[Gender characteristics of depressive disorders: clinical, psychological, neurobiological and translational aspects]. / Gendernye osobennosti depressivnykh rasstroistv: kliniko-psikhologicheskie, neirobiologicheskie i translyatsionnye aspekty.

Various studies have indicated that the prevalence of depression is almost twice as high among women as among men. A major factor associated with the development of depression and other affective disorders are adverse and psychologically traumatic life events that contribute to changes in the neuroendocrine system, altering the capacity to adapt to stress. These changes are involved in the pathogenesis of mental disorders, along with genetic and other factors, and are to a significant degree regulated by gender dependent mechanisms. While women have a high prevalence of depressive disorders, men show a higher rate of alcohol and substance abuse. These differences in the epidemiology are most likely explained by different predisposition to mental disorders in men and women and a diversity of biological consequences to adverse life events. Taking this into account, there is a need for a critical review of currently used approaches to modeling depressive disorders in preclinical studies, including the use of animals of both sexes. Adaptation of experimental models and protocols taking into account gender characteristics of neuroendocrine changes in response to stress, as well as structural-morphological, electrophysiological, molecular, genetic and epigenetic features, will significantly increase the translational validity of experimental work.

[Olfactory disorders as a multidisciplinary problem]. / Rasstroistva obonyaniya ­ mezhdistsiplinarnaya problema.

Olfactory dysfunction is a serious symptom that requires careful differential diagnosis. The article presents convincing evidence that dysosmia is not only a symptom of rinological pathology, but also a manifestation of various neurodegenerative diseases. Some patients with SARS-CoV-2 have neurological symptoms. Modern studies show that olfactory and gustatory dysfunctions are significant symptoms in the clinical presentation of the COVID-19 infection. The importance of olfactory diagnostics in relatives of patients with hereditary neurodegenerative diseases for the purpose of early detection of pathology is noted. We consider the possibility of introducing new methods for the diagnosis of olfactory dysfunction, which is a promising task both in the field of neurology and otorhinolaryngology, in order to prevent the development of neurodegenerative diseases at an early stage, improve the quality of life and social adaptation of patients.

Oxidative Damage of Proteins Precedes Loss of Cholinergic Phenotype in the Septal Neurons of Olfactory Bulbectomized Mice.

BACKGROUND: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer's disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer's disease. OBJECTIVE: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. METHODS: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. RESULTS: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. CONCLUSION: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer's disease.

[Pain perception and nonsuicidal self-injurious behavior]. / Vospriyatie boli pri nesuitsidal'nom samopovrezhdayushchem povedenii.

This review focuses on studies of pain threshold and tolerance in individuals with nonsuicidal self-injurious (NSSI) behavior. The data on methods of pain sensitivity studies are presented, with issues in animal modeling of NSSI discussed separately. The results of neuroimaging studies on pain sensitivity in individuals with NSSI are described, along with contribution of genetic factors, psychological variables, and disturbances in opioid and hypothalamic-pituitary-adrenal systems. A critical methodological analysis of the studies on pain sensitivity in individuals with NSSI was performed.

[New Technologies in the Diagnostics and Treatment of Brain Deseases: from Neurosciences to the Multidisciplinary Clinical Practice and Maintaining of Mental Health].

Over the past years, the prevalence of brain diseases and, consequently, their social significance and economic burden for society has been steadily increasing throughout the world. Brain diseases are a heterogeneous group of diseases that unite a number of disorders that are within the competence of both neurology and psychiatry, often concurrent or comorbid with each other. Z. P. Soloviev Research and Clinical Center for Neuropsychiatry is a leading medical organization in Moscow, which performs a full treatment cycle, studies the data and has postgraduate training programs in this field of medicine. It is conducting a number of relevant research programs; some in collaboration with international clinics. This study deals with the following programs: fundamental aspects of depression and stress-reactivity, suicidal and self-damaging behavior, usage of biofeedback and gravity therapy in rehabilitation and training programs for medical workers in successful communication.

Biochemical Mechanisms and Translational Relevance of Hippocampal Vulnerability to Distant Focal Brain Injury: The Price of Stress Response.

Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients' individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.

[Exosomes secretion and autophagy in long-term protection of neurons from excitotoxic damage]. / Sekretsiia ékzosom i autofagiia pri vyrabotke ustoichivosti neironov k ékzaitotoksicheskomu povrezhdeniiu.

In the model of induced neuronal resistance to the toxic effect of glutamate (deprivation of trophic factors), exosome secretion is demonstrated. Exosomes are secreted at the development of resistance during deprivation and at the first 24 h after preconditioning, as was shown by dot blot of extracellular fluid using anti-CD63 antibody. The autophagy inhibitor bafilomycin (0.01 µM) significantly reduces the quantity of the secreted exosomes at the stage of autophagy induction and at 24 h after induction. At the same time, inhibition of autophagy during the deprivation of trophic factors prevents the development of resistance, but inhibition of autophagy during the first 24 h after deprivation does not affect the development of resistance. We suggest that the long-term effects of preconditioning may be mediated by exosome secretion.

Expression of mRNAs for IL-1ß, IL-6, IL-10, TNFα, CX3CL1, and TGFß1 Cytokines in the Brain Tissues: Assessment of Contribution of Blood Cells with and without Perfusion.

Cytokines are important regulators of brain function under both normal and pathological conditions. Cytokines can be synthesized by resident cells of the central nervous system (CNS) (vascular endothelium, cells of the blood-brain barrier, parenchymal cells of the CNS) or cells in the lumen of blood vessels, as well as introduced with the bloodstream. The ratio between the quantity of cytokines synthesized in the CNS and those entering it from external sources under various conditions remains poorly understood. In this work, we studied the contribution of mRNAs from non-resident cells to the common pool of cytokine (TNFα, IL-1ß, IL-6, IL-10, CX3CL1, and TGFß1) mRNAs in the rat neocortex, hippocampus, dura matter, pia matter, and choroid plexus. We also evaluated the representation of various populations of resident and non-resident immune cells based on the expression of marker genes (Ncf1, Tbx21, Foxp3, RORγc). The removal of blood by transcardial perfusion led to a decrease in the quantity of the TNFα mRNA in the neocortex and hippocampus and of the IL-1ß, IL-6, and IL-10 mRNAs in the dura mater. The mRNA levels of other cytokines in studied structures were not affected by perfusion. Our findings suggest that mRNAs present in the blood can make a significant contribution to the mRNA levels of some cytokines in the CNS; therefore, preliminary perfusion of brain tissue is a necessary stage of experimental design for correct estimation of mRNA content in the brain.

The Missing Link: How Exosomes and miRNAs can Help in Bridging Psychiatry and Molecular Biology in the Context of Depression, Bipolar Disorder and Schizophrenia.

MicroRNAs (miRNAs) only recently have been recognized as promising molecules for both fundamental and clinical neuroscience. We provide a literature review of miRNA biomarker studies in three most prominent psychiatric disorders (depression, bipolar disorder and schizophrenia) with the particular focus on depression due to its social and healthcare importance. Our search resulted in 191 unique miRNAs across 35 human studies measuring miRNA levels in blood, serum or plasma. 30 miRNAs replicated in more than one study. Most miRNAs targeted neuroplasticity and neurodevelopment pathways. Various limitations do not allow us to make firm conclusions on clinical potential of studied miRNAs. Based on our results we discuss the rationale for future research investigations of exosomal mechanisms to overcome methodological caveats both in studying etiology and pathogenesis, and providing an objective back-up for clinical decisions.

Activation of microglia associated with lentiviral transduction: A semiautomated method of assessment.

Lentiviral transduction is a powerful tool and widely used in neuroscience research to manipulate gene expression of cells. However, the injection of lentiviral vectors in the brain is not totally benign, it potentially induces focal neuroinflammation. Upon inflammation, microglial cells get activated and can induce major changes in tissue environment, which may interfere with experimental results. In the current study, two weeks after the injection of control viral construction in the dentate gyrus (DG) of rats, an activation of microglia was detected. To access the activation status, we used a fast and accurate method of phenotype detection - measurement of fractal dimension (FD). Microglial morphology is a key indicator of neuroinflammation, therefore FD of microglial cells may serve as a reliable index of inflammation status in the brain. Here we present a detailed description of image processing procedure of images of individual microglial cells. The method allows to preserve the complex structure of microglial cells and their thin processes on the output image, which is important for accurate FD assessment.

[Acute period in a rat model of brain trauma: immediate seizures, damage to functional neocortical zones and behavioral disturbances]. / Ostryi period pri modelirovanii cherepno-mozgovoi travmy u krys: nemedlennye sudorogi, povrezhdenie funktsional'nykh zon novoi kory i narusheniia povedeniia.

BACKGROUND: Establishing the relationship between the damage in the neocortex and the functional manifestations of these lesions is important to understand the mechanisms of acute seizures and their consequences. An analysis of immediate seizures in patients with a traumatic brain injury (TBI) in practice is difficult, however it can be performed in animal models. AIM: To compare the damage to functional neocortical areas with the semiology of immediate seizures and behavioral disturbances in the acute period after lateral fluid percussion (TBI model) in rats. MATERIAL AND METHODS: The study was performed on 48 Wistar rats. TBI was modelled using lateral fluid-percussion injury to the right sensory-motor cortex. To study the semiology of immediate seizures, video recording was performed at the moment of the injury and 5 min after it. After that, a number of behavioral tests were employed. RESULTS AND CONCLUSION: This study presents the first detailed evaluation of damage to the functional neocortical areas in the acute period of TBI using the 'unfolded maps' approach. The focus of damage in the cortex increased from 3rd to 7th day and demonstrated a complex shape, extending far beyond the area of the direct impact. TBI induced immediate seizures with a variability which cannot be explained by the involvement of certain areas of the neocortex alone, as well as behavioral disturbances suggested to reflect developing necrosis predominantly in the sensory area of the neocortex.

[Molecular mechanisms of brain peptide-containing drugs: cortexin]. / Molekuliarnye mekhanizmy deistviia preparatov, soderzhashchikh peptidy mozga: korteksin.

The goal of treatment of brain pathologies may be regarded as re-establishment of optimal brain plasticity. Disturbances in neuroplasticity are associated with the appearance of multiple targets that should be subjects for pharmacological correction. Peptide hydrolysates derived from animal brain became a basis for multi-component organ-specific drugs which are widely used for treatment of cerebral pathologies. Potentially, the presence of many components in such drugs may be beneficial for simultaneous effects on different targets. In this article, new data are analyzed related to relevant molecular mechanisms underlying neuroprotective properties of cortexin. On a model of accelerated aging in rats, cortexin restored the ratio of pro- and antioxidative systems and demonstrated a significant anti-inflammatory effect both in the brain and at the systemic level. In in vitro experiments cortexin effectively and tissue-specifically inhibited brain caspase-8. Neuron-specific proteins ß5-tubulin, creatine kinase B and protein 14-3-3 α/ß were shown to be molecular partners of cortexin peptides in the brain. Thus, potential molecular mechanisms of cortexin neuroprotective effects are various and associated with key processes underlying neuroplasticity: signal transduction, energy metabolism, proteolytic protein modification, cell structure, as well as neuroinflammation. The pleiotropicity of mechanisms of cortexin action is based on the composition of the drug containing a variety of neuropeptides. The tissue specificity of these mechanisms determines to a significant degree the efficacy of the drug in treatment of cerebral pathologies.

[Effects of childhood trauma on the biochemical correlates of stress in men and women with nonpsychotic mental disorders]. / Vliianie travmatizatsii v detskom vozraste na biologicheskie korreliaty stressa u muzhchin i zhenshchin s pogranichnymi psikhicheskimi rasstroistvami.

AIM: To investigate gender differences in biochemical characteristics in patients with nonpsychotic mental disorders, and to study their association with childhood trauma. MATERIAL AND METHODS: Women (n=308) and men (92) between 18 and 45 years of age, without serious somatic comorbidities, were examined. Laboratory evaluation included markers of hypothalamic-pituitary-adrenal axis activity (cortisol), hypothalamic-pituitary-thyroid system (TSH), proinflammatory cytokines (Il-1ß and Il-6) and the brain derived neurotrophic factor (BDNF). All participants underwent psychometric testing, which included the Child Abuse and Trauma Scale (CATS), Beck and Hamilton depression scale (HAM-D) and Spielberger Anxiety Inventory (STAI). Correlations were studied between the biochemical parameters and total CATS scores and severity of depression and anxiety in subgroups of women and men with a depressive disorder. RESULTS AND CONCLUSION: The men and women in the total study population significantly differed by representation of the different diagnostic classes, which was reflected by differing levels of depressive and anxiety symptoms. The main finding was a correlation between the level of childhood trauma and morning serum cortisol levels in men with depressive disorder, which was absent in women.

[Early electrophysiological consequences of dosed traumatic-brain injury in rats]. / Rannie élektrofiziologicheskie posledstviia dozirovannoi cherepno-mozgovoi travmy u krys.

AIM: To analyze the pathological electrical activity during the acute period after traumatic brain injury (TBI) and to search for potential morphological correlates of this activity in the neocortex and hippocampus. MATERIAL AND METHODS: The study was performed on male Sprague Dawley rats. TBI was modeled using a lateral hydrodynamic impact in the sensorimotor cortex area. ECoG was continuously recorded one week before and one week after TBI. A histological analysis was performed one week after TBI. Brain slices were Nissl stained as well as immunohistochemically stained for astrocytes (GFAP) and microglia (Isolectin B4). The damage to the neocortex and hippocampus was evaluated. RESULTS AND CONCLUSION: The slowdown of the background activity one and six hours after TBI and appearance of epileptiform activity in a half of animals one week after TBI were shown. The number of discharges was correlated with the area of astrocyte gliosis in the neocortex and with the number of dark (ischemic-like) neurons in the hippocampus. Microglial activation did not correlate with the epileptiform activity. These data are important to understanding early mechanisms of post-trauma epileptogenesis.

[Epigenetic modifications of chromatin in epilepsy: a potential mechanism of pharmacoresistance?] / Épigeneticheskie modifikatsii khromatina pri épilepsii: potentsial'nyi mekhanizm farmakorezistentnosti?

Pharmacoresistance in epilepsy is an important problem from both clinical and fundamental perspectives. The existent hypotheses of pharmacoresistance are based on long term plastic rebuilding of the epileptic brain. One of potential mechanisms mediating such protracted changes are alterations of gene expression induced by epigenetic modifications of chromatin in brain cells of epileptic patients. Recently, changes in DNA methylation and histone post-translational modifications were reported in brain tissues of patients with pharmacoresistant epilepsy. Unfortunately, these data remain fragmentary and contradictory, therefore the results of animal models can partially fill this gap. The authors present a short review of the data concerning a potential role of epigenetic modifications in epilepsy.

[Staging of neuroplasticity alterations during epileptogenesis (temporal lobe epileply as an example)]. / Stadiinost' izmenenii neiroplastichnosti pri épileptogeneze na primere visochnoi épilepsii.

Using temporal lobe epilepsy as an example, staging of long term plasticity in the hippocampus is considered. Major stages demonstrating opposite alterations in neuroplasticity are active epileptogenesis and the period of established temporal lobe epilepsy. During the epileptogenesis, multiple events resulting in forming of epileptic neuronal nets occur: changes in glutamatergic and GABAergic neurons, increase of aberrant neurogenesis, axonal sprouting and dendrite remodeling, particularly, supported by an excessive enhancement of the BDNF system in specific hippocampal regions. As epileptogenesis progresses, this stage of an aberrant superplasticity is changing for opposite events accompanying formation of the epileptogenic focus and limiting plasticity: axonal damage, neuronal cell death, hippocampal sclerosis, suppression of neurogenesis. At this neurodegenerative stage of temporal epilepsy, the inclusion of neuroprotectants with neurotrophic properties (e.g. drugs containing cerebral peptide hydrolizates) into the treatment protocol appears promising. Potential use of such neuroprotectants during the active epileptogenesis period is discussed.

Molecular and Cellular Mechanisms of Sporadic Alzheimer's Disease: Studies on Rodent Models in vivo.

In this review, recent data are presented on molecular and cellular mechanisms of pathogenesis of the most widespread (about 95%) sporadic forms of Alzheimer's disease obtained on in vivo rodent models. Although none of the available models can fully reproduce the human disease, several key molecular mechanisms (such as dysfunction of neurotransmitter systems, especially of the acetylcholinergic system, ß-amyloid toxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction, disturbances in neurotrophic systems) are confirmed with different models. Injection models, olfactory bulbectomy, and senescence accelerated OXYS rats are reviewed in detail. These three approaches to in vivo modeling of sporadic Alzheimer's disease have demonstrated a considerable similarity in molecular and cellular mechanisms of pathology development. Studies on these models provide complementary data, and each model possesses its specific advantages. A general analysis of the data reported for the three models provides a multifaceted and the currently most complete molecular picture of sporadic Alzheimer's disease. This is highly relevant also from the practical viewpoint because it creates a basis for elaboration and preclinical studies of means for treatment of this disease.

[Peptide drug cortexin inhibits brain caspase-8]. / Peptidnyi preparat korteksin ingibiruet kaspazu-8 mozga.

Cortexin, a drug containing hydrolyzed brain peptides, has long been used in clinics, but the mechanisms of its action remain obscure. We have hypothesized that cortexin-related neuroprotection is associated with the ability of the drug to inhibit brain proteases. Cortexin effectively inhibited brain caspase-8, while its effects on caspase-1, -3, -9, cathepsin B and calpain were much less pronounced or absent. In addition, we isolated a peptide fraction from cortexin holding all the inhibitory capacity of the original drug, but with a much more simple composition. Both cortexin and its fraction prevented neuronal damage in a culture model of glutamate-induced cell death. Neuroprotective effect of Cortexin may be mediated by inhibition of the initiator caspase-8 in the brain.

Molecular Mechanisms of Neuroplasticity: An Expanding Universe.

Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.

Neonatal Proinflammatory Stress Induces Accumulation of Corticosterone and Interleukin-6 in the Hippocampus of Juvenile Rats: Potential Mechanism of Synaptic Plasticity Impairments.

Infectious diseases in early postnatal ontogenesis can induce neuroinflammation, disrupt normal central nervous system development, and contribute to pathogenesis of cerebral pathologies in adults. To study long-term consequences of such early stress, we induced neonatal proinflammatory stress (NPS) by injecting bacterial lipopolysaccharide into rat pups on postnatal days 3 and 5 and then assessed the levels of corticosterone, proinflammatory cytokines and their mRNAs, and neurotrophins and their mRNAs in the hippocampus and neocortex of the one-month-old animals. Long-term potentiation (LTP) was studied in hippocampal slices as an index of synaptic plasticity. NPS-induced impairments of LTP were accompanied by the accumulation of corticosterone and IL-6 in the hippocampus. In the neocortex, a decrease in exon IV BDNF mRNA was detected. We suggest that excessive corticosterone delivery to hippocampal receptors and proinflammatory changes persisting during brain maturation are among the principal molecular mechanisms responsible for NPS-induced neuroplasticity impairments.