This review summarizes the currently known biochemical neuroadaptive mechanisms of remote ischemic conditioning. In particular, it focuses on the significance of the pro-adaptive effects of remote ischemic conditioning which allow for the prevention of the neurological and cognitive impairments associated with hippocampal dysregulation after brain damage. The neuroimmunohumoral pathway transmitting a conditioning stimulus, as well as the molecular basis of the early and delayed phases of neuroprotection, including anti-apoptotic, anti-oxidant, and anti-inflammatory components, are also outlined. Based on the close interplay between the effects of ischemia, especially those mediated by interaction of hypoxia-inducible factors (HIFs) and steroid hormones, the involvement of the hypothalamic–pituitary–adrenocortical system in remote ischemic conditioning is also discussed. Full article

Mollusks are unique animals with a relatively simple central nervous system (CNS) containing giant neurons with identified functions. With such simple CNS, mollusks yet display sufficiently complex behavior, thus ideal for various studies of behavioral processes, including long-term memory (LTM) formation. For our research, we use the formation of the fear avoidance reflex in the terrestrial mollusk Helix lucorum as a learning model. We have shown previously that LTM formation in Helix requires epigenetic modifications of histones leading to both activation and inactivation of the specific genes. It is known that microRNAs (miRNAs) negatively regulate the expression of genes; however, the role of miRNAs in behavioral regulation has been poorly investigated. Currently, there is no miRNAs sequencing data being published on Helix lucorum, which makes it impossible to investigate the role of miRNAs in the memory formation of this mollusk. In this study, we have performed sequencing and comparative bioinformatics analysis of the miRNAs from the CNS of Helix lucorum. We have identified 95 different microRNAs, including microRNAs belonging to the MIR-9, MIR-10, MIR-22, MIR-124, MIR-137, and MIR-153 families, known to be involved in various CNS processes of vertebrates and other species, particularly, in the fear behavior and LTM. We have shown that in the CNS of Helix lucorum MIR-10 family (26 miRNAs) is the most representative one, including Hlu-Mir-10-S5-5p and Hlu-Mir-10-S9-5p as top hits. Moreover, we have shown the involvement of the MIR-10 family in LTM formation in Helix. The expression of 17 representatives of MIR-10 differentially changes during different periods of LTM consolidation in the CNS of Helix. In addition, using comparative analysis of microRNA expression upon learning in normal snails and snails with deficient learning abilities with dysfunction of the serotonergic system, we identified a number of microRNAs from several families, including MIR-10, which expression changes only in normal animals. The obtained data can be used for further fundamental and applied behavioral research. Full article

The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression. Full article

The hypothalamus is a primary regulator of homeostasis, biological rhythms and adaptation to different environment factors. It also participates in the aging regulation. The expression of neurons containing Lin28 was studied by immunohistochemistry in male rats aged 2, 6, 12, and 24 months in the tuberal region of the rat hypothalamus. We have shown for the first time the presence of Lin28-immunoreactive (IR) neurons in the ventromedial nucleus (VMH) and their absence in the dorsomedial and arcuate nuclei in all studied animals. With aging, the percentage of Lin28-IR neurons increases from 37 ± 4.7 in 2-month-old rat until 76 ± 4.6 in 6-month-old and further decreases to 41 ± 7.3 in 12-month-old rat and 28 ± 5.5 in 24-month-old rats. Many VMH Lin28-IR neurons colocalized components of insulin signaling including mTOR, Raptor, PI3K and Akt. The percentage of Lin28/Akt-IR neurons was maximal in 6-month-old and 1-year-old rats compared to 2-month-old and 2-year-old animals. The proportion of Lin28/PI3K-IR neurons significantly increased from 77 ± 1.2 in 2-month-old rat until 99 ± 0.3 in 24-month-old rats and 96–99% of Lin28-IR neurons colocalized mTOR and mTORC1 component Raptor without statistically significant differences in all studied age groups. Thus, Lin28 expresses only in the VMH neurons of the tuberal nuclei of the hypothalamus and the Lin 28 expression changes during the development together with the components of PI3K-Akt-mTOR signaling. Full article

Being involved in development of Huntington’s, Parkinson’s and Alzheimer’s diseases, kynurenine pathway (KP) of tryptophan metabolism plays a significant role in modulation of neuropathology. Accumulation of a prooxidant 3-hydroxykynurenine (3-HOK) leads to oxidative stress and neuronal cell apoptosis. Drosophila mutant cardinal (cd¹) with 3-HOK excess shows age-dependent neurodegeneration and short-term memory impairments, thereby presenting a model for senile dementia. Although cd gene for phenoxazinone synthase (PHS) catalyzing 3-HOK dimerization has been presumed to harbor the cd¹ mutation, its molecular nature remained obscure. Using next generation sequencing, we have shown that the cd gene in cd¹ carries a long deletion leading to PHS active site destruction. Contrary to the wild type Canton-S (CS), cd¹ males showed defective long-term memory (LTM) in conditioned courtship suppression paradigm (CCSP) at days 5–29 after eclosion. The number of dopaminergic neurons (DAN) regulating fly locomotor activity showed an age-dependent tendency to decrease in cd¹ relative to CS. Thus, in accordance with the concept “from the gene to behavior” proclaimed by S. Benzer, we have shown that the aberrant PHS sequence in cd¹ provokes drastic LTM impairments and DAN alterations. Full article

Lipofuscin granules from retinal pigment epithelium (RPE) cells contain bisretinoid fluorophores, which are photosensitizers and are phototoxic to cells. In the presence of oxygen, bisretinoids are oxidized to form various products, containing aldehydes and ketones, which are also potentially cytotoxic. In a prior study, we identified that bisretinoid oxidation and degradation products have both hydrophilic and amphiphilic properties, allowing their diffusion through the lipofuscin granule membrane into the RPE cell cytoplasm, and are thiobarbituric acid (TBA)-active. The purpose of the present study was to determine if these products exhibit a toxic effect to the RPE cell also in the absence of light. The experiments were performed using the lipofuscin-fed ARPE-19 cell culture. The RPE cell viability analysis was performed with the use of flow cytofluorimetry and laser scanning confocal microscopy. The results obtained indicated that the cell viability of the lipofuscin-fed ARPE-19 sample was clearly reduced not immediately after visible light irradiation for 18 h, but after 4 days maintaining in the dark. Consequently, we could conclude that bisretinoid oxidation products have a damaging effect on the RPE cell in the dark and can be considered as an aggravating factor in age-related macular degeneration progression. Full article

We performed RNA sequencing of the dorsal and ventral parts of the hippocampus and compared it with previously published data to determine the differences in the dorsoventral gradients of gene expression that may result from biological or technical variability. Our data suggest that the dorsal and ventral parts of the hippocampus differ in the expression of genes related to signaling pathways mediated by classical neurotransmitters (glutamate, GABA, monoamines, etc.) as well as peptide and Wnt ligands. These hippocampal parts also diverge in the expression of axon-guiding molecules (both receptors and ligands) and splice isoforms of genes associated with intercellular signaling and cell adhesion. Furthermore, analysis of differential expressions of genes specific for astrocytes, microglia, oligodendrocytes, and vascular cells suggests that non-neuronal cells may also differ in the characteristics between hippocampal parts. Analysis of expression of transposable elements showed that depletion of ribosomal RNA strongly increased the representation of transposable elements in the RNA libraries and helped to detect a weak predominance of expression of these elements in the ventral hippocampus. Our data revealed new molecular dimensions of functional differences between the dorsal and ventral hippocampus and points to possible cascades that may be involved in the longitudinal organization of the hippocampus. Full article

Human brain state is usually estimated by brain-specific substances in peripheral tissues, but, for most analytes, a concordance between their content in the brain and periphery is unclear. In this systematic review, we summarized the investigated correlations in humans. PubMed was searched up to June 2022. We included studies measuring the same endogenous neurospecific analytes in the central nervous system and periphery in the same subjects. Not eligible were studies of cerebrospinal fluid, with significant blood–brain barrier disruption, of molecules with well-established blood-periphery concordance or measured in brain tumors. Seventeen studies were eligible. Four studies did not report on correlation and four revealed no significant correlation. Four molecules were examined twice. For BDNF, there was no correlation in both studies. For phenylalanine, glutamine, and glutamate, results were contradictory. Strong correlations were found for free tryptophan (r = 0.97) and translocator protein (r = 0.90). Thus, only for three molecules was there some certainty. BDNF in plasma or serum does not reflect brain content, whereas free tryptophan (in plasma) and translocator protein (in blood cells) can serve as peripheral biomarkers. We expect a breakthrough in the field with advanced in vivo metabolomic analyses, neuroimaging techniques, and blood assays for exosomes of brain origin. Full article

A paradoxical reduction in anxiety levels in chronic predator stress paradigm (PS) in Sprague–Dawley rats has recently been shown in previous works. In this paper, we studied the possible neurobiological mechanism of this phenomenon. We segregated PS-exposed Sprague–Dawley rats into the high- and low-anxiety phenotypes. The long-lasting effects of PS on corticosterone levels, blood flow speed in the carotid arteries, diffusion coefficient, and 1H nuclear magnetic resonance spectra in the hippocampus were compared in the high-anxiety and low-anxiety rats. In addition, we evaluated the gene BDNF expression in the hippocampus which is considered to be a main factor of neuroplasticity. We demonstrated that in low-anxiety rats, the corticosterone level was decreased and carotid blood flow speed was increased. Moreover, in the hippocampus of low-anxiety rats compared to the control group and high-anxiety rats, the following changes were observed: (a) a decrease in N-acetyl aspartate levels with a simultaneous increase in phosphoryl ethanol amine levels; (b) an increase in lipid peroxidation levels; (c) a decrease in apparent diffusion coefficient value; (d) an increase in BDNF gene expression. Based on these findings, we proposed that stress-induced anxiety reduction is associated with the elevation of BDNF gene expression directly. Low corticosterone levels and a rise in carotid blood flow speed might facilitate BDNF gene expression. Meanwhile, the decrease in apparent diffusion coefficient value and decrease in N-acetyl aspartate levels, as well as an increase in the lipid peroxidation levels, in the hippocampus possibly reflected destructive changes in the hippocampus. We suggested that in Sprague–Dawley rats, these morphological alterations might be considered as an impetus for further increase in neuroplasticity in the hippocampus. Full article

Autophagy is a regulated mechanism of degradation of misfolded proteins and organelles in the cell. Neurons are highly differentiated cells with extended projections, and therefore, their functioning largely depends on the mechanisms of autophagy. For the first time in an animal model using immunohistochemistry, dot analysis, and qRT-PCR, the autophagy (macroautophagy) activity in neurons of two brain regions (hippocampus and neocortex) under normoxia and after exposure to hypoxia was studied. It was found that under normoxia, the autophagic activity was higher in the hippocampal neurons than in the neocortex of rats. In the hippocampus, the exposure of rats to hypoxia resulted in a decrease in the content of autophagy markers LC3 and p62, which was followed by activation of the autophagy-related gene expression. In the neocortex, no changes in these marker proteins were observed after the exposure to hypoxia. These data indicate that the neurons in the hippocampus and neocortex differ in the autophagy response to hypoxia, which may reflect the physiological and functional differences of the pyramidal cells of these brain regions and may to some extent account for the extreme vulnerability of the CA1 hippocampal neurons and relatively high resistance of the neocortical neurons to hypoxia. Full article

Since the 1980s, the concept of dopamine-rich brain centers as clusters of only dopaminergic neurons has been fundamentally revised. It has been shown that, in addition to dopaminergic neurons, most of these centers contain neurons expressing one of the enzymes of dopamine synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). We have obtained convincing evidence that in rats, the hypothalamic periventricular nucleus (PeVN) is one of the largest dopamine-rich centers, containing dopaminergic and monoenzymatic neurons. Indeed, using double immunostaining for TH and AADC, the PeVN was shown to contain almost three thousand dopaminergic and monoenzymatic neurons. According to high-performance liquid chromatography, PeVN contains L-DOPA and dopamine, which, apparently, are synthesized in monoenzymatic TH neurons and bienzymatic neurons, respectively. According to confocal microscopy, neurons (cell bodies, fibers), which were immunopositive only to TH, only to AADC, or both, are in close topographic relationships with each other and with the 3rd ventricle. These data suggest the mutual regulation of the neurons, as well as the delivery of dopamine and L-DOPA to the third ventricle, which is confirmed by their detection in the cerebrospinal fluid. Thus, evidence has been obtained that PeVN is one of the largest dopamine-rich centers of the brain, containing dopaminergic and monoenzymatic neurons. Full article

ISIAH (inherited stress-induced arterial hypertension) rats are characterized by high blood pressure and decreased Trpm8 gene expression in the anterior hypothalamus. Thermosensitive ion channel TRPM8 plays a critical role in the transduction of moderately cold stimuli that give rise to cool sensations. In normotensive animals, the activation of skin TRPM8 is known to induce changes in gene expression in the hypothalamus and induce alterations of thermoregulatory responses. In this work, in hypertensive rats, we studied the effects of activation of the peripheral TRPM8 by cooling and by application of a 1% menthol suspension on (1) the maintenance of body temperature balance and (2) mRNA expression of thermosensitive TRP ion channels in the hypothalamus. In these hypertensive animals, (1) pharmacological activation of peripheral TRPM8 did not affect the thermoregulatory parameters either under thermoneutral conditions or during cold exposure; (2) the expression of Trpm8 in the anterior hypothalamus approximately doubled (to the level of normotensive animals) under the influence of (a) slow cooling and (b) at pharmacological activation of the peripheral TRPM8 ion channel. The latter fact seems the quite important because it allows the proposal of a tool for correcting at least some parameters that distinguish a hypertensive state from the normotensive one. Full article

We studied the effects of stimulation of the medial septal area on the gene expression in the dorsal and ventral hippocampus. Rats under urethane anesthesia were implanted with a recording electrode in the right hippocampus and stimulating electrode in the dorsal medial septum (dMS) or medial septal nucleus (MSN). After one-hour-long deep brain stimulation, we collected ipsi- and contralateral dorsal and ventral hippocampi. Quantitative PCR showed that deep brain stimulation did not cause any changes in the intact contralateral dorsal and ventral hippocampi. A comparison of ipsi- and contralateral hippocampi in the control unstimulated animals showed that electrode implantation in the ipsilateral dorsal hippocampus led to a dramatic increase in the expression of immediate early genes (c-fos, arc, egr1, npas4), neurotrophins (ngf, bdnf) and inflammatory cytokines (il1b and tnf, but not il6) not only in the area close to implantation site but also in the ventral hippocampus. Moreover, the stimulation of MSN but not dMS further increased the expression of c-fos, egr1, npas4, bdnf, and tnf in the ipsilateral ventral but not dorsal hippocampus. Our data suggest that the activation of medial septal nucleus can change the gene expression in ventral hippocampal cells after their priming by other stimuli. Full article

Two short arginine-containing tripeptides, H-Arg-Arg-Arg-OH (TP1) and Ac-Arg-Arg-Arg-NH₂ (TP2), have been shown by the patch-clamp method to modulate the Na_V1.8 channels of DRG primary sensory neurons, which are responsible for the generation of nociceptive signals. Conformational analysis of the tripeptides indicates that the key role in the ligand-receptor binding of TP1 and TP2 to the Na_V1.8 channel is played by two positively charged guanidinium groups of the arginine side chains located at the characteristic distance of ~9 Å from each other. The tripeptide effect on the Na_V1.8 channel activation gating device has been retained when the N- and C-terminal groups of TP1 were structurally modified to TP2 to protect the attacking peptide from proteolytic cleavage by exopeptidases during its delivery to the molecular target, the Na_V1.8 channel. As demonstrated by the organotypic tissue culture method, the agents do not affect the DRG neurite growth, which makes it possible to expect the absence of adverse side effects at the tissue level upon administration of TP1 and TP2. The data obtained indicate that both tripeptides can have great therapeutic potential as novel analgesic medicinal substances. Full article

Transposable elements (TEs) have been extensively studied for decades. In recent years, the introduction of whole-genome and whole-transcriptome approaches, as well as single-cell resolution techniques, provided a breakthrough that uncovered TE involvement in host gene expression regulation underlying multiple normal and pathological processes. Of particular interest is increased TE activity in neuronal tissue, and specifically in the hippocampus, that was repeatedly demonstrated in multiple experiments. On the other hand, numerous neuropathologies are associated with TE dysregulation. Here, we provide a comprehensive review of literature about the role of TEs in neurons published over the last three decades. The first chapter of the present review describes known mechanisms of TE interaction with host genomes in general, with the focus on mammalian and human TEs; the second chapter provides examples of TE exaptation in normal neuronal tissue, including TE involvement in neuronal differentiation and plasticity; and the last chapter lists TE-related neuropathologies. We sought to provide specific molecular mechanisms of TE involvement in neuron-specific processes whenever possible; however, in many cases, only phenomenological reports were available. This underscores the importance of further studies in this area. Full article

The molecular mechanisms of sleep cycle integration at the beginning and the end of the inactive period are not clear. Sleep cycles with a predominance of deep slow-wave sleep (SWS) seem to be associated with accelerated protein synthesis in the brain. The inducible Hsp70 chaperone corrects protein conformational changes and has protective properties. This research explores (1) whether the Hspa1 gene encoding Hsp70 protein activates during the daily rapid-eye-movement sleep (REMS) maximum, and (2) whether a lower daily deep SWS maximum affects the Hspa1 expression level during the subsequent REMS. Combining polysomnography in male Wistar rats, RT-qPCR, and Western blotting, we reveal a three-fold Hspa1 upregulation in the nucleus reticularis pontis oralis, which regulates REMS. Hspa1 expression increases during the daily REMS maximum, 5–7 h after the natural peak of deep SWS. Using short-term selective REMS deprivation, we demonstrate that REMS rebound after deprivation exceeds the natural daily maximum, but it is not accompanied by Hspa1 upregulation. The results suggest that a high proportion of deep SWS, usually observed after sleep onset, is a necessary condition for Hspa1 upregulation during subsequent REMS. The data obtained can inform the understanding of the molecular mechanisms integrating SWS and REMS and key biological function(s) of sleep. Full article