39 results on '"Sütt, S."'
Search Results
2. Stk25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and NAFLD in mice
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Mahlapuu, M., primary, Duran, E.N., additional, Aghajan, M., additional, Amrutkar, M., additional, Sütt, S., additional, Cansby, E., additional, Booten, S., additional, Watt, A., additional, Ståhlman, M., additional, Stefan, N., additional, Haering, H.-U., additional, Staiger, H., additional, Boren, J., additional, and Marschall, H.-U., additional
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- 2018
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3. Wfs1-deficient animals have brain-region-specific changes of Na + , K + -ATPase activity and mRNA expression of α 1 and β 1 subunits
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Sütt, S., Altpere, A., Reimets, R., Visnapuu, T., Loomets, M., Raud, S., Salum, T., Mahlapuu, R., Kairane, C., Zilmer, M., and Vasar, E.
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- 2015
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4. Lawsonia intracellularis and Porcine Circovirus type-2 infection in Estonia
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Järveots, T., primary, Saar, T., additional, Põdersoo, D., additional, Rüütel-Boudinot, S., additional, Sütt, S., additional, Tummeleht, L., additional, Suuroja, T., additional, and Lindjärv, R., additional
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- 2016
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5. THU-441 - Stk25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and NAFLD in mice
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Mahlapuu, M., Duran, E.N., Aghajan, M., Amrutkar, M., Sütt, S., Cansby, E., Booten, S., Watt, A., Ståhlman, M., Stefan, N., Haering, H.-U., Staiger, H., Boren, J., and Marschall, H.-U.
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- 2018
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6. Trib3 is developmentally and nutritionally regulated in the brain but is dispensable for spatial memory, fear conditioning and sensing of amino acid-imbalanced diet
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Hashimoto, K., Örd, T., Innos, J., Lilleväli, K., Tekko, T., Sütt, S., Örd, D., Kõks, S., Vasar, E., Hashimoto, K., Örd, T., Innos, J., Lilleväli, K., Tekko, T., Sütt, S., Örd, D., Kõks, S., and Vasar, E.
- Abstract
Tribbles homolog 3 (TRIB3) is a mammalian pseudokinase that is induced in neuronal cell cultures in response to cell death-inducing stresses, including neurotrophic factor deprivation. TRIB3 is an inhibitor of activating transcription factor 4 (ATF4), the central transcriptional regulator in the eukaryotic translation initiation factor 2α (eIF2α) phosphorylation pathway that is involved in the cellular stress response and behavioral processes. In this article, we study the expression of Trib3 in the mouse brain, characterize the brain morphology of mice with a genetic ablation of Trib3 and investigate whether Trib3 deficiency alters eIF2α-dependent cognitive abilities. Our data show that the consumption of a leucine-deficient diet induces Trib3 expression in the anterior piriform cortex, the brain region responsible for detecting essential amino acid intake imbalance. However, the aversive response to leucine-devoid diet does not differ in Trib3 knockout and wild type mice. Trib3 deletion also does not affect long-term spatial memory and reversal learning in the Morris water maze and auditory or contextual fear conditioning. During embryonic development, Trib3 expression increases in the brain and persists in the early postnatal stadium. Neuroanatomical characterization of mice lacking Trib3 revealed enlarged lateral ventricles. Thus, although the absence of Trib3 does not alter the eIF2α pathway-dependent cognitive functions of several areas of the brain, including the hippocampus, amygdala and anterior piriform cortex, Trib3 may serve a role in other central nervous system processes and molecular pathways.
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- 2014
7. Effect of chronic valproic acid treatment on hepatic gene expression profile in Wfs1 knockout mouse
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Punapart, M., Eltermaa, M., Oflijan, J., Sütt, S., Must, A., Kõks, S., Schalkwyk, L.C., Fernandes, C., Vasar, E., Soomets, U., Terasmaa, A., Punapart, M., Eltermaa, M., Oflijan, J., Sütt, S., Must, A., Kõks, S., Schalkwyk, L.C., Fernandes, C., Vasar, E., Soomets, U., and Terasmaa, A.
- Abstract
Valproic acid (VPA) is a widely used anticonvulsant and mood-stabilizing drug whose use is often associated with drug-induced weight gain. Treatment with VPA has been shown to upregulate Wfs1 expression in vitro. Aim of the present study was to compare the effect of chronic VPA treatment in wild type (WT) and Wfs1 knockout (KO) mice on hepatic gene expression profile. Wild type, Wfs1 heterozygous, and homozygous mice were treated with VPA for three months (300 mg/kg i.p. daily) and gene expression profiles in liver were evaluated using Affymetrix Mouse GeneChip 1.0 ST array. We identified 42 genes affected by Wfs1 genotype, 10 genes regulated by VPA treatment, and 9 genes whose regulation by VPA was dependent on genotype. Among the genes that were regulated differentially by VPA depending on genotype was peroxisome proliferator-activated receptor delta (Ppard), whose expression was upregulated in response to VPA treatment in WT, but not in Wfs1 KO mice. Thus, regulation of Ppard by VPA is dependent on Wfs1 genotype.
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- 2014
8. Wfs1‐deficient animals have brain‐region‐specific changes of Na+, K+‐ATPase activity and mRNA expression of α1 and β1 subunits
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Sütt, S., primary, Altpere, A., additional, Reimets, R., additional, Visnapuu, T., additional, Loomets, M., additional, Raud, S., additional, Salum, T., additional, Mahlapuu, R., additional, Kairane, C., additional, Zilmer, M., additional, and Vasar, E., additional
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- 2014
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9. Wfs1-deficient mice display altered function of serotonergic system and increased behavioral response to antidepressants
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Visnapuu, T., Raud, S., Loomets, M., Reimets, R., Sütt, S., Luuk, H., Plaas, M., Kõks, S., Volke, V., Alttoa, A., Harro, J., Vasar, E., Visnapuu, T., Raud, S., Loomets, M., Reimets, R., Sütt, S., Luuk, H., Plaas, M., Kõks, S., Volke, V., Alttoa, A., Harro, J., and Vasar, E.
- Abstract
It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.
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- 2013
10. Lsamp–/– mice display lower sensitivity to amphetamine and have elevated 5-HT turnover
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Innos, J., Leidmaa, E., Philips, M-A, Sütt, S., Alttoa, A., Harro, J., Kõks, S., Vasar, E., Innos, J., Leidmaa, E., Philips, M-A, Sütt, S., Alttoa, A., Harro, J., Kõks, S., and Vasar, E.
- Abstract
In mice, the limbic system-associated membrane protein (Lsamp) gene has been implicated in locomotion, anxiety, fear reaction, learning, social behaviour and adaptation. Human data links the LSAMP gene to several psychiatric disorders and completed suicide. Here, we investigated changes in major monoamine systems in mice lacking the Lsamp gene. First, the locomotor and rewarding effects of amphetamine were studied in Lsamp–/– mice and Lsamp+/+ mice. Second, monoamine levels in major brain regions in response to saline and amphetamine injections were measured and, third, the expression levels of dopamine system-related genes in the brain were studied in these mice. Lsamp–/– mice displayed lower sensitivity to amphetamine in the motility box. Likewise, in the place preference test, the rewarding effect of amphetamine was absent in Lsamp–/– mice. In all brain regions studied, Lsamp–/– mice displayed lower serotonin (5-HT) baseline levels, but a greater 5-HT turnover rate, and amphetamine increased the level of 5-HT and lowered 5-HT turnover to a greater extent in Lsamp–/– mice. Finally, Lsamp–/– mice had lower level of dopamine transporter (DAT) mRNA in the mesencephalon. In conclusion, Lsamp-deficiency leads to increased endogenous 5-HT-ergic tone and enhanced 5-HT release in response to amphetamine. Elevated 5-HT function and reduced activity of DAT are the probable reasons for the blunted effects of amphetamine in these mice. Lsamp–/– mice are a promising model to study the neurobiological mechanisms of deviant social behaviour and adaptation impairment observed in many psychiatric disorders.
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- 2013
11. Evidence for impaired function of dopaminergic system in Wfs1-deficient mice
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Visnapuu, T., Plaas, M., Reimets, R., Raud, S., Terasmaa, A., Kõks, S., Sütt, S., Luuk, H., Hundahl, C.A., Eskla, K-L, Altpere, A., Alttoa, A., Harro, J., Vasar, E., Visnapuu, T., Plaas, M., Reimets, R., Raud, S., Terasmaa, A., Kõks, S., Sütt, S., Luuk, H., Hundahl, C.A., Eskla, K-L, Altpere, A., Alttoa, A., Harro, J., and Vasar, E.
- Abstract
Immunohistological studies suggest abundant expression of Wfs1 protein in neurons and nerve fibers that lie in the vicinity of dopaminergic (DA-ergic) fibers and neurons. Therefore, we sought to characterize the function of DA-ergic system in Wfs1-deficient mice. In wild-type mice, amphetamine, an indirect agonist of DA, caused significant hyperlocomotion and increase in tissue DA levels in the dorsal and ventral striatum. Both effects of amphetamine were significantly blunted in homozygous Wfs1-deficient mice. Motor stimulation caused by apomorphine, a direct DA receptor agonist, was somewhat stronger in Wfs1-deficient mice compared to their wild-type littermates. However, apomorphine caused a similar reduction in levels of DA metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) in the dorsal and ventral striatum in all genotypes. Behavioral sensitization to repeated treatment with amphetamine (2.5 mg/kg) was observed in wild-type, but not in Wfs1-deficient mice. The expression of DA transporter gene (Dat) mRNA was significantly lower in the midbrain of male and female homozygous mice compared to wild-type littermates. Altogether, the blunted effects of amphetamine and the reduced gene expression of DA transporter are probably indicative of an impaired functioning of the DA-ergic system in Wfs1-deficient mice.
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- 2013
12. S.2.05 Wolframin (WFS1) deficient mice display increased anxiety and reduced adaptation in a novel environment
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Vasar, E., Kõks, S., Luuk, H., Plaas, M., Sütt, S., Raud, S., Kurrikoff, K., Abramov, U., and Innos, J.
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- 2009
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13. Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats
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Sütt, S., Raud, S., Abramov, U., Innos, J., Luuk, H., Plaas, M., Kõks, S., Zilmer, K., Mahlapuu, R., Zilmer, M., Vasar, E., Sütt, S., Raud, S., Abramov, U., Innos, J., Luuk, H., Plaas, M., Kõks, S., Zilmer, K., Mahlapuu, R., Zilmer, M., and Vasar, E.
- Abstract
Male Wistar rats exhibit significant variations in exploratory behaviour in the elevated plus-maze (EPM) model of anxiety. We have now investigated the relation between exploratory behaviour and levels of corticosterone and systemic oxidative stress. Also, the expression levels of endocannabinoid-related and wolframin (Wfs1) genes were measured in the forebrain structures. The rats were divided into high, intermediate and low exploratory activity groups. Exposure to EPM significantly elevated the serum levels of corticosterone in all rats, but especially in the high exploratory group. Oxidative stress indices and expression of endocannabinoid-related genes were not significantly affected by exposure to EPM. Wfs1 mRNA level was highly dependent on exploratory behaviour of animals. In low exploratory activity rats, Wfs1 gene expression was reduced in the temporal lobe, whereas in high exploratory activity group it was reduced in the mesolimbic area and hippocampus. Altogether, present study indicates that in high exploratory activity rats, the activation of brain areas related to novelty seeking is apparent, whereas in low exploratory activity group the brain structures linked to anxiety are activated.
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- 2010
14. Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABAA receptors in Wfs1-deficient mice
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Raud, S., Sütt, S., Luuk, H., Plaas, M., Innos, J., Kõks, S., Vasar, E., Raud, S., Sütt, S., Luuk, H., Plaas, M., Innos, J., Kõks, S., and Vasar, E.
- Abstract
Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. In clinical studies a relation between mutations in the Wfs1 gene and increased susceptibility for mood disorders has been established. According to our previous studies, mice lacking Wfs1 gene displayed increased anxiety in stressful environment. As the GABA-ergic system plays a significant role in the regulation of anxiety, we analyzed the expression of GABA-related genes in the forebrain structures of wild-type and Wfs1-deficient mice. Experimentally naïve Wfs1-deficient animals displayed a significant down-regulation of α1 (Gabra1) and α2 (Gabra2) subunits of GABAA receptors in the temporal lobe and frontal cortex. Exposure of wild-type mice to the elevated plus-maze decreased levels of Gabra1 and Gabra2 genes in the temporal lobe. A similar tendency was also established in the frontal cortex of wild-type animals exposed to behavioral test. In Wfs1-deficient mice the elevated plus-maze exposure did not induce further changes in the expression of Gabra1 and Gabra2 genes. By contrast, the expression of Gad1 and Gad2 genes, enzymes responsible for the synthesis of GABA, was not significantly affected by the exposure of mice to the elevated plus-maze or by the invalidation of Wfs1 gene. Altogether, the present study demonstrates that increased anxiety of Wfs1-deficient mice is probably linked to reduced expression of Gabra1 and Gabra2 genes in the frontal cortex and temporal lobe.
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- 2009
15. Cat odour-induced anxiety—a study of the involvement of the endocannabinoid system
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Sütt, S., Raud, S., Areda, T., Reimets, A., Kõks, S., Vasar, E., Sütt, S., Raud, S., Areda, T., Reimets, A., Kõks, S., and Vasar, E.
- Abstract
Rationale Recent evidence suggests the involvement of the endocannabinoid (EC) system in the regulation of anxiety. Objectives The aim of present work was to study the role of the EC system in cat odour-induced anxiety in rats. Materials and methods Male Wistar rats were exposed to cat odour in home and motility cages. Exposure of rats to elevated zero-maze was used to determine changes in anxiety. Effect of rimonabant (0.3–3 mg/kg), antagonist of CB1 receptors, was studied on cat odour-induced alterations in exploratory behaviour. Real-time PCR was used to determine gene expression levels of EC-related genes in the brain. Results Anxiogenic-like action of cat odour was evident in the elevated zero-maze. Cat odour increased the expression of FAAH, the enzyme responsible for the degradation of anandamide, in the mesolimbic area. By contrast, in the amygdala and periaqueductal grey (PAG) levels of NAPE-PLD, the enzyme related to the synthesis of anandamide, and FAAH were remarkably decreased. Cat odour also decreased the expression of enzymes related to metabolism of 2-archidonoyl-glycerol in the amygdala and PAG. Pre-treatment of rats with rimonabant (0.3–3 mg/kg) reduced the exploratory behaviour of rats, but did not affect cat odour-induced changes. Conclusion Exposure to cat odour induces anxiogenic-like effect on the behaviour in rats. Cat odour also causes moderate increase in expression of EC-related genes in the mesolimbic area, whereas significant down-regulation is established in the amygdala and PAG. Relation of predator odour-induced anxiety to the inhibition of the EC system in the amygdala and PAG is supported by behavioural studies where blockade of CB1 receptors by rimonabant induces anxiogenic-like action.
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- 2008
16. Cat odor exposure induces distinct changes in the exploratory behavior and Wfs1 gene expression in C57Bl/6 and 129Sv mice
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Raud, S., Sütt, S., Plaas, M., Luuk, H., Innos, J., Philips, M-A, Kõks, S., Vasar, E., Raud, S., Sütt, S., Plaas, M., Luuk, H., Innos, J., Philips, M-A, Kõks, S., and Vasar, E.
- Abstract
129Sv and C57Bl/6 (Bl6) strains are two most widely used inbred mice strains for generation of transgenic animals. The present study confirms the existence of substantial differences in the behavior of these two mice strains. The exploratory behavior of Bl6 mice in a novel environment was significantly higher compared to 129Sv mice. The exposure of mice to cat odor-induced an anxiety-like state in Bl6, but not in 129Sv mice. The levels of Wfs1 gene expression did not differ in the prefrontal cortex, mesolimbic area and temporal lobe of experimentally naive Bl6 and 129Sv mice. However, after cat odor exposure the expression of Wfs1 gene was significantly lower in the mesolimbic area and temporal lobe of Bl6 mice compared to 129Sv strain. Dynamics of Wfs1 gene expression and exploratory behavior suggest that the down-regulation of Wfs1 gene in Bl6 mice might be related to the increased anxiety. Further studies are needed to test the robustness and possible causal relationship of this finding.
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- 2007
17. Screen for genes in periaqueductal grey of male Wistar rats related to reduced exploratory activity in the elevated plus-maze
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Nelovkov, A., Sütt, S., Raud, S., Vasar, E., Kõks, S., Nelovkov, A., Sütt, S., Raud, S., Vasar, E., and Kõks, S.
- Abstract
Aim of a present study was to find genes in the periaqueductal grey (PAG) related to the exploratory behavior in rats. Male Wistar rats were divided according to their exploratory behavior in the elevated plus-maze model of anxiety into two groups: high (non-anxious) and low (anxious) exploratory activity. Differential expression of genes was analyzed using the cDNA representational difference analysis (RDA). Q-RT-PCR was used to confirm most prominent changes and functional annotation of the identified genes was performed to establish pathways related to exploratory behavior of rats. We found different genetic activation related to the exploratory activity of rats. Rats with low exploratory activity showed increase in the intracellular signal transduction and in GABA, vasopressin and adrenergic receptor activities. Functional annotation confirmed significant induction of cAMP system and GTPases in rats with anxious-type behavior. On the other hand, rats with high exploratory activity in the elevated plus-maze (non-anxious type of behavior) had increased activity of genes forming “behavioral fear response” system. These changes were specific to PAG, because they were not found in the cerebellum. In addition, plasma corticosterone levels were significantly higher in rats with non-anxious behavior compared to anxious behavior. Our results show that non-anxious behavior is related to activation of “fear response system” and more intense activation of HPA axis. Possibly it means that this system helps animals to cope with the threatening circumstances. More detailed analysis of this potential “fear response system” is necessary in the further studies for understanding its role in the regulation of emotional behavior.
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- 2007
18. Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats
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Sütt, S., primary, Raud, S., additional, Abramov, U., additional, Innos, J., additional, Luuk, H., additional, Plaas, M., additional, Kõks, S., additional, Zilmer, K., additional, Mahlapuu, R., additional, Zilmer, M., additional, and Vasar, E., additional
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- 2009
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19. Wfs1-deficient animals have brain-region-specific changes of Na+, K+-ATPase activity and mRNA expression of α1 and β1 subunits.
- Author
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Sütt, S., Altpere, A., Reimets, R., Visnapuu, T., Loomets, M., Raud, S., Salum, T., Mahlapuu, R., Kairane, C., Zilmer, M., and Vasar, E.
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- 2015
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20. STE20-type kinase TAOK3 regulates hepatic lipid partitioning.
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Xia Y, Caputo M, Cansby E, Anand SK, Sütt S, Henricsson M, Porosk R, Marschall HU, Blüher M, and Mahlapuu M
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- Cells, Cultured, Female, Humans, Lipid Metabolism, Male, Protein Serine-Threonine Kinases genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Liver metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Objective: Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid storage in hepatocytes, has recently emerged as a leading global cause of chronic liver disease. The aim of this study was to examine the role of STE20-type protein kinase TAOK3, which has previously been shown to associate with hepatic lipid droplets, in the initiation and aggravation of human NAFLD., Methods: The correlation between TAOK3 mRNA expression and the severity of NAFLD was investigated in liver biopsies from 62 individuals. In immortalized human hepatocytes, intracellular fat deposition, lipid metabolism, and oxidative and endoplasmic reticulum stress were analyzed when TAOK3 was overexpressed or knocked down by small interfering RNA. Subcellular localization of TAOK3 was characterized in human and mouse hepatocytes by immunofluorescence microscopy., Results: We found that the TAOK3 transcript levels in human liver biopsies were positively correlated with the key lesions of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Overexpression of TAOK3 in cultured human hepatocytes exacerbated lipid storage by inhibiting β-oxidation and triacylglycerol secretion while enhancing lipid synthesis. Conversely, silencing of TAOK3 attenuated lipid deposition in human hepatocytes by stimulating mitochondrial fatty acid oxidation and triacylglycerol efflux while suppressing lipogenesis. We also found aggravated or decreased oxidative/endoplasmic reticulum stress in human hepatocytes with increased or reduced TAOK3 levels, respectively. The subcellular localization of TAOK3 in human and mouse hepatocytes was confined to intracellular lipid droplets., Conclusions: This study provides the first evidence that hepatic lipid droplet-coating kinase TAOK3 is a critical regulatory node controlling liver lipotoxicity and susceptibility to NAFLD., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
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- 2021
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21. STK25 regulates oxidative capacity and metabolic efficiency in adipose tissue.
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Sütt S, Cansby E, Paul A, Amrutkar M, Nuñez-Durán E, Kulkarni NM, Ståhlman M, Borén J, Laurencikiene J, Howell BW, Enerbäck S, and Mahlapuu M
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- 3T3-L1 Cells, Adipocytes metabolism, Animals, Cells, Cultured, Diet, High-Fat, Intracellular Signaling Peptides and Proteins genetics, Lipid Droplets metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Serine-Threonine Kinases genetics, Adipose Tissue metabolism, Intracellular Signaling Peptides and Proteins physiology, Lipid Metabolism genetics, Oxidative Stress genetics, Protein Serine-Threonine Kinases physiology
- Abstract
Whole-body energy homeostasis at over-nutrition critically depends on how well adipose tissue remodels in response to excess calories. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid storage in non-adipose tissue and systemic insulin resistance in the context of nutritional stress. Here, we investigated the role of STK25 in regulation of adipose tissue dysfunction in mice challenged with a high-fat diet. We found that overexpression of STK25 in high-fat-fed mice resulted in impaired mitochondrial function and aggravated hypertrophy, inflammatory infiltration and fibrosis in adipose depots. Reciprocally, Stk25- knockout mice displayed improved mitochondrial function and were protected against diet-induced excessive fat storage, meta-inflammation and fibrosis in brown and white adipose tissues. Furthermore, in rodent HIB-1B cell line, STK25 depletion resulted in enhanced mitochondrial activity and consequently, reduced lipid droplet size, demonstrating an autonomous action for STK25 within adipocytes. In summary, we provide the first evidence for a key function of STK25 in controlling the metabolic balance of lipid utilization vs lipid storage in brown and white adipose depots, suggesting that repression of STK25 activity offers a potential strategy for establishing healthier adipose tissue in the context of chronic exposure to dietary lipids., (© 2018 Society for Endocrinology.)
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- 2018
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22. Serine/threonine protein kinase 25 antisense oligonucleotide treatment reverses glucose intolerance, insulin resistance, and nonalcoholic fatty liver disease in mice.
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Nuñez-Durán E, Aghajan M, Amrutkar M, Sütt S, Cansby E, Booten SL, Watt A, Ståhlman M, Stefan N, Häring HU, Staiger H, Borén J, Marschall HU, and Mahlapuu M
- Abstract
Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty-first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression. Here, we investigated the effect of antisense oligonucleotides (ASOs) targeting Stk25 on the metabolic and molecular phenotype of mice after chronic exposure to dietary lipids. We found that Stk25 ASOs efficiently reversed high-fat diet-induced systemic hyperglycemia and hyperinsulinemia, improved whole-body glucose tolerance and insulin sensitivity, and ameliorated liver steatosis, inflammatory infiltration, apoptosis, hepatic stellate cell activation, and nutritional fibrosis in obese mice. Moreover, Stk25 ASOs suppressed the abundance of liver acetyl-coenzyme A carboxylase (ACC) protein, a key regulator of both lipid oxidation and synthesis, revealing the likely mechanism underlying repression of hepatic fat accumulation by ASO treatment. We also found that STK25 protein levels correlate significantly and positively with NASH development in human liver biopsies, and several common nonlinked single-nucleotide polymorphisms in the human STK25 gene are associated with altered liver fat, supporting a critical role of STK25 in the pathogenesis of NAFLD in humans. Conclusion : Preclinical validation for the metabolic benefit of pharmacologically inhibiting STK25 in the context of obesity is provided. Therapeutic intervention aimed at reducing STK25 function may provide a new strategy for the treatment of patients with NAFLD, type 2 diabetes, and related complex metabolic diseases. ( Hepatology Communications 2018;2:69-83).
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- 2017
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23. Protein kinase STK25 aggravates the severity of non-alcoholic fatty pancreas disease in mice.
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Nuñez-Durán E, Chanclón B, Sütt S, Real J, Marschall HU, Wernstedt Asterholm I, Cansby E, and Mahlapuu M
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- Animals, Blood Glucose analysis, C-Peptide blood, Gene Expression, Glucose Tolerance Test, Inflammation pathology, Insulin blood, Insulin metabolism, Insulin Secretion, Insulin-Secreting Cells pathology, Insulin-Secreting Cells physiology, Intracellular Signaling Peptides and Proteins genetics, Islets of Langerhans pathology, Islets of Langerhans physiopathology, Leptin blood, Lipid Metabolism, Mice, Mice, Transgenic, Obesity metabolism, Pancreatic Diseases pathology, Protein Serine-Threonine Kinases genetics, Adipose Tissue metabolism, Diet, High-Fat, Intracellular Signaling Peptides and Proteins physiology, Pancreatic Diseases physiopathology, Protein Serine-Threonine Kinases physiology
- Abstract
Characterising the molecular networks that negatively regulate pancreatic β-cell function is essential for understanding the underlying pathogenesis and developing new treatment strategies for type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of ectopic fat storage, meta-inflammation, and fibrosis in liver and skeletal muscle. Here, we assessed the role of STK25 in control of progression of non-alcoholic fatty pancreas disease in the context of chronic exposure to dietary lipids in mice. We found that overexpression of STK25 in high-fat-fed transgenic mice aggravated diet-induced lipid storage in the pancreas compared with that of wild-type controls, which was accompanied by exacerbated pancreatic inflammatory cell infiltration, stellate cell activation, fibrosis and apoptosis. Pancreas of Stk25 transgenic mice also displayed a marked decrease in islet β/α-cell ratio and alteration in the islet architecture with an increased presence of α-cells within the islet core, whereas islet size remained similar between genotypes. After a continued challenge with a high-fat diet, lower levels of fasting plasma insulin and C-peptide, and higher levels of plasma leptin, were detected in Stk25 transgenic vs wild-type mice. Furthermore, the glucose-stimulated insulin secretion was impaired in high-fat-fed Stk25 transgenic mice during glucose tolerance test, in spite of higher net change in blood glucose concentrations compared with wild-type controls, suggesting islet β-cell dysfunction. In summary, this study unravels a role for STK25 in determining the susceptibility to diet-induced non-alcoholic fatty pancreas disease in mice in connection to obesity. Our findings highlight STK25 as a potential drug target for metabolic disease., (© 2017 The authors.)
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- 2017
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24. Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle.
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Chursa U, Nuñez-Durán E, Cansby E, Amrutkar M, Sütt S, Ståhlman M, Olsson BM, Borén J, Johansson ME, Bäckhed F, Johansson BR, Sihlbom C, and Mahlapuu M
- Subjects
- Animals, Blotting, Western, Chromatography, Liquid, Diet, High-Fat, Insulin Resistance genetics, Intracellular Signaling Peptides and Proteins genetics, Lipid Metabolism genetics, Mass Spectrometry, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria pathology, Protein Serine-Threonine Kinases genetics, Proteomics, Rats, Real-Time Polymerase Chain Reaction, Insulin Resistance physiology, Intracellular Signaling Peptides and Proteins metabolism, Lipid Metabolism physiology, Mitochondria metabolism, Muscle, Skeletal metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Aims/hypothesis: Understanding the molecular networks controlling ectopic lipid deposition and insulin responsiveness in skeletal muscle is essential for developing new strategies to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of liver steatosis, hepatic lipid metabolism and whole body glucose and insulin homeostasis. Here, we assessed the role of STK25 in control of ectopic fat storage and insulin responsiveness in skeletal muscle., Methods: Skeletal muscle morphology was studied by histological examination, exercise performance and insulin sensitivity were assessed by treadmill running and euglycaemic-hyperinsulinaemic clamp, respectively, and muscle lipid metabolism was analysed by ex vivo assays in Stk25 transgenic and wild-type mice fed a high-fat diet. Lipid accumulation and mitochondrial function were also studied in rodent myoblasts overexpressing STK25. Global quantitative phosphoproteomics was performed in skeletal muscle of Stk25 transgenic and wild-type mice fed a high-fat diet to identify potential downstream mediators of STK25 action., Results: We found that overexpression of STK25 in transgenic mice fed a high-fat diet increases intramyocellular lipid accumulation, impairs skeletal muscle mitochondrial function and sarcomeric ultrastructure, and induces perimysial and endomysial fibrosis, thereby reducing endurance exercise capacity and muscle insulin sensitivity. Furthermore, we observed enhanced lipid accumulation and impaired mitochondrial function in rodent myoblasts overexpressing STK25, demonstrating an autonomous action for STK25 within cells. Global phosphoproteomic analysis revealed alterations in the total abundance and phosphorylation status of different target proteins located predominantly to mitochondria and sarcomeric contractile elements in Stk25 transgenic vs wild-type muscle, respectively, providing a possible molecular mechanism for the observed phenotype., Conclusions/interpretation: STK25 emerges as a new regulator of the complex interplay between lipid storage, mitochondrial energetics and insulin action in skeletal muscle, highlighting the potential of STK25 antagonists for type 2 diabetes treatment.
- Published
- 2017
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25. STK25 is a critical determinant in nonalcoholic steatohepatitis.
- Author
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Amrutkar M, Chursa U, Kern M, Nuñez-Durán E, Ståhlman M, Sütt S, Borén J, Johansson BR, Marschall HU, Blüher M, and Mahlapuu M
- Subjects
- Animals, Choline Deficiency complications, Disease Models, Animal, Lipid Metabolism genetics, Mice, Transgenic, Triglycerides metabolism, Choline Deficiency metabolism, Hepatocytes metabolism, Intracellular Signaling Peptides and Proteins metabolism, Liver metabolism, Non-alcoholic Fatty Liver Disease metabolism, Obesity metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and 10-20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) with a high risk of cirrhosis, liver failure, and hepatocellular carcinoma. Despite its high medical importance, the molecular mechanisms controlling progression from simple liver steatosis to NASH remain elusive. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid deposition, systemic glucose, and insulin homeostasis. To elucidate the role of STK25 in the development of NASH, we challenged Stk25-knockout and transgenic mice with a methionine and choline-deficient (MCD) diet. We show that Stk25
-/- mice are protected against MCD-diet-induced NASH, as evidenced by repressed liver steatosis, oxidative damage, inflammation, and fibrosis, whereas Stk25 transgenic mice developed a more severe NASH phenotype, compared with corresponding wild-type littermates. Consistently, NASH features were suppressed in STK25-deficient human hepatocytes cultured in MCD medium, and reciprocally enhanced in STK25-overexpressing cells. We also found a significant positive correlation in human liver biopsies between STK25 expression and NASH development. The study provides evidence for multiple roles of STK25 in NASH pathogenesis and future investigations to address the potential therapeutic relevance of pharmacological STK25 inhibitors in prevention and treatment of NASH are warranted.-Amrutkar, M., Chursa, U., Kern, M., Nuñez-Durán, E., Ståhlman, M., Sütt, S., Borén, J., Johansson, B. R., Marschall, H.-U., Blüher, M., Mahlapuu, M. STK25 is a critical determinant in nonalcoholic steatohepatitis., (© FASEB.)- Published
- 2016
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26. Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice.
- Author
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Raud S, Reimets R, Loomets M, Sütt S, Altpere A, Visnapuu T, Innos J, Luuk H, Plaas M, Volke V, and Vasar E
- Subjects
- Animals, Anxiety drug therapy, Anxiety physiopathology, Central Nervous System Depressants pharmacokinetics, Dose-Response Relationship, Drug, Ethanol pharmacokinetics, Exploratory Behavior drug effects, Exploratory Behavior physiology, Female, Frontal Lobe drug effects, Frontal Lobe metabolism, GABA-A Receptor Agonists pharmacology, Ketamine pharmacology, Membrane Proteins genetics, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Motor Activity drug effects, Motor Activity physiology, Pentobarbital pharmacology, RNA, Messenger metabolism, Receptors, GABA-A metabolism, Temporal Lobe drug effects, Temporal Lobe metabolism, Wolfram Syndrome genetics, Central Nervous System Depressants pharmacology, Ethanol pharmacology, Membrane Proteins deficiency
- Abstract
Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle-treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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27. Initiation and developmental dynamics of Wfs1 expression in the context of neural differentiation and ER stress in mouse forebrain.
- Author
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Tekko T, Lilleväli K, Luuk H, Sütt S, Truu L, Örd T, Möls M, and Vasar E
- Subjects
- Aging pathology, Animals, Animals, Newborn, Cell Differentiation, Endoplasmic Reticulum ultrastructure, Endoplasmic Reticulum Chaperone BiP, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Stress, Physiological, Aging physiology, Embryonic Development physiology, Endoplasmic Reticulum physiology, Gene Expression Regulation, Developmental physiology, Membrane Proteins metabolism, Neural Stem Cells cytology, Neural Stem Cells physiology
- Abstract
Wolframin (Wfs1) is a membrane glycoprotein that resides in the endoplasmic reticulum (ER) and regulates cellular Ca(2+) homeostasis. In pancreas Wfs1 attenuates unfolded protein response (UPR) and protects cells from apoptosis. Loss of Wfs1 function results in Wolfram syndrome (OMIM 222300) characterized by early-onset diabetes mellitus, progressive optic atrophy, diabetes insipidus, deafness, and psychiatric disorders. Similarly, Wfs1-/- mice exhibit diabetes and increased basal anxiety. In the adult central nervous system Wfs1 is prominent in central extended amygdala, striatum and hippocampus, brain structures largely involved in behavioral adaptation of the organism. Here, we describe the initiation pattern of Wfs1 expression in mouse forebrain using mRNA in situ hybridization and compare it with Synaptophysin (Syp1), a gene encoding synaptic vesicle protein widely used as neuronal differentiation marker. We show that the expression of Wfs1 starts during late embryonic development in the dorsal striatum and amygdala, then expands broadly at birth, possessing several transitory regions during maturation. Syp1 expression precedes Wfs1 and it is remarkably upregulated during the period of Wfs1 expression initiation and maturation, suggesting relationship between neural activation and Wfs1 expression. Using in situ hybridization and quantitative real-time PCR we show that UPR-related genes (Grp78, Grp94, and Chop) display dynamic expression in the perinatal brain when Wfs1 is initiated and their expression pattern is not altered in the brain lacking functional Wfs1., (Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
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28. Trib3 is developmentally and nutritionally regulated in the brain but is dispensable for spatial memory, fear conditioning and sensing of amino acid-imbalanced diet.
- Author
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Örd T, Innos J, Lilleväli K, Tekko T, Sütt S, Örd D, Kõks S, Vasar E, and Örd T
- Subjects
- Animals, Brain embryology, Conditioning, Classical, Diet, Gene Deletion, Gene Expression Regulation, Leucine metabolism, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Signal Transduction, Amino Acids metabolism, Brain metabolism, Cell Cycle Proteins metabolism, Fear, Spatial Memory
- Abstract
Tribbles homolog 3 (TRIB3) is a mammalian pseudokinase that is induced in neuronal cell cultures in response to cell death-inducing stresses, including neurotrophic factor deprivation. TRIB3 is an inhibitor of activating transcription factor 4 (ATF4), the central transcriptional regulator in the eukaryotic translation initiation factor 2α (eIF2α) phosphorylation pathway that is involved in the cellular stress response and behavioral processes. In this article, we study the expression of Trib3 in the mouse brain, characterize the brain morphology of mice with a genetic ablation of Trib3 and investigate whether Trib3 deficiency alters eIF2α-dependent cognitive abilities. Our data show that the consumption of a leucine-deficient diet induces Trib3 expression in the anterior piriform cortex, the brain region responsible for detecting essential amino acid intake imbalance. However, the aversive response to leucine-devoid diet does not differ in Trib3 knockout and wild type mice. Trib3 deletion also does not affect long-term spatial memory and reversal learning in the Morris water maze and auditory or contextual fear conditioning. During embryonic development, Trib3 expression increases in the brain and persists in the early postnatal stadium. Neuroanatomical characterization of mice lacking Trib3 revealed enlarged lateral ventricles. Thus, although the absence of Trib3 does not alter the eIF2α pathway-dependent cognitive functions of several areas of the brain, including the hippocampus, amygdala and anterior piriform cortex, Trib3 may serve a role in other central nervous system processes and molecular pathways.
- Published
- 2014
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29. Effect of chronic valproic Acid treatment on hepatic gene expression profile in wfs1 knockout mouse.
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Punapart M, Eltermaa M, Oflijan J, Sütt S, Must A, Kõks S, Schalkwyk LC, Fernandes C, Vasar E, Soomets U, and Terasmaa A
- Abstract
Valproic acid (VPA) is a widely used anticonvulsant and mood-stabilizing drug whose use is often associated with drug-induced weight gain. Treatment with VPA has been shown to upregulate Wfs1 expression in vitro. Aim of the present study was to compare the effect of chronic VPA treatment in wild type (WT) and Wfs1 knockout (KO) mice on hepatic gene expression profile. Wild type, Wfs1 heterozygous, and homozygous mice were treated with VPA for three months (300 mg/kg i.p. daily) and gene expression profiles in liver were evaluated using Affymetrix Mouse GeneChip 1.0 ST array. We identified 42 genes affected by Wfs1 genotype, 10 genes regulated by VPA treatment, and 9 genes whose regulation by VPA was dependent on genotype. Among the genes that were regulated differentially by VPA depending on genotype was peroxisome proliferator-activated receptor delta (Ppard), whose expression was upregulated in response to VPA treatment in WT, but not in Wfs1 KO mice. Thus, regulation of Ppard by VPA is dependent on Wfs1 genotype.
- Published
- 2014
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30. Wfs1-deficient mice display altered function of serotonergic system and increased behavioral response to antidepressants.
- Author
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Visnapuu T, Raud S, Loomets M, Reimets R, Sütt S, Luuk H, Plaas M, Kõks S, Volke V, Alttoa A, Harro J, and Vasar E
- Abstract
It has been shown that mutations in the WFS1 gene make humans more susceptible to mood disorders. Besides that, mood disorders are associated with alterations in the activity of serotonergic and noradrenergic systems. Therefore, in this study, the effects of imipramine, an inhibitor of serotonin (5-HT) and noradrenaline (NA) reuptake, and paroxetine, a selective inhibitor of 5-HT reuptake, were studied in tests of behavioral despair. The tail suspension test (TST) and forced swimming test (FST) were performed in Wfs1-deficient mice. Simultaneously, gene expression and monoamine metabolism studies were conducted to evaluate changes in 5-HT- and NA-ergic systems of Wfs1-deficient mice. The basal immobility time of Wfs1-deficient mice in TST and FST did not differ from that of their wild-type littermates. However, a significant reduction of immobility time in response to lower doses of imipramine and paroxetine was observed in homozygous Wfs1-deficient mice, but not in their wild-type littermates. In gene expression studies, the levels of 5-HT transporter (SERT) were significantly reduced in the pons of homozygous animals. Monoamine metabolism was assayed separately in the dorsal and ventral striatum of naive mice and mice exposed for 30 min to brightly lit motility boxes. We found that this aversive challenge caused a significant increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT, in the ventral and dorsal striatum of wild-type mice, but not in their homozygous littermates. Taken together, the blunted 5-HT metabolism and reduced levels of SERT are a likely reason for the elevated sensitivity of these mice to the action of imipramine and paroxetine. These changes in the pharmacological and neurochemical phenotype of Wfs1-deficient mice may help to explain the increased susceptibility of Wolfram syndrome patients to depressive states.
- Published
- 2013
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31. Evidence for impaired function of dopaminergic system in Wfs1-deficient mice.
- Author
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Visnapuu T, Plaas M, Reimets R, Raud S, Terasmaa A, Kõks S, Sütt S, Luuk H, Hundahl CA, Eskla KL, Altpere A, Alttoa A, Harro J, and Vasar E
- Subjects
- Amphetamine pharmacology, Animals, Apomorphine pharmacology, Central Nervous System Sensitization physiology, Corpus Striatum drug effects, Corpus Striatum metabolism, Dopamine metabolism, Dopamine Agents pharmacology, Dopamine Plasma Membrane Transport Proteins metabolism, Dopaminergic Neurons drug effects, Female, Gene Expression drug effects, Male, Mice, Mice, Congenic, Motor Activity drug effects, Motor Activity physiology, Receptors, Dopamine D2 metabolism, Corpus Striatum physiology, Dopaminergic Neurons physiology, Membrane Proteins deficiency, Membrane Proteins physiology
- Abstract
Immunohistological studies suggest abundant expression of Wfs1 protein in neurons and nerve fibers that lie in the vicinity of dopaminergic (DA-ergic) fibers and neurons. Therefore, we sought to characterize the function of DA-ergic system in Wfs1-deficient mice. In wild-type mice, amphetamine, an indirect agonist of DA, caused significant hyperlocomotion and increase in tissue DA levels in the dorsal and ventral striatum. Both effects of amphetamine were significantly blunted in homozygous Wfs1-deficient mice. Motor stimulation caused by apomorphine, a direct DA receptor agonist, was somewhat stronger in Wfs1-deficient mice compared to their wild-type littermates. However, apomorphine caused a similar reduction in levels of DA metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) in the dorsal and ventral striatum in all genotypes. Behavioral sensitization to repeated treatment with amphetamine (2.5 mg/kg) was observed in wild-type, but not in Wfs1-deficient mice. The expression of DA transporter gene (Dat) mRNA was significantly lower in the midbrain of male and female homozygous mice compared to wild-type littermates. Altogether, the blunted effects of amphetamine and the reduced gene expression of DA transporter are probably indicative of an impaired functioning of the DA-ergic system in Wfs1-deficient mice., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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32. Lsamp⁻/⁻ mice display lower sensitivity to amphetamine and have elevated 5-HT turnover.
- Author
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Innos J, Leidmaa E, Philips MA, Sütt S, Alttoa A, Harro J, Kõks S, and Vasar E
- Subjects
- Animals, Conditioning, Psychological, Corpus Striatum metabolism, Dopamine Plasma Membrane Transport Proteins metabolism, Drug Resistance genetics, GPI-Linked Proteins genetics, Gene Expression, Mental Disorders psychology, Mesencephalon metabolism, Mice, Knockout, Motor Activity, Reward, Social Behavior Disorders psychology, Temporal Lobe metabolism, Amphetamine pharmacology, Cell Adhesion Molecules, Neuronal genetics, Disease Models, Animal, Mental Disorders genetics, Mice, Serotonin metabolism, Social Behavior Disorders genetics
- Abstract
In mice, the limbic system-associated membrane protein (Lsamp) gene has been implicated in locomotion, anxiety, fear reaction, learning, social behaviour and adaptation. Human data links the LSAMP gene to several psychiatric disorders and completed suicide. Here, we investigated changes in major monoamine systems in mice lacking the Lsamp gene. First, the locomotor and rewarding effects of amphetamine were studied in Lsamp(-/-) mice and Lsamp(+/+) mice. Second, monoamine levels in major brain regions in response to saline and amphetamine injections were measured and, third, the expression levels of dopamine system-related genes in the brain were studied in these mice. Lsamp(-/-) mice displayed lower sensitivity to amphetamine in the motility box. Likewise, in the place preference test, the rewarding effect of amphetamine was absent in Lsamp(-/-) mice. In all brain regions studied, Lsamp(-/-) mice displayed lower serotonin (5-HT) baseline levels, but a greater 5-HT turnover rate, and amphetamine increased the level of 5-HT and lowered 5-HT turnover to a greater extent in Lsamp(-/-) mice. Finally, Lsamp(-/-) mice had lower level of dopamine transporter (DAT) mRNA in the mesencephalon. In conclusion, Lsamp-deficiency leads to increased endogenous 5-HT-ergic tone and enhanced 5-HT release in response to amphetamine. Elevated 5-HT function and reduced activity of DAT are the probable reasons for the blunted effects of amphetamine in these mice. Lsamp(-/-) mice are a promising model to study the neurobiological mechanisms of deviant social behaviour and adaptation impairment observed in many psychiatric disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2013
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33. Porcine proliferative enteropathy in Estonian pig herds: histopathology and detection of Lawsonia intracellularis by PCR.
- Author
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Järveots T, Saar T, Lepp E, Suuroja T, Lindjärv R, Nathues H, Sütt S, and Põdersoo D
- Subjects
- Animals, Desulfovibrionaceae Infections epidemiology, Desulfovibrionaceae Infections pathology, Estonia epidemiology, Female, Ileal Diseases epidemiology, Ileal Diseases pathology, Ileum microbiology, Ileum ultrastructure, Intestines pathology, Lawsonia Bacteria genetics, Male, Microscopy, Electron, Transmission veterinary, Polymerase Chain Reaction veterinary, Swine, Swine Diseases microbiology, Swine Diseases pathology, Desulfovibrionaceae Infections veterinary, Ileal Diseases veterinary, Ileum pathology, Lawsonia Bacteria isolation & purification, Swine Diseases epidemiology
- Abstract
Lawsonia intracellularis is the causative agent of proliferative enteritis in pigs (PPE). This bacterium is difficult to culture from clinical samples and antemortem demonstration is therefore usually performed by PCR on faecal samples. The aim of this study was to elucidate the frequency of L. intracellularis infection in pig herds in Estonia using PCR, histopathological methods and electronmicroscopical studies. The frequency of demonstration of L. intracellularis was highest in 9-12 weeks old pigs (68.1%). It was more frequent in growing pigs with enteritis on small farms where the system of "all-in all-out" was not practiced and where standards of hygiene were poor. Gross and histopathological studies demonstrated that characteristic macroscopic changes associated with PPE were localised to the distal jejunum and ileum.Thickened longitudinal and circumferential folds occurred in the mucosa of the affected regions of the bowel. Samples from pigs aged 4 to 20 weeks exhibited the most intensive inflammatory changes. The distal part of the jejunum, ileum and the upper third of proximal colon and cecum wall were visibly thickened with reduced luminal diameter. Hyperplasia of lymphoid tissue and, in many cases, pseudomembranous or fibrinous inflammation was found. L. intracellularis was detected in 56 young pigs using histopathological methods. Additionally, in 8 of these pigs intracellular bacteria were demonstrated in ilial epithelial cells by transmission electronmicroscopical (TEM) investigation. On the basis of these TEM investigations it was concluded that L. intracellularis causes disturbances of normal growth, differentiation and apoptosis of the epithelial cells of ileum.
- Published
- 2011
34. Relation of exploratory behaviour to plasma corticosterone and Wfs1 gene expression in Wistar rats.
- Author
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Sütt S, Raud S, Abramov U, Innos J, Luuk H, Plaas M, Kõks S, Zilmer K, Mahlapuu R, Zilmer M, and Vasar E
- Subjects
- Analysis of Variance, Animals, Anxiety blood, Anxiety genetics, Anxiety metabolism, Behavior, Animal physiology, Calmodulin-Binding Proteins metabolism, Gene Expression, Male, Membrane Proteins metabolism, Oxidative Stress physiology, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Brain metabolism, Calmodulin-Binding Proteins genetics, Corticosterone blood, Exploratory Behavior physiology, Membrane Proteins genetics
- Abstract
Male Wistar rats exhibit significant variations in exploratory behaviour in the elevated plus-maze (EPM) model of anxiety. We have now investigated the relation between exploratory behaviour and levels of corticosterone and systemic oxidative stress. Also, the expression levels of endocannabinoid-related and wolframin (Wfs1) genes were measured in the forebrain structures. The rats were divided into high, intermediate and low exploratory activity groups. Exposure to EPM significantly elevated the serum levels of corticosterone in all rats, but especially in the high exploratory group. Oxidative stress indices and expression of endocannabinoid-related genes were not significantly affected by exposure to EPM. Wfs1 mRNA level was highly dependent on exploratory behaviour of animals. In low exploratory activity rats, Wfs1 gene expression was reduced in the temporal lobe, whereas in high exploratory activity group it was reduced in the mesolimbic area and hippocampus. Altogether, present study indicates that in high exploratory activity rats, the activation of brain areas related to novelty seeking is apparent, whereas in low exploratory activity group the brain structures linked to anxiety are activated.
- Published
- 2010
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35. Relation between increased anxiety and reduced expression of alpha1 and alpha2 subunits of GABA(A) receptors in Wfs1-deficient mice.
- Author
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Raud S, Sütt S, Luuk H, Plaas M, Innos J, Kõks S, and Vasar E
- Subjects
- Animals, Disease Models, Animal, Exploratory Behavior physiology, Female, Glutamate Decarboxylase genetics, Glutamate Decarboxylase metabolism, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Prosencephalon metabolism, Protein Subunits genetics, Protein Subunits metabolism, Receptors, GABA-A genetics, Anxiety genetics, Down-Regulation genetics, Membrane Proteins deficiency, Receptors, GABA-A metabolism
- Abstract
Mutations in the coding region of the WFS1 gene cause Wolfram syndrome, a rare multisystem neurodegenerative disorder of autosomal recessive inheritance. In clinical studies a relation between mutations in the Wfs1 gene and increased susceptibility for mood disorders has been established. According to our previous studies, mice lacking Wfs1 gene displayed increased anxiety in stressful environment. As the GABA-ergic system plays a significant role in the regulation of anxiety, we analyzed the expression of GABA-related genes in the forebrain structures of wild-type and Wfs1-deficient mice. Experimentally naïve Wfs1-deficient animals displayed a significant down-regulation of alpha1 (Gabra1) and alpha2 (Gabra2) subunits of GABA(A) receptors in the temporal lobe and frontal cortex. Exposure of wild-type mice to the elevated plus-maze decreased levels of Gabra1 and Gabra2 genes in the temporal lobe. A similar tendency was also established in the frontal cortex of wild-type animals exposed to behavioral test. In Wfs1-deficient mice the elevated plus-maze exposure did not induce further changes in the expression of Gabra1 and Gabra2 genes. By contrast, the expression of Gad1 and Gad2 genes, enzymes responsible for the synthesis of GABA, was not significantly affected by the exposure of mice to the elevated plus-maze or by the invalidation of Wfs1 gene. Altogether, the present study demonstrates that increased anxiety of Wfs1-deficient mice is probably linked to reduced expression of Gabra1 and Gabra2 genes in the frontal cortex and temporal lobe.
- Published
- 2009
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36. Wfs1-deficient mice display impaired behavioural adaptation in stressful environment.
- Author
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Luuk H, Plaas M, Raud S, Innos J, Sütt S, Lasner H, Abramov U, Kurrikoff K, Kõks S, and Vasar E
- Subjects
- Amphetamine administration & dosage, Amphetamine pharmacology, Animals, Apomorphine administration & dosage, Apomorphine pharmacology, Central Nervous System Stimulants administration & dosage, Central Nervous System Stimulants pharmacology, Corticosterone blood, Diazepam administration & dosage, Diazepam pharmacology, Dopamine Agonists administration & dosage, Dopamine Agonists pharmacology, Exploratory Behavior drug effects, Fear psychology, Female, GABA Modulators administration & dosage, GABA Modulators pharmacology, Genotype, Maze Learning drug effects, Membrane Proteins genetics, Memory drug effects, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity drug effects, Polymerase Chain Reaction, Adaptation, Psychological, Anxiety psychology, Conditioning, Classical, Membrane Proteins deficiency, Membrane Proteins physiology, Stress, Physiological
- Abstract
Wfs1-deficient mice were generated by disrupting the 8th exon of Wfs1 gene. Reproduction rates of homozygous Wfs1-deficient mice were slightly below the expected values, they displayed intolerance to glucose and overall lower body weight. The present behavioural study was performed in female Wfs1-deficient mice due to their milder metabolic disturbances. Non-fasting blood glucose levels did not differ between homozygous Wfs1-deficient mice and wild-type littermates. While there was no difference in baseline plasma corticosterone, exposure to stress induced a nearly three-fold elevation of corticosterone in Wfs1-deficient mice in relation to wild-type littermates. Wfs1-deficient mice did not display obvious shortcomings in sensory and motor functioning as exemplified by intact responses in conditioned learning paradigms and rota-rod test. Locomotor activity of Wfs1-deficient mice was significantly lower only in brightly lit environment. Short-term isolation had a significant anxiogenic-like effect on the behaviour of Wfs1-deficient mice in dark/light exploration test. Lower exploratory activity of Wfs1-deficient mice in the plus-maze was antagonised by pre-treatment with diazepam (1 mg/kg), a GABA(A) receptor agonist. Wfs1-deficient mice displayed increased anxiety-like behaviour in hyponeophagia test. The locomotor stimulatory effects of amphetamine (2.5-7.5 mg/kg) and apomorphine (3 mg/kg) were significantly attenuated and facilitated, respectively, in Wfs1-deficient mice. There were no differences between Wfs1-deficient mice and wild-types in forced swimming behaviour and conditioned fear responses. Subtle impairments in reversal learning were apparent in Wfs1-deficient mice in the Morris water maze. Altogether, the present study demonstrates impaired behavioural adaptation of Wfs1-deficient mice in stress-inducing situations. It is likely that Wfs1 protein plays a major role in the behavioural adaptation mechanisms to novel and stressful environments.
- Published
- 2009
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37. Cat odour-induced anxiety--a study of the involvement of the endocannabinoid system.
- Author
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Sütt S, Raud S, Areda T, Reimets A, Kõks S, and Vasar E
- Subjects
- Amidohydrolases biosynthesis, Amidohydrolases genetics, Amygdala enzymology, Amygdala metabolism, Animals, Cats, DNA, Complementary biosynthesis, DNA, Complementary isolation & purification, Exploratory Behavior drug effects, Limbic System physiology, Male, Motor Activity drug effects, Periaqueductal Gray enzymology, Periaqueductal Gray metabolism, Phospholipase D biosynthesis, Piperidines pharmacology, Predatory Behavior, Pyrazoles pharmacology, RNA biosynthesis, RNA isolation & purification, Rats, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Rimonabant, Anxiety psychology, Cannabinoid Receptor Modulators physiology, Endocannabinoids, Odorants
- Abstract
Rationale: Recent evidence suggests the involvement of the endocannabinoid (EC) system in the regulation of anxiety., Objectives: The aim of present work was to study the role of the EC system in cat odour-induced anxiety in rats. Materials and methods Male Wistar rats were exposed to cat odour in home and motility cages. Exposure of rats to elevated zero-maze was used to determine changes in anxiety. Effect of rimonabant (0.3-3 mg/kg), antagonist of CB1 receptors, was studied on cat odour-induced alterations in exploratory behaviour. Real-time PCR was used to determine gene expression levels of EC-related genes in the brain., Results: Anxiogenic-like action of cat odour was evident in the elevated zero-maze. Cat odour increased the expression of FAAH, the enzyme responsible for the degradation of anandamide, in the mesolimbic area. By contrast, in the amygdala and periaqueductal grey (PAG) levels of NAPE-PLD, the enzyme related to the synthesis of anandamide, and FAAH were remarkably decreased. Cat odour also decreased the expression of enzymes related to metabolism of 2-archidonoyl-glycerol in the amygdala and PAG. Pre-treatment of rats with rimonabant (0.3-3 mg/kg) reduced the exploratory behaviour of rats, but did not affect cat odour-induced changes., Conclusion: Exposure to cat odour induces anxiogenic-like effect on the behaviour in rats. Cat odour also causes moderate increase in expression of EC-related genes in the mesolimbic area, whereas significant down-regulation is established in the amygdala and PAG. Relation of predator odour-induced anxiety to the inhibition of the EC system in the amygdala and PAG is supported by behavioural studies where blockade of CB1 receptors by rimonabant induces anxiogenic-like action.
- Published
- 2008
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38. Cat odor exposure induces distinct changes in the exploratory behavior and Wfs1 gene expression in C57Bl/6 and 129Sv mice.
- Author
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Raud S, Sütt S, Plaas M, Luuk H, Innos J, Philips MA, Kõks S, and Vasar E
- Subjects
- Analysis of Variance, Animals, Anxiety chemically induced, Anxiety physiopathology, Behavior, Animal, Brain anatomy & histology, Female, Membrane Proteins genetics, Mice, Mice, Inbred Strains, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Species Specificity, Brain metabolism, Cats, Exploratory Behavior physiology, Gene Expression Regulation physiology, Membrane Proteins metabolism, Odorants
- Abstract
129Sv and C57Bl/6 (Bl6) strains are two most widely used inbred mice strains for generation of transgenic animals. The present study confirms the existence of substantial differences in the behavior of these two mice strains. The exploratory behavior of Bl6 mice in a novel environment was significantly higher compared to 129Sv mice. The exposure of mice to cat odor-induced an anxiety-like state in Bl6, but not in 129Sv mice. The levels of Wfs1 gene expression did not differ in the prefrontal cortex, mesolimbic area and temporal lobe of experimentally naive Bl6 and 129Sv mice. However, after cat odor exposure the expression of Wfs1 gene was significantly lower in the mesolimbic area and temporal lobe of Bl6 mice compared to 129Sv strain. Dynamics of Wfs1 gene expression and exploratory behavior suggest that the down-regulation of Wfs1 gene in Bl6 mice might be related to the increased anxiety. Further studies are needed to test the robustness and possible causal relationship of this finding.
- Published
- 2007
- Full Text
- View/download PDF
39. Screen for genes in periaqueductal grey of male Wistar rats related to reduced exploratory activity in the elevated plus-maze.
- Author
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Nelovkov A, Sütt S, Raud S, Vasar E, and Kõks S
- Subjects
- Animals, Anxiety etiology, Corticosterone blood, DNA, Complementary analysis, Gene Expression Profiling methods, Gene Expression Regulation physiology, Gene Library, Male, Nerve Tissue Proteins genetics, Oligonucleotide Array Sequence Analysis, RNA, Messenger analysis, Rats, Rats, Wistar, Stress, Psychological complications, Stress, Psychological metabolism, Anxiety metabolism, Exploratory Behavior physiology, Maze Learning physiology, Nerve Tissue Proteins metabolism, Periaqueductal Gray metabolism
- Abstract
Aim of a present study was to find genes in the periaqueductal grey (PAG) related to the exploratory behavior in rats. Male Wistar rats were divided according to their exploratory behavior in the elevated plus-maze model of anxiety into two groups: high (non-anxious) and low (anxious) exploratory activity. Differential expression of genes was analyzed using the cDNA representational difference analysis (RDA). Q-RT-PCR was used to confirm most prominent changes and functional annotation of the identified genes was performed to establish pathways related to exploratory behavior of rats. We found different genetic activation related to the exploratory activity of rats. Rats with low exploratory activity showed increase in the intracellular signal transduction and in GABA, vasopressin and adrenergic receptor activities. Functional annotation confirmed significant induction of cAMP system and GTPases in rats with anxious-type behavior. On the other hand, rats with high exploratory activity in the elevated plus-maze (non-anxious type of behavior) had increased activity of genes forming "behavioral fear response" system. These changes were specific to PAG, because they were not found in the cerebellum. In addition, plasma corticosterone levels were significantly higher in rats with non-anxious behavior compared to anxious behavior. Our results show that non-anxious behavior is related to activation of "fear response system" and more intense activation of HPA axis. Possibly it means that this system helps animals to cope with the threatening circumstances. More detailed analysis of this potential "fear response system" is necessary in the further studies for understanding its role in the regulation of emotional behavior.
- Published
- 2007
- Full Text
- View/download PDF
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