The social avoidance that normally develops when a mouse repeatedly experiences defeat by a dominant animal disappears when it lacks a gene for a memory molecule in a brain circuit for social learning, scientists funded by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) have discovered. Mice engineered to lack this memory molecule continued to welcome strangers in spite of repeated social defeat. Their unaltered peers subjected to the same hard knocks became confirmed loners — unless the researchers treated them with antidepressants.
“For both mice and men, social status is important; for mice, losing to a dominant mouse usually means that they avoid the dominant and they avoid social situations,” explained NIMH director Dr. Thomas Insel. “These new findings add to a growing literature on the molecular basis of social behavior, helping us to know where as well as how social information is encoded in the brain.”
The results reveal neural mechanisms by which social learning is shaped by psychosocial experience and how antidepressants act in this particular brain circuit. They also suggest new strategies for treating mood disorders such as depression, social phobia and post-traumatic stress disorder, in which social withdrawal is a prominent symptom. Drs. Olivier Berton and Eric Nestler, University of Texas Southwestern Medical Center (UTSMC), and colleagues, report on their study in the February 10, 2005 issue of Science.
Coursing from a hub in the center of the brain (ventral tegmental area), the relevant circuit mediates responses to emotionally important environmental stimuli via release of dopamine.
Activity of this neurotransmitter is regulated in the circuit by brain derived neurotrophic factor (BDNF), which is known to play a key role in memory (http://www.nimh.nih.gov/Press/prbdnf.cfm). Berton, Nestler and colleagues suspected that BDNF plays a similarly pivotal role in social learning.
To find out, they first subjected mice to a different dominant mouse daily for 10 days. Even 4 weeks later, the “socially defeated” animals vigorously avoided former aggressors or unfamiliar mice. BDNF increased markedly in their social memory circuit. Yet, the social avoidance behavior was reversible by giving the animals antidepressants.
Next, borrowing a page from gene therapy, the researchers injected mice with a kind of molecular magic bullet (using transgenic techniques and a virus) that selectively turned off BDNF expression in the social learning circuit. This exerted an antidepressant-like effect; the mice were spared from developing social avoidance behavior following repeated social defeat.
“Without BDNF in the circuit, an animal can’t learn that a social stimulus is threatening and respond appropriately,” explained Nestler.
He and his colleagues also discovered that social defeat triggered an upheaval in gene expression in the target area of the circuit, the nucleus accumbens, located deep in the front part of the brain — 309 genes increased in expression while 17 decreased. This pattern persisted even 4 weeks later, with 127 genes still increased and 9 decreased, paralleling the changes seen in social behavior. The researchers suggest that this alteration in gene expression encodes the motivational changes induced by aggression. When BDNF was deleted, or the animals were given antidepressants, most of the changes in gene expression reversed.
Identification of the products of the genes turned on and off by social defeat, BDNF and antidepressants revealed the workings of the molecular pathways involved in dopamine regulation of social motivational processes. The results suggest that chronic treatment with antidepressants restores social approach behaviors partly by interfering with the cascade of activity triggered by BDNF as the organism adapts to experience.
The researchers say the study “suggests new directions for antidepressant drug discovery.”
Also participating in the study were: Colleen McClung, Vaishnav Krishnan, William Renthal, Scott Russo, Danielle Graham, Nadia Tsankova, Lisa Monteggia, David Self, UTSMC; Ralph Dileone, Yale University; Carlos Bolanos, Florida State University; Maribel Rios, Tufts University.
From NIH
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 or social withdrawal) in defeated losers as parameters of depression. We repeatedly noted in our experiments (Kudryavtseva, 2003, review) 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 social 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 ? 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 Kudriavtseva 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. Obviously, it is a great success. Taking into consideration these data and our molecular studies, it may be suggested that the sensory contact paradigm (sensory contact model, Kudryavtseva, 1991) 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 Kudriavtseva et al., 2004), as an addition to the traditional “From gene to behavior.â€
References:
Kudryavtseva NN. (1991) The sensory contact model for the study of aggressive and submissive behaviors in male mice. Aggres Behav 17(5):285-291.
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.
Kudriavtseva NN, Filipenko ML, Bakshtanovskaia IV, Avgustinovich DF, Alekseenko OV, Beilina AG. Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: From behavior to gene. Genetika, 2004, 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.
Kudryavtseva NN Use of the “partition” test in behavioral and pharmacological experiments. Neurosci Behav Physiol. 2003 Jun;33(5):461-71. Review.
Kudryavtseva NN
also Kuriavtseva in PubMed)
The headline for this article sounds like a back-formed acronym for something. Too bad it doesn’t spell anything interesting.