Regrowing the adult brain: NF-κB controls functional circuit formation and tissue homeostasis in the dentate gyrus.
Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus) of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders.
Molecular Neurobiology, Faculty of Biology, University of Bielefeld, Bielefeld, Germany.
Yvonne
Y
Imielski
Jens C
JC
Schwamborn
Patrick
P
Lüningschrör
Peter
P
Heimann
Magdalena
M
Holzberg
Hendrikje
H
Werner
Oliver
O
Leske
Andreas W
AW
Püschel
Sylvie
S
Memet
Rolf
R
Heumann
Alain
A
Israel
Christian
C
Kaltschmidt
Barbara
B
Kaltschmidt
D000818:Animals; D017209:Apoptosis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018891:Dentate Gyrus / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009415:Nerve Net / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis; D012038:Regeneration; D015398:Signal Transduction; D013037:Spatial Behavior / Q000502:physiology
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D016328:NF-kappa B; D017868:Cyclic AMP-Dependent Protein Kinases