Brain-derived neurotrophic factor is required for axonal growth of selective groups of neurons in the arcuate nucleus

Abstract

ObjectiveBrain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development, and the Bdnf gene produces two populations of transcripts with either a short or long 3′ untranslated region (3′ UTR). Deficiencies in BDNF signaling have been shown to cause severe obesity in humans; however, it remains unknown how BDNF signaling impacts the organization of neuronal circuits that control energy balance.MethodsWe examined the role of BDNF on survival, axonal projections, and synaptic inputs of neurons in the arcuate nucleus (ARH), a structure critical for the control of energy balance, using Bdnfklox/klox mice, which lack long 3′ UTR Bdnf mRNA and develop severe hyperphagic obesity.ResultsWe found that a small fraction of neurons that express the receptor for BDNF, TrkB, also expressed proopiomelanocortin (POMC) or neuropeptide Y (NPY)/agouti-related protein (AgRP) in the ARH. Bdnfklox/klox mice had normal numbers of POMC, NPY, and TrkB neurons in the ARH; however, retrograde labeling revealed a drastic reduction in the number of ARH axons that project to the paraventricular hypothalamus (PVH) in these mice. In addition, fewer POMC and AgRP axons were found in the dorsomedial hypothalamic nucleus (DMH) and the lateral part of PVH, respectively, in Bdnfklox/klox mice. Using immunohistochemistry, we examined the impact of BDNF deficiency on inputs to ARH neurons. We found that excitatory inputs onto POMC and NPY neurons were increased and decreased, respectively, in Bdnfklox/klox mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice.ConclusionThis study shows that the majority of TrkB neurons in the ARH are distinct from known neuronal populations and that BDNF plays a critical role in directing projections from these neurons to the DMH and PVH. We propose that hyperphagic obesity due to BDNF deficiency is in part attributable to impaired axonal growth of TrkB-expressing ARH neurons.

Neurotrophic factor control of satiety and body weight

“…2). This view is supported by the observation that the axonal number of ARH neurons is significantly reduced in the PVH of mutant mice that lack the long form of Bdnf mRNA and display marked hyperphagia 76,88 . It has been shown that the long form of Bdnf mRNA is transported to dendrites for local translation 94 .…”

“…It contains at least three neuronal populations on the basis of the expression of three markers: POMC, AgRP, and RIP-Cre. The ARH also expresses TrkB, and the majority of ARH TrkB neurons are distinct from these three neuronal populations 88 . Some ARH TrkB neurons are activated in response to either fasting or refeeding after fasting 88 , indicating that these neurons may play a role in the control of food intake.…”

“…The ARH also expresses TrkB, and the majority of ARH TrkB neurons are distinct from these three neuronal populations 88 . Some ARH TrkB neurons are activated in response to either fasting or refeeding after fasting 88 , indicating that these neurons may play a role in the control of food intake. It is necessary to further evaluate the role of ARH TrkB neurons in the control of energy balance by deleting the Ntrk2 gene or altering the activity of these neurons.…”

POMC Neurons: From Birth to Death

“…In addition, brain-derived neurotrophic factor (Bdnf) a critical gene in synaptic plasticity, neural circuit development, and energy metabolism regulation (36), plays a role in POMC axonal growth. Deletion of the long 3′UTR Bdnf mRNA transcript leads to a decrease of α-MSH projections into the dorsomedial hypothalamus but not the PVH without affecting POMC cell number (37). Considering that leptin was shown to increase Bdnf mRNA and protein levels in the hypothalamus, BDNF may also play a role in leptin signaling and axonal growth of POMC neurons (38).…”

Developmental specification of metabolic circuitry

“…This process appears to be dependent on the long form of BDNF being transported to dendrites where it is locally translated. A similar mechanism influences axon targeting of the PVH by ARH neurons(Liao et al, 2015). Mice that lack the long form of BDNF show reduced leptin signaling in the VMH and diminished physiological responses to leptin.…”