Berton O, McClung CA, DiLeone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ.
Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science.
2006 Feb 10
Comments on News and Primary Papers
Comment by: NN Kudryavtseva
Submitted 23 February 2006
Posted 23 February 2006
Berton and colleagues show very impressive data of molecular studies demonstrating numerous changes of gene expression in brain under repeated social defeats. However, the behavioral or pharmacological data that the authors use to support the development of depression in socially defeated mice may be interpreted otherwise.
The authors used decreases in the level of social communication (they called it avoidance-approach behavior) in defeated losers as parameters of depression. We repeatedly noted in our experiments on the social model of depression induced by social confrontations in mice of the C57BL/6J strain (Kudryavtseva et al., 1991) that even one or two social defeats lead to a decrease of communication in mice. Thus, avoidance behavior cannot be used as a specific parameter of depression; rather, it may represent anxiety. However, our experiments demonstrated that longer experience of defeats over 20-30 days (but not 10 days, as used by Berton et al.) in male mice produces development of a depression-like state (anxious depression): similarities of symptoms, etiological factors (social unavoidable emotional stress, permanent anxiety), sensitivity to chronic antidepressants and anxiolytics (imipramine, tianeptine, citalopram, fluoxetine, buspirone, etc.), as well as brain neurochemistry changes (serotonergic and dopaminergic systems) (Kudryavtseva et al., 1991; for reviews see Kudryavtseva, Avgustinovich, 1998; Avgustinovich et al., 2004).
In our molecular studies, we also demonstrated changes of gene expression in the brains of male mice after daily agonistic interactions. Three experimental groups were compared: the losers with repeated experience of social defeats; winners with repeated aggression accompanied by social victories; and controls (very important—the same strain). In has been shown that MAOA and SERT mRNA levels in the raphe nuclei of the losers were higher than in the controls and winners. TH and DAT gene expression in the ventral tegmental area was higher and κ opioid receptor gene expression was lower in the winners in comparison with the losers and controls (see Filipenko et al., 2001; 2002; Goloshchapov et al., 2005; reviewed in Kudryavtseva et al., 2004). Thus, there are different specific changes in gene expression in different brain areas in male mice with opposite social behaviors—winners and losers.
As for BDNF, there is an emerging body of data suggesting that different mood disorders are associated with changed BDNF. I think that changes of BDNF gene expression in the losers may be nonspecific for depression state. Expression of the BDNF gene in the winners should be investigated to confirm or reject this idea.
Again, Berton et al. (2006) have demonstrated very impressive data. Taking into consideration these data and our molecular studies, it may be suggested that the sensory contact paradigm (sensory contact model) may be used for the study of association between agonistic behavior and gene expression. We called this scientific direction “From behavior to gene” (reviewed in Kudryavtseva et al., 2004), as an addition to the traditional “From gene to behavior.”
Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain.
Pharmacol Biochem Behav. 1991 Feb;38(2):315-20.
Kudryavtseva NN, Avgustinovich DF. (1998) Behavioral and physiological markers of experimental depression induced by social conflicts (DISC). Aggress Behav. 24:271-286.
Filipenko ML, Alekseyenko OV, Beilina AG, Kamynina TP, Kudryavtseva NN. Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience.
Brain Res Mol Brain Res. 2001 Nov 30;96(1-2):77-81.
Filipenko ML, Beilina AG, Alekseyenko OV, Dolgov VV, Kudryavtseva NN. Repeated experience of social defeats increases serotonin transporter and monoamine oxidase A mRNA levels in raphe nuclei of male mice.
Neurosci Lett. 2002 Mar 15;321(1-2):25-8.
Kudryavtseva et al. (2004) Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: From behavior to gene. Genetika, 40(6):732-748.
Avgustinovich DF, Alekseenko OV, Bakshtanovskaia IV, Koriakina LA, Lipina TV, Tenditnik MV, Bondar' NP, Kovalenko IL, Kudriavtseva NN. [Dynamic changes of brain serotonergic and dopaminergic activities during development of anxious depression: experimental study]
Usp Fiziol Nauk. 2004 Oct-Dec;35(4):19-40. Review. Russian.
Goloshchapov AV, Filipenko ML, Bondar NP, Kudryavtseva NN, Van Ree JM. Decrease of kappa-opioid receptor mRNA level in ventral tegmental area of male mice after repeated experience of aggression.
Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):290-2. Epub 2005 Jan 6.
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