Abstract
BackgroundNewborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG.ResultsIn contrast to the suprachiasmatic nucleus, we observed a non-rhythmic constitutive expression of mPER2 in the dentate gyrus. We provide evidence that mPER2 is expressed in proliferating neural stem/progenitor cells (NPCs) and persists in early post-mitotic and mature newborn neurons from the adult DG. In vitro and in vivo analysis of a mouse line mutant in the mPer2 gene (Per2Brdm1), revealed a higher density of dividing NPCs together with an increased number of immature newborn neurons populating the DG. However, we showed that the lack of mPer2 does not change the total amount of mature adult-generated hippocampal neurons, because of a compensatory increase in neuronal cell death.ConclusionTaken together, these data demonstrated a functional link between the constitutive expression of mPER2 and the intrinsic control of neural stem/progenitor cells proliferation, cell death and neurogenesis in the dentate gyrus of adult mice.
Highlights
Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus
Constitutive expression of period 2 protein (mPER2) in the adult dentate gyrus The expression profile of mPER2 in the DG region of the hippocampus was established by immunohistochemistry using two different polyclonal antibodies on 40 μm-thick coronal sections from P45 adult male mice. Both antimPER2 antibodies lead to similar expression patterns (See Additional file 1A–B). mPER2 was highly expressed throughout the adult hippocampus and in the granule cell layer (GCL), subgranular layer (SGL) and the hilus (H) of the DG (Fig. 1A)
In order to determine whether mPER2 expression levels could undergo rhythmic oscillations in the DG, immunostainings and Western blots were performed at several circadian time points including ZT0, ZT6, ZT12 and ZT18
Summary
Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Hormonal cycles and psychosocial stress [6,7], serotonin metabolism [8], depression [9], aging [10,11], physical activity [12], sleep deprivation [13] and enriched living conditions [14] influence the rate of neuronal renewal and survival in various adult organisms This suggests that mechanisms controlling life-long neurogenesis in the postnatal CNS are adapted to complex extrinsic inputs. Recent work has consistently shown a diurnal rhythm of neurogenesis among the olfactory projection neurons in the crustacean brain, with peak of neuroblasts proliferation during the hours surrounding dusk, the most active period for lobsters [15] These data suggest the possibility that light-controlled rhythms may be primary regulators of neuronal proliferation, and that previously demonstrated hormonal and activity-driven influences over adult neurogenesis may be secondary events in a complex circadian control pathway
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