptoms was associated with increased neurodegeneration and depletion of compensatory processes in the nigrostriatal system, associated with the acceleration of the formation of pathological aggregated forms of α-synuclein. The obtained data indicate that AQP4 deficiency in the SNpc accelerates the development of Parkinson-like pathology.
Russian Journal of Physiology. 2025;111(10):1659-1675
1659-1675
METHODOLOGICAL ARTICLES
A Combination of in vitro and in vivo Approaches to Studying the Mechanisms of Myocardial Hypertrophy Development in Adult Rats with Renovascular Hypertension
Resumo
Hypertrophic changes in the ventricular myocardium accompany most cardiovascular diseases and represent a serious risk factor for sudden cardiac death. To date, a wide range of in vitro and in vivo models of hypertrophy have been developed; however, none of them allow for the simultaneous investigation of both biochemical and physiological aspects of its pathogenesis. This study proposes a method based on the induction of left ventricular hypertrophy (LVH) resulting from renovascular hypertension in rats, followed by the isolation of cardiomyocytes from their hearts. The study included 68 animals (32 1K1C type rats, 16 1K type rats, and 20 sham-operated (SO) rats). To induce LVH in the “one kidney one clip” (1K1C) rats, a clip was placed on the renal artery of the left kidney to restrict blood flow, after which the right kidney was removed. In the “one kidney” (1K) group, the right kidney was removed while the left kidney was remained intact, whereas in SO rats, the abdominal cavity was opened and then sutured without any manipulation of the kidneys. The latter two groups served as controls. After 1.5 months, the left ventricular mass in 1K1C rats exceeded that in both control groups by 1.2 times, while the arterial pressure in the 1K1C group increased by 1.4 times compared to both controls. Additionally, 1K1C rats exhibited a 1.4-fold increase in serum and urinary urea concentrations and a 1.5-fold enhancement in renal excretion, as assessed by creatinine clearance, compared to the control groups. The serum concentration of B-type natriuretic peptide (BNP) in 1K1C rats was twice as high as in the control groups. After LVH induction, primary cardiomyocyte cultures were derived from the hearts of control and hypertrophic rats. In the conditioned medium of the primary culture of ventricular cardiomyocytes from 1K1C rats, the BNP concentration was 3.4 times higher than in the control groups. Thus, it was demonstrated that cardiomyocytes isolated from 1K1C rats retain a hypertrophic phenotype, and this combined approach can be used to study cardiac hypertrophy in vivo and in vitro.
Russian Journal of Physiology. 2025;111(10):1676-1696
1676-1696