The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the transcription factor Freud-1 ...(encoded by the
Cc2d1a
gene), which regulates numerous intracellular signaling pathways and acts as a silencer for 5-HT
1A
serotonin and D2 dopamine receptors. Disruption of the Freud-1 functions leads to the development of various psychopathologies. In this study, we found an increase in the expression of the
Cc2d1a
/Freud-1 gene in the hippocampus of BTBR mice (model of autistic-like behavior) in comparison with C57Bl/6J mice and examined how restoration of the
Cc2d1a
/Freud-1 expression in the hippocampus of BTBR mice affects their behavior, expression of 5-HT
1A
serotonin and D2 dopamine receptors, and CREB and NF-κB intracellular signaling pathways in these animals. Five weeks after administration of the adeno-associated viral vector (AAV) carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a small hairpin RNA (shRNA) that suppressed expression of the
Cc2d1a
/Freud-1 gene, we observed an elevation in the anxiety levels, as well as the increase in the escape latency and path length to the platform in the Morris water maze test, which was probably associated with a strengthening of the active stress avoidance strategy. However, the
Cc2d1a
/Freud-1 knockdown did not affect the spatial memory and phosphorylation of the CREB transcription factor, although such effect was found in C57Bl/6J mice in our previous study. These results suggest the impairments in the CREB-dependent effector pathway in BTBR mice, which may play an important role in the development of the autistic-like phenotype. The knockdown of
Cc2d1a
/Freud-1 in the hippocampus of BTBR mice did not affect expression of the 5-HT
1A
serotonin and D2 dopamine receptors and key NF-κB signaling genes (
Nfkb1
and
Rela
). Our data suggest that the transcription factor Freud-1 plays a significant role in the pathogenesis of anxiety and active stress avoidance in autism.
The mechanisms of autism are of extreme interest due to the high prevalence of this disorder in the human population. In this regard, special attention is given to the transcription factor Freud-1 ...(encoded by the Cc2d1a gene), which regulates numerous intracellular signaling pathways and acts as a silencer for 5-HT.sub.1A serotonin and D2 dopamine receptors. Disruption of the Freud-1 functions leads to the development of various psychopathologies. In this study, we found an increase in the expression of the Cc2d1a/Freud-1 gene in the hippocampus of BTBR mice (model of autistic-like behavior) in comparison with C57Bl/6J mice and examined how restoration of the Cc2d1a/Freud-1 expression in the hippocampus of BTBR mice affects their behavior, expression of 5-HT.sub.1A serotonin and D2 dopamine receptors, and CREB and NF-kappaB intracellular signaling pathways in these animals. Five weeks after administration of the adeno-associated viral vector (AAV) carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a small hairpin RNA (shRNA) that suppressed expression of the Cc2d1a/Freud-1 gene, we observed an elevation in the anxiety levels, as well as the increase in the escape latency and path length to the platform in the Morris water maze test, which was probably associated with a strengthening of the active stress avoidance strategy. However, the Cc2d1a/Freud-1 knockdown did not affect the spatial memory and phosphorylation of the CREB transcription factor, although such effect was found in C57Bl/6J mice in our previous study. These results suggest the impairments in the CREB-dependent effector pathway in BTBR mice, which may play an important role in the development of the autistic-like phenotype. The knockdown of Cc2d1a/Freud-1 in the hippocampus of BTBR mice did not affect expression of the 5-HT.sub.1A serotonin and D2 dopamine receptors and key NF-kappaB signaling genes (Nfkb1 and Rela). Our data suggest that the transcription factor Freud-1 plays a significant role in the pathogenesis of anxiety and active stress avoidance in autism.
Autism spectrum disorders (ASDs) are some of the most common neurodevelopmental disorders; however, the mechanisms underlying ASDs are still poorly understood. Serotonin (5-HT) and brain-derived ...neurotrophic factor (BDNF) are known as key players in brain and behavioral plasticity and interact with each other. 5-HT
receptor is a principal regulator of the brain 5-HT system, which modulates normal and pathological behavior. Here we investigated effects of adeno-associated-virus-based 5-HT
receptor overexpression in the hippocampus of BTBR mice (which are a model of autism) on various types of behavior and on the expression of 5-HT
receptor, proBDNF, mature BDNF, and BDNF receptors (TrkB and p75
). The 5-HT
receptor overexpression in BTBR mice reduced stereotyped behavior in the marble-burying test and extended the time spent in the center in the open field test. Meanwhile, this overexpression failed to affect social behavior in the three-chambered test, immobility time in the tail suspension test, locomotor activity in the open field test, and associative learning within the "operant wall" paradigm. The 5-HT
receptor overexpression in the hippocampus raised hippocampal 5-HT
receptor mRNA and protein levels. Additionally, the 5-HT
receptor overexpression lowered both mRNA and protein levels of TrkB receptor but failed to affect proBDNF, mature BDNF, and p75
receptor expression in the hippocampus of BTBR mice. Thus, obtained results suggest the involvement of the 5-HT and BDNF systems' interaction mediated by 5-HT
and TrkB receptors in the mechanisms underlying autistic-like behavior in BTBR mice.
Structural variations are a pervasive feature of human genomes, and there is growing recognition of their role in disease development through their impact on spatial chromatin architecture. This ...understanding has led us to investigate the clinical significance of CNVs in noncoding regions that influence TAD structures. In this study, we focused on the Epb41l4a locus, which contains a highly conserved TAD boundary present in both human chromosome 5 and mouse chromosome 18, and its association with neurodevelopmental phenotypes. Analysis of human data from the DECIPHER database indicates that CNVs within this locus, including both deletions and duplications, are often observed alongside neurological abnormalities, such as dyslexia and intellectual disability, although there is not enough evidence of a direct correlation or causative relationship. To investigate these possible associations, we generated mouse models with deletion and inversion mutations at this locus and carried out RNA-seq analysis to elucidate gene expression changes. We found that modifications in the Epb41l4a TAD boundary led to dysregulation of the Nrep gene, which plays a crucial role in nervous system development. These findings underscore the potential pathogenicity of these CNVs and highlight the crucial role of spatial genome architecture in gene expression regulation.
Topologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not ...always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors: Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at the Kit locus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that although Kit is highly active in both mast cells and melanocytes, deletion of the TAD boundary between the Kit and Kdr genes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between the Kit and Kdr genes have a phenotypic manifestation of the mutation - a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.
Key message
Although the radial diameter and wall thickness of conifer tracheids from dry environments are climatic-sensitive across the full ring area, each cell parameter has a specific zone in a ...ring where its climatic response reaches the maximum.
Seasonal dynamics of the timing and rate in cell production and differentiation imprint climate signals into intra-ring variations of anatomical wood structure (e.g. intra-annual density fluctuations). Despite recent methodological advances in quantitative wood anatomy, our understanding of xylem response to climate at the finest scale of intra-ring resolution is incomplete. The goal of this study is to investigate intra-ring changes of tracheid dimensions (cell radial diameter and wall thickness) controlled by moisture stress. Anatomical wood parameters of
Pinus sylvestris
and
Larix sibirica
from two drought-susceptible locations in Khakassia, South Siberia, were analysed. We found that inter-annual variation of tracheid parameters regularly exceeds the variation between radial tracheid files. This suggests that the climatic signal is recorded throughout the entire ring. However, each cell parameter has a specific zone in the ring where its climatic response reaches the maximum. The climatic response of the radial cell diameter has a temporal shift across the ring, which is particularly apparent in pine rings. The climatic response of cell wall thickness at the intra-ring scale has a more complex pattern. Our results facilitate investigation of the climate impact on tree rings at the finest intra-ring scale by quantifying the timing of climatic impact on ring structure and identifying specifically when climate impacts the formation of a particular cell.
Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is a causative agent of a severe neurological disease. There are three main TBEV subtypes: the European (TBEV-Eu), Far ...Eastern (TBEV-FE), and Siberian (TBEV-Sib). Currently, three lineages within TBEV-Sib have been recorded. In this study, the genetic and biological characteristics of a new original strain, TBEV-2871, isolated in the Novosibirsk province of Western Siberia, Russia were investigated. The strain has low neuroinvasiveness in mice. Phylogenetic analysis demonstrated that TBEV-2871 belongs to TBEV-Sib, but does not cluster with any of the TBEV-Sib lineages. The TBEV-2871 strain has 88–89% nucleotide sequence identity with the other TBEV-Sib strains, 84–86% nucleotide sequence identity with the TBEV-FE and TBEV-Eu subtypes and is genetically close to the subtype division border. The TBEV-2871 polyprotein sequence includes 43 unique amino acid substitutions, 30 of which are recorded at positions that are conserved among all TBEV subtypes. Strain TBEV-2871 and two similar but not identical isolates found in Kemerovo province, Western Siberia are separated into a new lineage tentatively named Obskaya after the name of Ob riber, in the vicinity of which the TBEV-2871 was first found. A molecular evolution investigation demonstrated that within TBEV-Sib, the Obskaya lineage likely separated 1535years ago, which is even earlier than the Baltic lineage.
•Tick-borne encephalitis virus (TBEV), TBEV-2871 strain, was isolated in Siberia, Russia.•TBEV-2871 presents a new Obskaya lineage within TBEV Siberian subtype (TBEV-Sib).•Within TBEV-Sib, Obskaya lineage had separated from common ancestor 1535 years ago.•TBEV-2871 strain is genetically close to the subtype division border.•TBEV-2871 polyprotein sequence includes 43 amino acid unique substitutions.•Studied TBEV strain indicates low neuroinvasiveness for mice.
The article is devoted to the estimation of the impact of hypotensive therapy on the state of cerebral perfusion in patients with AH, associated with type 2 DM using 99mTc-HMPAO brain SPECT. It has ...been shown that the signs of the brain hypoperfusion and reduced cerebrovascular reserve are observed in patients with AH in combination with type 2 DM even when focal neurological symptoms are absent. Using 99mTc-HMPAO brain SPECT it has been found that carvedilol therapy of about 6 months has a positive effect on the cerebral perfusion and cerebrovascular reserve status in these patients.
The article is devoted to the estimation of the impact of hypotensive therapy on the state of cerebral perfusion in patients with AH, associated with type 2 DM using super(99m) Tc-HMPAO brain SPECT. ...It has been shown that the signs of the brain hypoperfusion and reduced cerebrovascular reserve are observed in patients with AH in combination with type 2 DM even when focal neurological symptoms are absent. Using super(99m) Tc-HMPAO brain SPECT it has been found that carvedilol therapy of about 6 months has a positive effect on the cerebral perfusion and cerebrovascular reserve status in these patients.
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