Abstract
Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.
Highlights
Generation of functional neurons from precursors is not restricted to prenatal and early postnatal development, but occurs in the adult brain [1,2,3]
The present study demonstrated novel influence of genetic disruption of the molecular clockwork on adult neurogenesis and neuronal plasticity
Expression levels of genes encoding for regulators of cell cycle control were significantly altered in Bmal1-/- mice; indicating that high oxidative stress, as a consequence of circadian disruption, leads to premature aging of the neurogenic niche
Summary
Generation of functional neurons from precursors is not restricted to prenatal and early postnatal development, but occurs in the adult brain [1,2,3]. In SGZ, adult neurogenesis is a multistep process which includes: (1) proliferation of neural stem/progenitor cells (NPCs), (2) migration and differentiation, (3) death or survival of the newly-generated cells (4) and, maturation of the latter by acquiring the morphological and electrophysiological properties of mature granular neurons and their integration within the hippocampal synaptic network [2]. Adult neurogenesis is highly dynamic and modulated by various internal and external factors, including signaling within the local stem cell niche [10], aging [11], brain disorders [12], stressful experience [9], sleep deprivation [13] and circadian molecular clock [14,15,16,17].
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