The mesolimbic dopamine system is associated with hedonic mechanisms that drive appetitive behavior and intake of highly palatable, energy-dense food. However, the mechanisms governing this pathway during food consumption-related processes remain poorly understood. The multidisciplinary studies described here indicate an essential role of BDNF in the control of hedonic feeding via positive regulation of mesolimbic dopamine transmission. We showed that selective targeting of Bdnf
in the VTA of mice caused increased intake of palatable HFF but not of SC. This is in contrast to our previous findings demonstrating that mice depleted of BDNF in the VMH exhibited hyperphagic behavior when fed SC ad libitum
(Unger et al., 2007
). The results also differ from rats with selective RNAi-mediated knockdown of leptin receptors in the VTA, which exhibited increased intake of SC and higher sensitivity to palatable food (Hommel et al., 2006
). Our observations indicate that the effects of BDNF on eating behavior are context-dependent and influenced by the neural substrates. Whereas hypothalamic BDNF appears to regulate homeostatic food intake, in the VTA, this neurotrophin appears to largely affect hedonic processes driving palatable food consumption.
Because BDNF was depleted in the VTA of adult mice that had normal BDNF expression throughout development, the observed behavioral alterations cannot be attributed to developmental defects. Instead, they indicate a regulatory role of BDNF in the mature brain. Consistent with this assertion, we found that expression of TrkB and BDNF mRNA in the VTA of sated wild type mice was influenced by intake of palatable HFF. The site of these expression changes suggests that BDNF might act presynaptically through autocrine mechanisms to modulate dopamine-producing cells in the VTA during food reward-related processes. Evidentiary is our finding that BDNF2L/2LCk-cre mice exhibited diminished evoked release of dopamine in the NAc shell, a target site of VTA dopamine neurons. Because HPLC analysis demonstrated normal dopamine content in the mutant NAc, this defect cannot be attributed to deficient dopamine synthesis. Moreover, reduced extracellular dopamine levels persisted in the presence of a DAT inhibitor, indicating that defective presynaptic release rather than enhanced dopamine clearance mediated the observed deficit.
Diminished dopamine secretion was only evident in the NAc shell and not in the NAc core of BDNF2L/2LCk-cre
mutant mice. A divergence in function in these ventral striatal compartments was reported previously. For example, intake of palatable food was reported to induce dopamine release preferentially in the NAc shell compared to the core (Tanda and Di Chiara, 1998
). Furthermore, in vivo
microdialysis studies in rats revealed that whereas unpredicted consumption of palatable food led to release of dopamine in the shell, food anticipation was related to secretion in the core (Bassareo and Di Chiara, 1999
). Directly relevant to the diminished dopamine signal in the NAc shell of BDNF2L/2LCk-cre
mutants, is the observation that inhibition of the NAc shell by local infusion of muscimol, a GABAA
receptor agonist, resulted in dramatic hyperphagic behavior in animals fed ad libitum
(Baldo et al., 2005
Administration of a D1R selective agonist normalized the excessive intake of HFF exhibited by BDNF mutant mice in a 4-hour HFF consumption test. Indeed, similar doses of D1R agonist had a far more profound and extended effect in the mutants compared to wild types. This finding provides further evidence of a link between deficits in dopamine transmission elicited by perturbed BDNF signaling and increased intake of palatable food. It also suggests that homeostatic adaptations take place in BDNF mutants that confer hypersensitivity to D1R stimulation. This notion is supported by studies involving dopamine-deficient mice, which exhibited hypersensitivity to D1R agonists that was ameliorated by 4 days of DOPA treatment (Kim et al., 2000
). The enhanced responses of BDNF2L/2LCk-Cre
to SKF38393 were not due to changes in D1R expression in the NAc or dorsal striatum of BDNF mutant mice. It is possible that depleted BDNF might lead to compensatory changes including increased affinity for D1R ligand or enhanced G protein coupling to D1 receptors, which was demonstrated previously to confer hypersensitivity to dopamine (Gainetdinov et al., 2003
Deficits in dopamine secretion were not limited to the NAc of BDNF mutant mice. Marked decreases were also observed in the dorsal striatum. Moreover, increased content of dopamine in this region was evident in BDNF2L/2LCk-cre
mice, perhaps indicative of a compensatory homeostatic response to the reduced extracellular levels of dopamine in the mutants. Dopamine transmission in the dorsal striatum, which is densely innervated by dopaminergic fibers from the substantia nigra, has been linked to food reward processes. Release of dopamine in the dorsal striatum of healthy human subjects was induced by ingestion of palatable food and the amount of dopamine released correlated with the degree of experienced pleasure reported (Small et al., 2003
). Therefore, we cannot rule out the possibility that deficient dopamine signaling in the dorsal striatum of BDNF2L/2LCk-cre
mutants contributes to their excessive intake of palatable food. Nevertheless, it is clear from the studies described here that BDNF produced in the VTA plays a pivotal part in the control of feeding behavior.
BDNF was reported previously to facilitate synaptic sensitization of VTA dopamine neurons following cocaine withdrawal, which might represent a mechanism mediating drug craving and relapse (Pu et al., 2006
). Moreover, Graham et al. demonstrated that selective depletion of BDNF in the mesolimbic system resulted in reduced cocaine self-administration, indicating that BDNF promotes the development and persistence of addictive behavior (Graham et al., 2007
). In contrast, we found that deleting Bdnf
in the VTA of mice resulted in increased intake of palatable high fat food, a natural reward. An important distinction between these studies is that Graham et al. targeted Bdnf
in the NAc of mice and attributed the observed alterations to disrupted BDNF signaling at post synaptic sites in the NAc. This model was further supported by studies showing that TrkB knock down in the NAc but not in the VTA reduced cocaine reward (Graham et al., 2009
). For our studies, we deleted Bdnf
in the VTA and we postulated that BDNF acts presynaptically to positively modulate dopaminergic activity during food reward-related processes. Therefore, the findings from both of these studies suggest a disassociation of disease mechanisms mediating drug addiction and eating disorders.
Altered dopaminergic transmission has been linked to the emergence of eating disorders and obesity. However, conflicting disease mechanisms have been proposed. One model proposes that a heightened response of the dopaminergic reward circuitry to palatable food underlies excessive eating (Dawe et al., 2004
). An alternative model postulates that hypoactivity of this neural system leads to reward deficiency syndrome and behaviorally, to compensatory overeating to boost a deficient dopaminergic system (Blum et al., 2000
; Pothos et al., 1998
; Wang et al., 2002
). Based on our findings, we propose that perturbed BDNF signaling impedes activity of the mesolimbic dopamine pathway, leading to reward deficiency and compensatory overeating of palatable food. Consistent with this model, it was reported that over expression of
-FosB resulted in reduced protein levels of BDNF and concomitant molecular changes in the NAc consistent with deficient dopamine signaling, including reduced levels of DARPP-32 and pCREB (Teegarden et al., 2008
). Notably, consumption of palatable HFF for six weeks completely reversed these abnormalities in
Rodent studies have shed some light onto putative pathological mechanisms involving dopamine systems and underlying eating disorders. Hyperphagic dietary obese and obesity-prone rats and leptin-deficient ob/ob
mice exhibited reduced evoked dopamine release in the NAc (Pothos et al., 1998
; Fulton et al., 2006
; Geiger et al., 2009
). Moreover, ob/ob
mice displayed reductions in food intake and body weights when treated with D1R and D2R agonists (Bina and Cincotta, 2000
). Some intriguing evidence comes from studies involving dopamine-deficient mice. They exhibit decreased food intake and without intervention fail to eat enough to sustain life beyond 48 hours (Szczypka et al., 1999
). However, whereas dopamine production selectively restored in the dorsal striatum of mutants rescued feeding of normal chow, restoration in either the NAc or dorsal striatum led to increased intake of palatable food (Szczypka et al., 2001
). Furthermore, when ob/ob
mice were crossed with dopamine-deficient mice, their hyperphagic behavior was diminished (Szczypka et al., 2000
). These findings in dopamine-deficient mice demonstrate the important role of dopamine in more than one aspect of feeding motivation and a need to compensate for a complete dopamine deficit that might be absent in animals where central dopamine is present but hypofunctioning. The complexity of mechanisms underlying appetite control and the need for additional investigations to resolve these differences are evident. Nonetheless, the studies described here strongly support a pivotal role of BDNF in the positive regulation of mesolimbic dopamine transmission during food-reward processes.
In summary, we showed that the mesolimbic dopamine system is a newly identified target of action of BDNF for the control of feeding behavior. Moreover, that BDNF in the VTA has higher relevance in the regulation of hedonic processes impacting consumption of palatable food. Our findings implicate the dopaminergic reward circuit in the disease mechanisms triggered by perturbed BDNF signaling and leading to excessive food intake and obesity.