New insights into the mechanisms underlying the effects of BDNF on eating behavior.

Food intake is a complex behavior resulting from interactions between homeostatic and hedonic regulatory mechanisms acting in the energy balance and reward centers of the brain. Alterations in feeding behavior are often pervasive and can lead to obesity and its associated medical complications, including metabolic and cardiovascular disorders and psychological distress. A compelling body of evidence emerged recently, indicating a pivotal role of brain-derived neurotrophic factor (BDNF) in pathological processes leading to abnormal food intake and excessive weight gain. BDNF signals through the TrkB receptor to promote neuronal survival, differentiation, and synaptic plasticity. Perturbing central BDNF signaling in mice results in hyperphagic behavior and obesity (Xu et al, 2003; Unger et al, 2007). In humans, BDNF haploinsufficiency was linked to elevated food intake and severe weight gain (Han et al, 2008). These findings have significant clinical implications, as the BdnfVal66Met allele, which impedes regulated BDNF secretion, is highly prevalent in humans (Shimizu et al, 2004). Previous work indicated that hypothalamic BDNF participates in homeostatic processes that preserve energy levels essential for survival. Recently, we demonstrated an intimate involvement of BDNF in the regulation of hedonic feeding via the positive modulation of the mesolimbic dopamine pathway (Cordeira et al, 2010). This neural circuit mediates motivated and reward-seeking behaviors, including consumption of palatable food, and has well-established roles in drug addiction. Mice with selective deletion of Bdnf in the ventral tegmental area (VTA), a principal source of mesolimbic BDNF, consumed significantly more palatable high-fat food than control mice, while exhibiting normal intake of standard chow. Furthermore, evoked release of dopamine by mesolimbic fibers in the nucleus accumbens was diminished in mice lacking central BDNF, suggesting decreased VTA dopamine neuron activity and concomitant reductions in neurotransmitter release. It was proposed previously that hypoactivity of the mesolimbic system might result in reward deficiency syndrome and, behaviorally, in compensatory overeating to enhance a deficient dopaminergic system. In support of this model, hyperphagic leptin-deficient mice were also reported to have reduced evoked dopamine release in the nucleus accumbens (Fulton et al, 2006). Moreover, we found that administration of a dopamine-1 receptor agonist abrogated overeating in BDNF mutant mice. The results argue strongly that BDNF is a natural modulator of hedonic food intake and that dysregulation of BDNF signaling in the reward circuitry increases the drive to eat in the absence of a homeostatic requirement. BDNF facilitates synaptic sensitization of VTA dopamine neurons following cocaine withdrawal, which might represent a mechanism mediating cue-associated drug craving and relapse (Pu et al, 2006). Many questions remain regarding the effects of BDNF on excitability within the VTA during food reward-related processes. For example, does BDNF facilitate forms of synaptic plasticity in the VTA necessary for food reward learning? Does deficient BDNF signal affect the firing rate of dopamine neurons and impede transitions to burst firing and subsequent dopamine release during food reward-related processes? A better understanding of the cellular and molecular mechanisms underlying the anorexigenic effects of this pleiotropic neurotrophin will facilitate the development of novel therapies for appetitive disorders.