卷 60, 编号 1 (2024)

The role of serotonin 5-HT_5A receptors in the modulation of miniature inhibitory synaptic activity was studied using intracellular recording of miniature glycinergic inhibitory postsynaptic potentials (glymIPSPs) in the lumbar motoneurons of the isolated spinal cord of the frog Rana ridibunda. In a medium containing TTx, CNQX, DAP5, bicuculline, application of the serotonin receptor agonist 5-CT (10 µM) with high affinity for 5-HT_5A led to a suppression of frequency by 86%, as well as the disappearance of high-amplitude glymIPSPs (200–500 µV) at preservation of rare potentials with an amplitude of about 100 μV. This effect indicates the possibility of pre- and postsynaptic action of 5-CT at such a concentration, not limited to its effect only on 5-HT_5A receptors. The addition of methysergide, a blocker of 5-HT _1,2 receptors, to the medium reduced the average frequency of glymIPSPs by 67%, the frequency of high-amplitude events by 5 times and their average amplitude by 20%, which may indicate the participation of 5-HT_5A receptors in pre- and postsynaptic modulation in glymIPSPs of motoneurons. Application of 1 μM 5-CT led to a decrease in the frequency of glymIPSPs by 49% without a noticeable change in the amplitude of glymIPSPs, and the subsequent introduction of SB-699551, a selective antagonist of 5-HT_5A receptors, into the solution increased the frequency of events by 41%, which confirms the involvement of 5-HT_5A receptors in presynaptic modulation of glymIPSPs. Immunofluorescence study showed that supra- and intraspinal 5-HT+ ir neurons produce abundant branching in the lumbar region with the possibility of forming axosomatic contacts with labeled motoneurons and axodendritic contacts on the proximal and distal portions of their dendrites. It is also possible to form contacts in the perimedullary plexus, penetrated by the distal dendrites of motoneurons and astrocytic processes. This represents the structural basis for post-, pre- and extrasynaptic modulation of motoneuron activity by serotonin. The possibility of postsynaptic modulation of motoneuron activity through 5-HT_5A receptors is confirmed by the point-like fluorescence of the 5-HT_5ARlike+ signal on the dendrites and bodies of labeled motoneurons, which is present in the neuropil but absent in the perimedullary plexus. Double labeling with antibodies to the 5-HT_5A receptor and the Ca ²⁺ -binding protein, parvalbumin, revealed 5-HT_5ARlike+ localization in the myelin sheath of dorsal and ventromedial funiculi fibers. In preparations after long-term stimulation of the ventral roots through suction electrodes when labeling motor neurons with biocytin, a bright 5-HT_5ARlike+ signal was detected in the myelin of motor axons, dorsal root fibers entering the brain in the region of the dorsal horn and individual fibers of the ventromedial funiculus. The participation of extrasynaptic 5-HT_5A receptors in the functioning of feedback circuits of lumbar motoneuron activity, with the possible participation of glial elements in these circuits, is discussed.

Rat forebrain ischemia and subsequent three-day reperfusion were found to result in an increase in the levels of autophagy marker LC3B-II and glial fibrillary acidic protein (GFAP) and activation of caspase-3 in the hippocampus and frontal cortex. At the same time, intranasal administration of 0.5 IU insulin to rats with forebrain ischemia and reperfusion (before ischemia and daily during reperfusion) markedly and significantly diminished the level of LC3B-II and caspase-3 activity in the hippocampus and frontal cortex. It demonstrates the ability of insulin to inhibit the activation of autophagy and apoptosis in forebrain structures during ischemia and reperfusion. It was not possible to find out a significant decrease in the level of GFAP in these brain structures under the influence of insulin administration to animals. Intranasal administration of insulin has been found to activate the protein kinase Akt (which activates the mTORC1 complex, known to inhibit autophagy processes) and to inhibit the protein kinase AMPK (initiating autophagy processes) in the hippocampus and cerebral cortex of rats with forebrain ischemia and reperfusion. These effects of insulin apparently underly its ability to diminish the autophagic and apoptotic neuronal death. The data on the modulation by insulin, administered intranasally to rats with forebrain ischemia and reperfusion, of Akt and AMPK activities are in agreement with more detailed studies of the possible mechanism of the neuroprotective action of insulin, which we previously made in vitro on cortical neurons under oxidative stress conditions.

The immune response to spinal cord injury is realized by local and systemic inflammation, followed by repair and restoration of the function of damaged organs. The opportunity to control pro-inflammatory activity and stimulate regenerative processes is an important aspect of the research. Extracellular vesicles (EVs) secreted by activated monocyte-like cells may be a useful tool to drive the polarization of the immune response towards M1 or M2. The aim of the study was to investigate the systemic effects of extracellular vesicles, produced by activated monocyte-like cells of the THP-1 line, after spinal cord injury in zebrafish. It was shown that intracoelomic administration to Danio rerio fish with spinal cord injury of EVs secreted by THP-1 cells, activated by the tumor necrosis factor (TNF), led to a proinflammatory effect, manifested by an increase in the expression of il-6 and tnf-α genes in the brain tissue, and to a less pronounced change in activity in the tissues of the heart, liver and kidney. In the same time, EVs, secreted by unactivated THP-1 cells as well as activated by the phorbol-12- myristate-13-acetate (PMA), did not show any activity. Thus, it was demonstrated that extracellular vesicles secreted by activated monocyte-like cells have the potential to influence on the polarization of the immune response after simulated spinal cord injury in zebrafish.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease characterised by progressive demyelination leading to the death of neurons in the central nervous system. The disease usually manifests in people aged 20–40 years, but in recent years there has been an increase in the number of cases with childhood MS debut. We assume that this may be related to the peculiarities of the taxonomic composition of the intestinal microbiota and its ability to produce B vitamins. Purpose: To identify changes in the composition of the gut microbiome in the debut of multiple sclerosis in children and adults and to assess the potential of the gut microbiome to metabolise and synthesise B vitamins. Fifteen children (9–17 years), 15 adults with MS manifested in childhood and 14 adults over 37 years of age with MS duration less than 1 year participated in the study. The composition of the intestinal microbiome was determined by sequencing the 16S rRNA gene on the Illumina platform with universal primers for the 16S rRNA V3-V4 variable region. The PICRUST algorithm using the KEGG reference genome database was used to predict the presence of B vitamin metabolic pathways in the intestinal microbiome. Children in MS debut were found to have specific microbiome changes different from those in adults. These changes include a decrease in alpha diversity as well as a reduction in dominant phylum and an increase in p_Verrucomicrobiota and p_Mycoplasmatota, which was accompanied by a decrease in the number of bacterial genes involved in the pathways of metabolism and synthesis of vitamins B1, B2, B3, B5 and B12. Such changes may be associated with early manifestation of MS symptoms in children. The findings highlight the importance of further study of the influence of the intestinal microbiome and its metabolic potential on the development and progression of MS, especially in childhood, and may contribute to the development of modern more effective methods of treatment and prevention of this demyelinating disease.

The features of the spatial-temporal structuring of intermuscular interaction during locomotion in conditions of full and partial unloading of body weight were studied. The extraction of muscle synergies was performed using the principal component analysis. It is established that the stability of muscle modules and stereotypical patterns of their temporary activation with varying degrees of afferentation are due to the implementation of motor synergy programs. It was revealed that only the presence, but not the power of the afferent flow from the receptor complex of the lower extremities makes a significant contribution to the formation of inter-extremity synergetic patterns and regulation of the degree of involvement of muscles in synergy. The formation of various time profiles in the structure of synergies is due to the redundancy of the organization of control structures, thanks to which reliable management of physiological functions is carried out. The implementation of synergy programs weakly depends on the magnitude and nature of proprioceptive and supportive afferentation. Only the presence, but not the power, of the afferent flow from the receptor complex of the lower extremities makes a significant contribution to the formation of interfacial synergetic patterns and the regulation of the degree of muscle involvement in synergy.