Down-regulation of serotonergic genes expression in the raphe nuclei of midbrain under chronic social defeat stress in male mice

Background: 
There is ample experimental evidence supporting the hypothesis that the brain serotonergic system is involved in the control of chronic social defeat stress (CSDS), depression and anxiety. The study aimed to analyze mRNA levels of the serotonergic genes in the raphe nuclei of the midbrain that may be associated with chronic social defeats consistently shown by male mice in special experimental settings. 

Methodology/Principal Findings: 
The serotonergic genes were the Tph2, Sert, Maoa and Htr1a. The Bdnf, Creb, Cphn, Gapdh, Hprt, B2M, 18S and Actb genes were also studied. The experimental groups were composed of male mice with experience of defeats in 21 daily encounters and male mice with the same track record of defeats followed by a no-defeat period without agonistic interactions (relative rest for 14 days). It has been shown that mRNA levels of the Tph2, Maoa, Sert, Htr1a, Bdnf and Creb genes in the raphe nuclei of defeated mice are decreased as compared with the controls. Under CSDS the Cphn, Gapdh, Hprt, B2M, 18S, Actb genes are also down-regulated. The expression of the serotonergic genes as well as the Cphn and Creb genes is not restored to the control level after the 2 weeks of relative rest. mRNA levels of other genes are not recovered to the control levels, although some up-regulation was observed in rested losers. Significant positive correlations were found between the total time of avoidance behavior demonstrated by the 21-day defeaters in agonistic interactions and Sert, Maoa, Bdnf, Gapdh and 18S mRNA levels. 

Conclusions: 
CSDS experience inducing the development of mixed anxious/depression-like state in male mice down-regulates the serotonergic genes expression associated with the synthesis, inactivation and reception of serotonin. The Bdnf and Creb genes as well as the cell and metabolic Cphn, Gapdh, Hprt, B2M, Actb and 18S genes in the midbrain raphe nuclei are also down-regulated under CSDS. Period of relative rest is not enough for most genes to recover expression to the control levels

Decrease of vanillin sucrose intake by victorious and defeated mice: development of anhedonia?

Hedonic reactions to various rewards play a key role in various forms of motivated behavior. The influence of repeated experience of social victories or defeats in daily agonistic interactions between male mice on voluntary consumption of vanillin sucrose solution used as hedonic reinforcer was studied. Intake of vanillin sucrose solution was shown to decrease in the winners and losers exposed to social confrontations as compared with the controls. Three days of deprivation failed to restore the intake of vanillin sucrose solution to the control level in the losers and did so in the winners. The results obtained imply that similar reaction of animals to a hedonic non-drug reinforcer may have different motivational origin depending on positive or negative social experience

Molecular implications of prolonged aggression experience: Th, Dat1, Snca and Bdnf gene expression in the ventral tegmental area of the victorious male mice

Th, Dat1, Snca and Bdnf were the genes whose mRNA levels in the ventral tegmental area of the midbrain were measured in male mice that were victorious in 20 daily agonistic interactions and in a group of such victorious mice that had later not been allowed to fight for 14 days. This experiment demonstrated increased Th, Dat1 and Snca but not Bdnf mRNA levels in the former group as compared to the controls. In the latter group, the expression of the Th and Dat1 genes was still enhanced, while the level of Snca mRNA did not differ from that in the controls. These findings suggest that positive fighting experience enhances the expression of the genes concerned with dopaminergic systems and this enhanced expression is preserved for a long time afterwards. Significant positive correlations were found between the level of aggression and Th and Snca mRNA levels in the winners

Snca and Bdnf gene expression in the VTA and raphe nuclei of midbrain in chronically victorious and defeated male mice

The study aimed to analyze the mRNA levels of Snca and Bdnf genes in the ventral tegmental area (VTA) and raphe nuclei of the midbrain in male mice that had each won or defeated 20 encounters in daily agonistic interactions. Groups of animals that had the same winning and losing track record followed by a no-fight period for 14 days were also studied. Snca mRNA levels were increased in the raphe nuclei in the losers and in the VTA of the winners. After fighting deprivation Snca mRNA levels were decreased to the control level in both groups. Snca mRNA levels were similar to the control level in the VTA of the losers and in the raphe nuclei of the winners. However Snca gene expression was increased in these areas after no-fight period in the winners and losers in comparison with respective mRNA levels in the undeprived animals. Significant positive correlations were found between the mRNA levels of Snca and Bdnf genes in the raphe nuclei. It was concluded, that social experience affects Snca gene expression depending on brain areas and functional activity of monoaminergic systems in chronically victorious or defeated mice

Application of the Sensory Contact Model for Pharmacological Studies under Simulated Clinical Conditions

The sensory contact model allows forming different psycho-pathological states (anxious depression, catalepsy, social withdrawal, pathological aggression, cognition disturbances, anhedonia, addictive states etc.) produced by repeated agonistic interactions in male mice and investigating the therapeutic and preventive properties of any drug as well as its efficiency under simulated clinical conditions. This approach can be useful for a better understanding of the drugs’ action in different stages of disease development in individuals. It is suggested that this behavioral approach and pharmacological designs may be applied for the screening of novel psychotropic drugs. 
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Anhedonia in the shadow of chronic social defeat stress, or When the experimental context matters

One of the core symptoms of major depression in human is anhedonia. For that reason, one of the main requirements towards experimental depression models is that they be able to demonstrate anhedonia in animals, that have been exposed to stressful events, and other behavioral changes attributable to a depression-like state. However, the results presented in the literature are contradictory: sweet solution intake, which is considered as a parameter of hedonic/anhedonic behavior in animals, responds quite differently to stressful situations in that it is either unaffected or increased or decreased. Different experimental designs used for the study of anhedonia in male mice exposed to chronic social defeat stress were tried to understand the reasons for so contradictory responses. Anhedonia appears as an abrupt reduction in sweet solution consumption in stressed animals and by failure to attain recovery after deprivation. However, it was also demonstrated that sucrose solution intake and preference strongly depend on the experimental context; that the possible critical factor may be prior acquaintance with the hedonic stimulus – or the lack whereof. Analysis of literature data and ours allowed us to conclude that the lack of a significant decrease in sweet solution intake in stressed animals is no evidence of lack of depression. This decrease is evidence of anhedonia only provided other symptoms of depression are present. Hedonic consumable intake can be decreased over various motivations, conditions or diseases, in particular, a high level of anxiety or pathological aggression

Genetic variability and population structure of endangered Panax ginseng in the Russian Primorye

<p>Abstract</p> <p>Background</p> <p>The natural habitat of wild <it>P. ginseng </it>is currently found only in the Russian Primorye and the populations are extremely exhausted and require restoration. Analysis of the genetic diversity and population structure of an endangered species is a prerequisite for conservation. The present study aims to investigate the patterns and levels of genetic polymorphism and population structures of wild <it>P. ginseng </it>with the AFLP method to (1) estimate the level of genetic diversity in the <it>P. ginseng </it>populations in the Russian Primorsky Krai, (2) calculate the distribution of variability within a population and among populations and (3) examine the genetic relationship between the populations.</p> <p>Methods</p> <p>Genetic variability and population structure of ten <it>P. ginseng </it>populations were investigated with Amplified Fragment Length Polymorphism (AFLP) markers. The genetic relationships among <it>P. ginseng </it>plants and populations were delineated.</p> <p>Results</p> <p>The mean genetic variability within populations was high. The mean level of polymorphisms was 55.68% at the population level and 99.65% at the species level. The Shannon's index ranged between 0.1602 and 0.3222 with an average of 0.2626 at the population level and 0.3967 at the species level. The analysis of molecular variances (AMOVA) showed a significant population structure in <it>P. ginseng</it>. The partition of genetic diversity with AMOVA suggested that the majority of the genetic variation (64.5%) was within populations of <it>P. ginseng</it>. The inter-population variability was approximately 36% of the total variability. The genetic relationships among <it>P. ginseng </it>plants and populations were reconstructed by Minimum Spanning tree (MS-tree) on the basis of Euclidean distances with ARLEQUIN and NTSYS, respectively. The MS-trees suggest that the southern <it>Uss</it>, <it>Part </it>and <it>Nad </it>populations may have promoted <it>P. ginseng </it>distribution throughout the Russian Primorye.</p> <p>Conclusion</p> <p>The <it>P. ginseng </it>populations in the Russian Primorye are significant in genetic diversity. The high variability demonstrates that the current genetic resources of <it>P. ginseng </it>populations have not been exposed to depletion.</p