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

Liao GY, Bouyer K, Kamitakahara A, Sahibzada N, Wang CH, Rutlin M, Simerly RB, Xu B - Mol Metab (2015)

Bottom Line: We 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.This 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.

ABSTRACT

Objective: Brain-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.

Methods: We 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 Bdnf (klox/klox) mice, which lack long 3' UTR Bdnf mRNA and develop severe hyperphagic obesity.

Results: We 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. Bdnf(klox/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 Bdnf (klox/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 Bdnf (klox/klox) mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice.

Conclusion: This 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.

No MeSH data available.


Related in: MedlinePlus

TrkB-expressing cells in the ARH. Representative confocal images acquired from brain sections of adult TrkBCreERT2/+;Ai9/+mice after tamoxifen injection. TrkB positive cells, at different anterior-posterior levels relative to Bregma, were marked by tdTomato in the ARH. White and yellow arrows indicate a few representative TrkB-expressing neurons and astrocytes, respectively. 3V, third ventricle. Scale bar, 50 μm.
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fig1: TrkB-expressing cells in the ARH. Representative confocal images acquired from brain sections of adult TrkBCreERT2/+;Ai9/+mice after tamoxifen injection. TrkB positive cells, at different anterior-posterior levels relative to Bregma, were marked by tdTomato in the ARH. White and yellow arrows indicate a few representative TrkB-expressing neurons and astrocytes, respectively. 3V, third ventricle. Scale bar, 50 μm.

Mentions: To investigate whether the obese phenotype in Bdnfklox/klox mice is associated with alterations in arcuate neurons, we first examined the expression of TrkB in the ARH and the relation of the TrkB neurons with other ARH neurons known to control energy balance. TrkB neurons were visualized through the utilization of TrkBCreERT2/+;Ai9/+ mice in which TrkB-expressing cells were marked by red fluorescent protein tdTomato, after tamoxifen induction. Abundant TrkB neurons and some TrkB astrocytes were detected through the whole ARH in TrkBCreERT2/+;Ai9/+ animals (Figure 1 and Supplementary Figure 1). Next, we examined whether TrkB neurons in the ARH express POMC since POMCARH → DMH projections are impaired in Bdnfklox/klox mice [15]. We generated Pomc-hrGFP;TrkBCreERT2/+;Ai9/+ mice to quantify TrkB neurons that are positive for POMC. Similarly, we generated Npy-hrGFP;TrkBCreERT2/+;Ai9/+ mice to examine co-expression of TrkB and NPY. In these mice, TrkB cells are labeled by tdTomato, while POMC or NPY neurons by GFP. Analysis of confocal images acquired from series of brain sections collected from Pomc-hrGFP;TrkBCreERT2/+;Ai9/+ mice (n = 3) showed that 13.8 ± 2.9% of the TrkB neurons expressed POMC while 16.5 ± 1.5% of the POMC neurons were TrkB-positive in the ARH (Figure 2A,D). In Npy-hrGFP;TrkBCreERT2/+;Ai9/+ animals (n = 4), 15.7 ± 3.2% of the TrkB neurons expressed NPY while 7.8 ± 2.3% of the NPY neurons were positive for TrkB in the ARH (Figure 2B,D).


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

Liao GY, Bouyer K, Kamitakahara A, Sahibzada N, Wang CH, Rutlin M, Simerly RB, Xu B - Mol Metab (2015)

TrkB-expressing cells in the ARH. Representative confocal images acquired from brain sections of adult TrkBCreERT2/+;Ai9/+mice after tamoxifen injection. TrkB positive cells, at different anterior-posterior levels relative to Bregma, were marked by tdTomato in the ARH. White and yellow arrows indicate a few representative TrkB-expressing neurons and astrocytes, respectively. 3V, third ventricle. Scale bar, 50 μm.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4443292&req=5

fig1: TrkB-expressing cells in the ARH. Representative confocal images acquired from brain sections of adult TrkBCreERT2/+;Ai9/+mice after tamoxifen injection. TrkB positive cells, at different anterior-posterior levels relative to Bregma, were marked by tdTomato in the ARH. White and yellow arrows indicate a few representative TrkB-expressing neurons and astrocytes, respectively. 3V, third ventricle. Scale bar, 50 μm.
Mentions: To investigate whether the obese phenotype in Bdnfklox/klox mice is associated with alterations in arcuate neurons, we first examined the expression of TrkB in the ARH and the relation of the TrkB neurons with other ARH neurons known to control energy balance. TrkB neurons were visualized through the utilization of TrkBCreERT2/+;Ai9/+ mice in which TrkB-expressing cells were marked by red fluorescent protein tdTomato, after tamoxifen induction. Abundant TrkB neurons and some TrkB astrocytes were detected through the whole ARH in TrkBCreERT2/+;Ai9/+ animals (Figure 1 and Supplementary Figure 1). Next, we examined whether TrkB neurons in the ARH express POMC since POMCARH → DMH projections are impaired in Bdnfklox/klox mice [15]. We generated Pomc-hrGFP;TrkBCreERT2/+;Ai9/+ mice to quantify TrkB neurons that are positive for POMC. Similarly, we generated Npy-hrGFP;TrkBCreERT2/+;Ai9/+ mice to examine co-expression of TrkB and NPY. In these mice, TrkB cells are labeled by tdTomato, while POMC or NPY neurons by GFP. Analysis of confocal images acquired from series of brain sections collected from Pomc-hrGFP;TrkBCreERT2/+;Ai9/+ mice (n = 3) showed that 13.8 ± 2.9% of the TrkB neurons expressed POMC while 16.5 ± 1.5% of the POMC neurons were TrkB-positive in the ARH (Figure 2A,D). In Npy-hrGFP;TrkBCreERT2/+;Ai9/+ animals (n = 4), 15.7 ± 3.2% of the TrkB neurons expressed NPY while 7.8 ± 2.3% of the NPY neurons were positive for TrkB in the ARH (Figure 2B,D).

Bottom Line: We 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.This 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.

ABSTRACT

Objective: Brain-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.

Methods: We 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 Bdnf (klox/klox) mice, which lack long 3' UTR Bdnf mRNA and develop severe hyperphagic obesity.

Results: We 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. Bdnf(klox/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 Bdnf (klox/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 Bdnf (klox/klox) mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice.

Conclusion: This 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.

No MeSH data available.


Related in: MedlinePlus