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.
References (106)
- et al.
Truncated TrkB mediates the endocytosis and release of BDNF and neurotrophin-4/5 by rat astrocytes and Schwann cells in vitro
Brain Res
(2000) - et al.
The neurotrophins NT-4/5 and BDNF augment serotonin, dopamine, and GABAergic systems during behaviorally effective infusions to the substantia nigra
Exp Neurol
(1994) - et al.
Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments
Neuroscience
(1999) - et al.
Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system
Neuroscience
(1995) - et al.
Antidepressant-like effects of cytidine in the forced swim test in rats
Biol Psychiatry
(2002) - et al.
Local infusion of brain-derived neurotrophic factor modifies the firing pattern of dorsal raphe serotonergic neurons
Brain Res
(1996) - et al.
Compartmental expression of trkB receptor protein in the developing striatum
Neuroscience
(1999) - et al.
Co-infusion with a TrkB-Fc receptor body carrier enhances BDNF distribution in the adult rat brain
Exp Neurol
(1998) - et al.
Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stressImplications for the psychobiology of depression
Biol Psychiatry
(1999) - et al.
Animal models for the study of antidepressant activity
Brain Res Brain Res Protoc
(2001)
Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clusters at neuromuscular junctions
Neuron
Truncated trkB.T1 is dominant negative inhibitor of trkB.TK+-mediated cell survival
Biochem Biophys Res Commun
Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development
Cell
Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system
Neuropharmacology
The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain
Cell
Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death
Cell
Dopamine receptors and learned helplessness in the ratAn autoradiographic study
Prog Neuropsychopharmacol Biol Psychiatry
Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system
Neuroscience
Neurobiology of depression
Neuron
Biochemical adaptations in the mesolimbic dopamine system in response to repeated stress
Neuropsychopharmacology
Characteristics of BDNF-induced weight loss
Exp Neurol
Behavioural despair in ratsA new model sensitive to antidepressant treatments
Eur J Pharmacol
“Behavioural despair” in rats and miceStrain differences and the effects of imipramine
Eur J Pharmacol
Chronic imipramine administration alters the activity and phosphorylation state of tyrosine hydroxylase in dopaminergic regions of rat brain
Neuropsychopharmacology
Brain-derived neurotrophic factor enhances function rather than survival of intrastriatal dopamine cell-rich grafts
Brain Res
Decreased limbic vesicular monoamine transporter 2 in a genetic rat model of depression
Brain Res
Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior
Brain Res
BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration
Brain Res
Antidepressant-like effect of brain-derived neurotrophic factor (BDNF)
Pharmacol Biochem Behav
Developing novel treatments for mood disordersAccelerating discovery
Biol Psychiatry
Neurotrophins and depression
Trends Pharmacol Sci
Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo
Proc Natl Acad Sci U S A
Anterograde transport of brain-derived neurotrophic factor and its role in the brain
Nature
In situ hybridization of trkB and trkC receptor mRNA in rat forebrain and association with high-affinity binding of [125I]BDNF [125I]NT-4/5 and [125I]NT-3
Eur J Neurosci
Differential distribution of exogenous BDNF, NGF, and NT-3 in the brain corresponds to the relative abundance and distribution of high-affinity and low-affinity neurotrophin receptors
J Comp Neurol
Truncated and catalytic isoforms of trkB are co-expressed in neurons of rat and mouse CNS
Eur J Neurosci
CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
Proc Natl Acad Sci U S A
Induction of noncatalytic TrkB neurotrophin receptors during axonal sprouting in the adult hippocampus
J Neurosci
Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine
J Neurosci
Selective binding and internalisation by truncated receptors restrict the availability of BDNF during development
Development
Hippocampal volume reduction in major depression
Am J Psychiatry
Dopamine and depression
J Neural Transm Gen Sect
Regulation of cocaine reward by CREB
Science
Expanded distribution of mRNA for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the rat brain after colchicine treatment
Proc Natl Acad Sci U S A
Antidepressant-like effect of neurotensin administered in the ventral tegmental area in the forced swimming test
Psychopharmacology (Berl)
Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNSEvidence for anterograde axonal transport
J Neurosci
Different effect of desipramine on locomotor activity in quinpirole-treated rats after repeated restraint and chronic mild stress
J Psychopharmacol
Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression
Exp Clin Psychopharmacol
Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants
Psychopharmacology (Berl)
Woodchuck hepatitis virus contains a tripartite posttranscriptional regulatory element
J Virol
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