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BDNF In the Nucleus Accumbens—Too Much of a Good Thing?

15 February 2006. The brain-derived neurotrophic factor (BDNF) has drawn much attention from neuroscientists since Yves-Alain Barde and colleagues isolated it from pig's brain in 1982 (Barde et al., 1982). It enhances the survival and migration of neurons from the earliest stages of neural development and continues helping those cells form and maintain networks into adulthood (see, e.g., Egan et al., 2003). But according to an article in the February 10 issue of Science, in the more complex domain of behavior, too much BDNF can sometimes be a bad thing. Eric Nestler, Olivier Berton, and colleagues at the University of Texas Southwestern Medical Center in Dallas, with collaborators at several other institutions, report a new mouse model of social withdrawal that has an excess of BDNF in the mesolimbic dopamine system and can be reversed with antidepressant compounds. Beyond their relevance to depression, the findings may be broadly applicable to other psychiatric disorders that have elements of social withdrawal, including schizophrenia.

A range of studies, from postmortem neurochemical studies to work in experimental models, has linked dysregulation of BDNF to depression, although the guiding hypothesis until recently has been that a deficit of the growth factor contributes to the disorder. Indeed, studies in animal models of depression have suggested that boosting brain BDNF reverses behavioral deficits in these models, perhaps by stimulating neurogenesis (for review, see Hashimoto et al., 2004). However, Nestler and colleagues have previously reported an instance that goes against that grain. (Eisch et al., 2003). They reproduced the beneficial effects of antidepressants on an animal model of stress by blocking BDNF activity in the mesolimbic dopamine system—the projection from dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (N Ac) in the basal forebrain.

In their current article, first author Berton and colleagues describe the creation of a new model of social withdrawal, a common feature of depression. Mice who were repeated "losers" in interactions with other, aggressive mice developed an aversion to contact with any other mice, even ones that didn't look like the aggressors and were non-threatening. This effect was reversed with either of the antidepressants imipramine (Tofranil) or fluoxetine (Prozac), administered chronically for four weeks, but not acutely, after the stressful conditioning. "It's been hard for researchers to find a condition in animals that responds to chronic administration of antidepressants. This is one of the few tests in which animals respond to chronic antidepressants, rather than acute antidepressants, and that's a very important part of this study because antidepressants only work in humans after long-term administration," said Nestler, quoted in a press release from UT Southwestern.

The researchers next investigated whether the mesolimbic dopamine system was involved in the social withdrawal. They report that levels of cFos, an immediate early gene used as a marker of neuronal activity, increased significantly in both the dopamine neurons of VTA and their targets in the N Ac, and this effect could be detected even 4 weeks after the end of the 10-day conditioning period. Given their previous findings regarding BDNF's role in the mesolimbic dopamine system in a stress model, the authors investigated whether BDNF also plays a role in the social withdrawal model. They found that BDNF levels increased significantly in the N Ac of socially withdrawn mice following the social stress, and remained elevated for 4 weeks.

The scientists next looked at the effect of removing BDNF from VTA cells. Cells located in the N Ac make very little BDNF, and most BDNF in the nucleus appears to be secreted by the terminals of the VTA axons that enter the area. This extracellular BDNF in the N Ac has effects at dopaminergic synapses on both the pre- and postsynaptic membranes via its TrkB receptors. The researchers used a viral vector to knock down the BDNF produced in VTA neurons before exposing mice to the social defeat paradigm. About 75 percent of the dopaminergic neurons were successfully transfected, with virtually complete loss of BDNF mRNA in those cells. This manipulation eliminated the social withdrawal—despite repeated losses in interactions with aggressive mice, the "losers" still approached strange mice readily, supporting a critical role for BDNF in the conditioning of this social aversion.

An important methodologic concern is that the experimental manipulation could have perturbed the cells more broadly than just reducing BDNF, or may even have killed a subset of the dopaminergic neurons. However, the authors find that there was no reduction in tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis (used as a marker for dopamine), and there was no apparent loss of cells. This last consideration is important, since studies in the other region of dopaminergic neurons, the substantia nigra, have found that suppressing BDNF kills, rather than protects dopaminergic cells there. Berton and colleagues note that VTA cells are less vulnerable than their substantia nigra cousins (Hung and Lee, 1996), which are selectively, and mysteriously, decimated in Parkinson disease.

Hypothesizing that the lasting behavioral conditioning reflects changes in the genetic targets of BDNF's signaling cascade in N Ac neurons, Nestler's team next used DNA microarrays to examine gene transcription in the N Ac. They report that 309 genes were up-regulated just after the social defeat conditioning, with 127 still elevated 4 weeks later, whereas 17 were immediately down-regulated, of which nine remained elevated 4 weeks later. These transcriptional alterations were eliminated by the virally mediated knockdown of BDNF in VTA neurons. Antidepressants were able to eliminate most of the transcription changes that persisted after 4 weeks.

Among the alterations in gene expression, the authors noted particularly players in the BDNF signaling cascade, such as phosphatidylinositol 3-kinase (PI3K) and mitogen activated protein kinase (MAPK). "These microarray data thereby suggest that chronic treatment with antidepressant restores social approach behaviors partly by interfering with the activity of neurotrophic cascades that mediate experience-induced neuroadaptations in the mesolimbic dopamine pathway," write the authors.

The effect of these findings on drug treatment options for depression remains to be seen, given the different roles that BDNF appears to play in different brain areas (for a new review on strategies for treatment of depression see Berton and Nestler, 2006). Likewise, it’s unclear at present how these finding might relate to schizophrenia. BDNF has been assayed in this disorder by various means, with findings of reduced expression in postmortem brain (see, e.g., Knable et al., 2004). Genetic association studies have failed to find consistent links between the BDNF gene and schizophrenia (most recently a negative study from Chen et al., 2006), though two recent studies report associations when the phenomenon under study is simplified to either psychosis (Rosa et al., 2006) or schizophrenia with a lifetime history of depressive symptoms (Schumacher et al., 2005). This last group also found an association of the BDNF gene with major depression, illustrating the revived interest in the notion of common etiologic factors, including genetic factors, for schizophrenia spectrum and affective disorders, especially the disorders that share psychosis as a symptom (for review, see Maier et al., 2005; Craddock et al., 2006).—Hakon Heimer.

Reference:
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. Science. 10 Feb 2006;311(5762):864-8. Abstract

 
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...  Read more


View all comments by NN Kudryavtseva
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