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Vol 56, No 3 (2025)
Articles
Brain insulin: delivery routes, mechanisms of action, and application of intranasal insulin for the treatment of diabetes mellitus and metabolic syndrome
Abstract
Insulin is traditionally considered a hormone of pancreatic origin that regulates glucose homeostasis and a wide range of metabolic and hormonal processes at the periphery. However, in recent decades, convincing evidence has been obtained that insulin also controls many processes in the brain, performing the functions of a neurotrophic factor, neuromodulator and neuroprotector, and some areas of the brain are capable of synthesizing insulin de novo. Insulin implements its effects in the central nervous system through the insulin signaling system, which in its structural and functional organization and regulatory mechanisms has significant similarities with that in the periphery. Since the total pool of insulin in the CNS consists of insulin produced by β-cells and entering the brain through the blood-brain barrier (BBB) and the hormone synthesized by brain structures, a decrease in its production or weakening of its transport through the BBB lead to insulin deficiency in the brain and disruption of its signaling. Other causes of weakened insulin signaling in the brain include central insulin resistance, neuroinflammation caused by increased activity of proinflammatory factors, the development of reactive astrogliosis and activation of microglia, as well as increased activity of enzymes that cause insulin degradation. One of the promising approaches for effective restoration of insulin signaling in the CNS is the use of intranasally administered insulin (IAI), which enters the brain directly through axonal pathways. Currently, IAI is used in the clinic to treat patients with Alzheimer's disease and cognitive deficit associated with type 2 diabetes mellitus (T2DM). However, the therapeutic potential of IAI is not limited to this. We have shown that IAI is effective in correcting metabolic and hormonal disorders associated with T1DM, T2DM, metabolic syndrome and obesity, and a number of its restorative effects are enhanced by the combined use of IAI with metformin, proinsulin C-peptide, and gangliosides, administered both systemically and intranasally. This indicates that the targets of IAI in diabetic pathology and obesity are not only brain structures, but also peripheral organs and tissues, including components of the gonadal and thyroid systems. This review is devoted to the problem of insulin signaling in the brain, its disorders in various pathologies, as well as the use of IAI to restore the activity of the brain's insulin system, including for the purpose of normalizing neurocognitive, metabolic and hormonal indicators in diabetic pathology.
Uspehi fiziologičeskih nauk. 2025;56(3):3-23
3-23
Perivascular Adipose Tissue: Role in Regulation of Vascular Tone at Normal Phisiological States and Obesity
Abstract
Perivascular adipose tissue (PVAT) surrounds most mammalian blood vessels, it may be considered as the 4th layer of the vessel wall due to existence of the close contact with the adventitia. The unique location of the PVAT determines the great significance of the paracrine influences of the factors secreted by it, many of which are vasoactive modulators (adipokines, angiotensins, gasotransmitters, cytokines). Under physiological conditions, the secretion of these substances causes a pronounced anticontractile effect on vascular smooth muscles, and the existence of mutual influences between PVAT and the vascular wall allows for fine regulation of vascular tone for adequate blood supply to organs and tissues in accordance with their metabolic needs. Dysfunctional changes occurring in adipose tissue during obesity lead to changes in the expression and secretion of substances, and the protective effect of PVAT on vascular tone is transformed to a procontractile effect, enhancing vascular reactivity to the action of vasoconstrictor agents and leading to an increase in arterial pressure. The objective of the review is to present the current state of research regarding the specific functioning of the PVAT, its influence on vascular tone through secreted substances both in normal conditions and under dysfunction caused by obesity. Special emphasis is placed on paracrine effects, studying which serves as a prerequisite for future development of therapies aimed at treating vascular disorders targeting the PVAT.
Uspehi fiziologičeskih nauk. 2025;56(3):24-42
24-42
Visual Target and Neural Networks
Abstract
The objective of this review is to present the results of our own studies of neural networks that detect and make decisions when recognizing “everyday” visual targets: faces, letters, text, and order in chaos. Digital methods of image synthesis and processing have made it possible to synthesize calibrated and test image sets that simulate visual scenes. These scenes contain targets and noise with specified statistical, spatial, and temporal characteristics that selectively activate and inhibit modules of large-scale neural networks of the human brain. It is shown how networks representing foveolar and macular vision interact. As a result of the work of opponent neural networks of the prefrontal cortex, decisions are made when recognizing targets. Each of the large-scale neural networks of the brain is involved in various combinations that ensure purposeful human activity. The work of mechanisms of local and global scene analysis when searching for targets is considered: recognition of text, facial expressions, and face rotation, matrices of Gabor elements with varying degrees of ordering. Models of these mechanisms are built on the basis of convolutional, diffusion and generative neural networks. The influence of statistical properties of images and their internal content on decision-making by humans and machines is shown. The ways of development of psychophysiological studies of the organization and activity of large-scale neural networks of the human “visual” system shown.
Uspehi fiziologičeskih nauk. 2025;56(3):43-59
43-59
Auditory Object Formation and Its Neural Correlates in Cortical Evoked Responses
Abstract
Hearing out of a specific sound in a complex acoustic environment, also known as auditory figure-ground segregation, presents a challenge that each listener must overcome on a daily basis. The constituents of acoustic scenes often overlap both in time and in frequency content. The human auditory system constantly analyzes them using concurrent and sequential grouping mechanisms, and either forms stable auditory objects, or shows perceptual switching between integrated and segregated organization of auditory stream. This review focuses on auditory evoked potentials (ERPs) as a tool for studying the perceptual separation of auditory objects in various experimental settings, and emphasizes the role of spatial sound features which can support auditory segregation, though spatial effects are generally weaker than spectral and temporal sound properties. The pre-attentive stage of simultaneous grouping and figure-ground segregation is reflected in object-related negativity (ORN). The next positive P400 wave likely represents cognitive processing related to decision making about the number of auditory objects. The analysis of ERPs allows for the study of different stages of auditory stream segregation, where ongoing stimulation does not vary and its perception switches regularly between two perceptual states. ERP components P1, N1, N2, P3a, MMN and the sustained response can serve as indicators of perceptual switching during segregation of auditory streams. To date, neural correlates of localization features during figure-ground segregation have remained underexplored. From a fundamental perspective, it is essential that auditory segregation occurs at the pre-attentive stage of perception. However, it can also be observed in late ERP components related to attention switching. Overall, ERPs can be a potential clinical tool for evaluating auditory object formation in real-life situations.
Uspehi fiziologičeskih nauk. 2025;56(3):60-79
60-79
Causes of brain aging and age-related changes in cognitive functions and the diversity of object models for studying these causes
Abstract
Due to the development of medicine and the improvement of the standard of living in the world, the proportion of the elderly population is increasing, so the study of the mechanisms of age-related changes in cognitive functions seems to be an urgent task. The purpose of this review is to provide data on the mechanisms of age-related changes in cognitive functions and to draw a conclusion on possible further directions of research in this area. The review presents modern theories of cognitive aging (reserve theory, compensatory theory, frontal lobe aging theory, inhibition deficit theory, sensory deprivation theory). Particular attention is paid to the molecular and genetic aspects of cognitive aging of the brain: the role of DNA integrity disorders and individual characteristics of DNA tandem repeats in connection with the dynamics of cognitive functions and aging of the nervous system are discussed, and the role of gene expression (BDNF, Rag1, APOE, etc.), which are associated with changes in cognitive functions, is considered. The novelty of this work is determined by the reliance on modern scientific literature, which allows us to identify promising areas for further study of the topic. These areas include the study of individual genes and molecular markers in terms of changes in their expression with age (such as mitogens EGF and FGF, neurotrophic factors BDNF, NGF, GDNF, synapsins, Rag1, APOE, etc.) and the study of the role of tandem repeats of the genome, including those located on satellite DNA (not many studies have been devoted to this topic). Understanding the mechanisms of cognitive aging at different levels of the body can contribute to the development of effective methods for the prevention and treatment of cognitive impairment.
Uspehi fiziologičeskih nauk. 2025;56(3):80-96
80-96
Regulation by Endothelial Cells of the Corneal Matrix Osmotic Balance
Abstract
The review summarizes modern data concerned the molecular mechanisms of corneal endothelial cells that regulate stromal hydration necessary to preserve its optical properties. The data concerned function of the corneal endothelium is reviewed in terms of the “pump-leak” model. The studies of the mechanisms regulating endothelial cell water-electrolyte balance, which is related with cell volume regulation are presented. The role of Na/K-ATPase as an electrogenic transporter and participant in the mechanoreceptor system, including proteins of tight junctions, adhesion complexes and extracellular matrix, that take a part in control of intraocular pressure, is reviewed. Data of endothelial cells plasma membrane molecular transporters and their regulation by the osmo-sensitive factor NFAT5 in are presented. There are section where presented results of the studies concerned regulation of endothelial regeneration and modern methods of cell and tissue engineering developed as approaches to the treatment of corneal edema caused by endothelial dysfunction.
Uspehi fiziologičeskih nauk. 2025;56(3):97-108
97-108