| Brain-derived neurotrophic factor (BDNF) is a critical component of neural circuits that regulate energy balance and affective behavior. BDNF and its cognate receptor TrkB are expressed in key weight-regulating and limbic regions of the brain, and disruptions in this signaling pathway have been implicated in obesity and psychiatric disorders. To date, the complete neural mechanisms by which BDNF regulates energy homeostasis and affective behavior remain to be elucidated.;The work described in the first half of this dissertation investigates the role of BDNF in body weight regulation. Central BDNF is necessary for normal energy balance; however, it is unclear which brain regions utilize BDNF to promote satiety. In addition, it remains to be determined whether hyperphagic behavior in BDNF mutant mice is a result of a developmental defect or whether BDNF serves a critical weight-regulating role in the adult animal. To address these questions, I used viral-mediated delivery of Cre recombinase to selectively deplete BDNF from two weight-regulating centers in the mature mouse brain, the ventromedial (VMH) and dorsomedal (DMH) hypothalamus, and asked whether the loss of BDNF from these regions alters food intake and body weight. I showed that mice with BDNF depletion from the VMH/DMH develop significant hyperphagia and obesity, but do not have alterations in energy expenditure. In addition, I used a mouse model with central BDNF depletion and administered agonists to receptors with known satiety roles. I showed that BDNF signaling is not required for appetite suppression mediated through the melanocortin 4, leptin, 5-HT2c and Y2 receptors. Together, these findings demonstrate that BDNF synthesized in the VMH/DMH is an integral component of central mechanisms mediating satiety in the adult mouse. Moreover, they show that BDNF is not a down-stream satiety signal of the melanocortin 4, leptin, 5-HT2c and Y2 receptors.;In the second half of this dissertation, I describe experiments which expand on data previously reported from our laboratory and others implicating BDNF in affective disorders. For these studies, I used established paradigms to compare and contrast behavioral alterations in mouse lines with prenatal or postnatal depletion of BDNF from the brain. I investigate the loss of central BDNF on depression, anxiety and locomotor activity and make determinations about the severity of these disorders with regard to the timing of BDNF depletion. I show that BDNF mutants are hyperactive, hyperaggeressive and depressive. Furthermore, I demonstrate that prenatal depletion of BDNF produces more severe aggressive- and depressive-like behavior. In total, this work shows that both pre- and postnatal expression of BDNF is required for normal modulation of behavior by neural circuits in the adult animal. |
