Abstract
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.
Highlights
The hippocampus is crucial for the formation of spatial or episodic memory [1]
The thickness of the dentate gyrus (DG) granular layer was reduced by about 50% (Fig. 1f)
We found that NF-kB signaling is crucial for tissue homeostasis and functional circuitry of the dentate gyrus during aging
Summary
The hippocampus is crucial for the formation of spatial or episodic memory [1]. In a traditional view the hippocampus was seen as a static structure which is only modified during development. Neurogenesis is a key-feature of the adult dentate gyrus, but the function of newborn neurons remains unclear [2]. Whereas a lot of information on the role of NF-kB in neuronal process growth is already available, one of the main questions that remained to be answered is: what is the physiological importance of the regulation of axonal growth by NF-kB signaling for neuronal development in vivo [18]. This question will be addressed here in a special brain region, the dentate gyrus. Taken together our findings suggest that NF-kB might have therapeutic potential for reversing dentate gyrus dysfunction as observed in Alzheimer’s disease and mood disorders
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