Original articleBrain-derived neurotrophic factor in the ventral midbrain–nucleus accumbens pathway: a role in depression
Introduction
Neurotrophins, including brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), were first described for their role in central nervous system development Ernfors et al., 1994, Jones et al., 1994, Klein et al., 1990b, Klein et al., 1993. Brain-derived neurotrophic factor is now appreciated not only for its impact on neurons in the adult brain, but also for its putative involvement in learning, motivation, and regulation of mood. Exogenous BDNF has positive effects on synaptic strength and neuronal arborization of hippocampal, cortical, and monoaminergic neurons Ghosh et al., 1994, Mamounas et al., 2000, Sklair-Tavron and Nestler, 1995. Endogenous hippocampal BDNF levels are decreased by stress, a precipitating factor in clinical depression, and increased by antidepressant treatments Nibuya et al., 1995, Smith et al., 1995. Addition of exogenous BDNF to the hippocampus or posterior midbrain nuclei attenuates depression-related phenotypes Shirayama et al., 2002, Siuciak et al., 1997. Via the full-length form of its receptor, BDNF is postulated to act on downstream signaling molecules, such as cyclic adenosine monophosphate response element binding protein (CREB), to mediate the hippocampal neuroadaptations seen after antidepressant treatment Nibuya et al., 1996, Thome et al., 2000. Overexpression of the truncated, endogenous form of the BDNF receptor prevents the efficacy of antidepressant medications (Saarelainen et al 2003). Taken together with studies reporting decreased hippocampal volume in clinical depression Bremner et al., 2000, Sheline and Mayberg, 1996, these data suggest a neurotrophic hypothesis of depression: decreased expression of BDNF might contribute to development of depression, and reversal of this decrease might help treat the disorder.
Although the hippocampus is undoubtedly involved in depression, it is likely that other brain regions are involved as well Mayberg, 2002, Tamminga et al., 2002. Given that clinical depression is marked by anhedonia, or lack ofreward, it has been suggested that dysfunction of the brain reward pathway contributes to the pathophysiology of depression D'Aquila et al., 2000, Di Chiara et al., 1999, Gambarana et al., 2001a, Nestler et al., 2002, Weiss et al., 1998. Dopaminergic cells in the ventral tegmental area (VTA) and their terminal fields in the nucleus accumbens (NAc) and frontal cortex mediate reinforcing effects of rewarding agents, such as drugs of abuse, food, and sex Bassareo and Di Chiara, 1999, Everitt et al., 1999, Koob, 1998. Research implicates dopamine (DA) and the VTA–NAc pathway in several aspects of depression Pallis et al., 2001, Serra et al., 1992, Yadid et al., 2001. For example, manipulation of the mesolimbic DA pathway alters behavior in depression-related tasks (Cervo et al 1992). Stress, a predisposing factor to clinical depression, or genetic models of depression alter signaling along the VTA–NAc pathway Gambarana et al., 2001b, Kram et al., 2002, Schwartz et al., 2003, Shumake et al., 2003, and treatment with antidepressants can reverse those alterations (Gambarana et al 2001b). Antidepressants have potent effects on dopaminergic signaling Brown and Gershon, 1993, Keck et al., 2002, Linner et al., 2001, and chronic antidepressant treatment results in myriad neuroadaptations within the VTA and NAc Dziedzicka-Wasylewska and Rogoz, 1995, Rosin et al., 1995, Zangen et al., 2001. Interestingly, some molecules implicated in depression (e.g., CREB, S-adenosyl-L-methionine) seem to produce different behavioral effects in the hippocampus versus VTA–NAc Barrot et al., 2002, Carlezon et al., 1998, Genedani et al., 2001, Nibuya et al., 1996, Pliakas et al., 2001, Thome et al., 2000. These studies emphasize that the pathophysiology of depression might be different within the VTA–NAc than within the hippocampus and other brain regions.
Given the neurotrophic hypothesis of depression, and that depression is marked by anhedonia, it is interesting that BDNF and TrkB in the VTA–NAc pathway influence appetitive behavior. Brain-derived neurotrophic factor infusions into the VTA–NAc have profound effects on drug-induced reward and biochemical changes in the VTA and NAc Berhow et al., 1996, Horger et al., 1999. Infusions of BDNF, but not nerve growth factor (NGF), into the VTA–NAc enhance cocaine-induced locomotion and responding for conditioned reinforcers. In addition, heterozygote BDNF knockout mice show reduced responses to cocaine (Horger et al 1999). Brain-derived neurotrophic factor signaling is likely altered after chronic exposure to drugs of abuse, because TrkB protein levels in the NAc are upregulated after withdrawal from cocaine (Toda et al 2002), and several postreceptor BDNF signaling proteins are altered in the VTA after chronic drug exposure Berhow et al., 1996, Wolf et al., 1999. It is not clear where BDNF acts within the VTA–NAc pathway to mediate appetitive behavior. Dopamine neurons in the VTA express high levels of BDNF messenger ribonucleic acid (mRNA) and protein Conner et al., 1997, Furukawa et al., 1998, Hung and Lee, 1996, and TrkB mRNA and protein is expressed throughout the VTA–NAc pathway Hofer et al., 1990, Merlio et al., 1992, Yan et al., 1997. The NAc has barely detectable levels of BDNF mRNA, but has high levels of BDNF protein (Conner et al 1997). Therefore, one source of NAc BDNF protein is via anterograde transport from the VTA Altar et al., 1997, Horger et al., 1999. In fact, BDNF from DA cells might be essential for NAc DA receptor expression (Guillin et al 2001), a role with wide implications for VTA–NAc function. Therefore, it is surprising that our knowledge of BDNF's role in the VTA–NAc pathway remains limited to its impact on appetitive behaviors.
Here, we show two lines of evidence that BDNF in the VTA–NAc pathway is also involved in depression-like behavior. First, we show that intra-VTA BDNF is prodepressive in the 2-day forced swim test (FST), which is used to study depression-like behavior. Second, we show that sequestration of endogenous BDNF in the terminal field of the VTA, the NAc, is antidepressive in FST. These data suggest that BDNF action in the VTA–NAc pathway might contribute to the development of a depression-like phenotype.
Section snippets
Animals
Adult male Sprague-Dawley rats (250–275 g; Charles River Laboratories, Wilmington, Massachusetts) were housed two per cage with water and rat chow available ad libitum. All experiments were performed in an Institutional Animal Care and Research Advisory Committee–approved vivarium and with approval of the local animal care and use committee.
Viral vector production and in vitro expression
The following complementary deoxyribonucleic acids (cDNAs) were used to construct adeno-associated viral vector (AAV) plasmids: N-terminally FLAG-tagged
Results
To address the role of BDNF in the VTA–NAc pathway in depression-related behavior, rats were given VTA-directed infusions of saline or BDNF via subcutaneous minipumps for 1 week. Saline- and BDNF-infused rats did not differ in weight after surgery (data not shown). One week after surgery, rats were placed in FST for 2 consecutive days. On day 1 of FST, rats that received saline or BDNF into the VTA did not differ in latency to immobility (Figure 1) or in counts of immobility, swimming, and
Discussion
The neurotrophic hypothesis of depression suggests that dysfunctional BDNF signaling in the adult brain contributes to the development of a depressive phenotype Altar, 1999, D'Sa and Duman, 2002, Nestler et al., 2002. Preclinical studies support this hypothesis. For example, BDNF infusions into the hippocampus and posterior midbrain nuclei produce antidepressant-like behaviors in the forced swim and learned helplessness tasks Shirayama et al., 2002, Siuciak et al., 1997. In striking contrast,
Acknowledgements
This work was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (AJE), the National Institute of Mental Health (EJN), and the Stanley Scholar Foundation at University of Texas Southwestern Medical Center (RDS).
We thank Dr. E. Castren, University of Kuopio, Finland for the generous gift of the cDNA used to make the AAVs for this study. We also thank Rebekah Norris for the excellent technical assistance in completion of the behavioral testing.
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