An Examination of the Role of Brain-derived Neurotrophic Factor in Neural Circuits Controlling Homeostatic and Hedonic Food Intake.
Abstract: Food intake
is a complex behavior coordinated, in part, by homeostatic mechanisms in the
hypothalamus balancing nutritional and caloric requirements. Hedonic pleasure derived
from indulging in palatable food is mediated by a midbrain circuit known as the
mesolimbic dopamine pathway. Brain-derived neurotrophic factor (BDNF) and its receptor,
TrkB, are critical components within these... read moretightly regulated circuits controlling food
intake. Evidence from rodent and human studies establish perturbed BDNF signaling as a
biological risk factor contributing to obesity and its associated medical complications.
However, the mechanisms underlying the satiety effects of BDNF and its role in the
pathogenesis of obesity are not completely understood. In this dissertation, I
investigate a mechanism mediating the satiety effects of BDNF in the ventromedial
hypothalamus (VMH), a region critical to maintaining energy homeostasis. I demonstrate
that reduced cell surface expression of α2δ-1, a calcium channel subunit and
thrombospondin receptor, contributes to the overeating and obesity triggered by BDNF
deficiency (BDNF2L/2LCk-cre) in mice. Accordingly, pharmacological inhibition of
α2δ-1 in wild type VMH induces overeating and weight gain. Furthermore,
viral-mediated rescue of α2δ-1 in the BDNF mutant VMH attenuated excessive
feeding and obesity and significantly improved metabolic function. These findings
demonstrate a previously unrecognized role of α2δ-1 in appetite control
facilitated by BDNF. I also present work investigating the regulatory effects of BDNF in
the mesolimbic dopamine pathway and hedonic feeding control. I demonstrate that
defective dopamine transmission underlies the pathological consumption of palatable food
in BDNF2L/2LCk-cre mice. Indeed, the hyperphagic behavior exhibited by BDNF2L/2LCk-cre
mice could be overcome by administration of a selective dopamine agonist. I also show
that selective Bdnf depletion in the ventral tegmental area, the origin of mesolimbic
dopamine fibers, significantly increases palatable food consumption leading to obesity.
These data indicate that BDNF signaling in the mesolimbic pathway is essential for
hedonic feeding control. In summary, the work presented in this dissertation provide
novel, mechanistic insight into the anorexigenic effects of BDNF in homeostatic and
hedonic feeding circuits, introducing new pharmaceutical strategies for the global
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Neuroscience.
Advisor: Maribel Rios.
Committee: Emmanuel Pothos, Beverly Rubin, and Efi Kokkotou.
Keyword: Neurosciences.read less