Newly born cells in the ageing dentate gyrus display normal migration, survival and neuronal fate choice but endure retarded early maturation

Abstract

Addition of new granule cells to the dentate gyrus (DG) from stem or progenitor cells declines considerably during ageing. However, potential age-related alterations in migration, enduring survival and neuronal fate choice of newly born cells, and rate of maturation and dendritic growth of newly differentiated neurons are mostly unknown. We addressed these issues by analysing cells that are positive for 5'-bromodeoxyuridine (BrdU), doublecortin (DCX), BrdU and DCX, and BrdU and neuron-specific nuclear antigen (NeuN) in the DG of young adult, middle-aged and aged F344 rats treated with daily injections of BrdU for 12 consecutive days. Analyses performed at 24 h, 10 days and 5 months after BrdU injections reveal that the extent of new cell production decreases dramatically by middle age but exhibits no change thereafter. Interestingly, fractions of newly formed cells that exhibit appropriate migration and prolonged survival, and fractions of newly born cells that differentiate into neurons, remain stable during ageing. However, in newly formed neurons of the middle-aged and aged DG, the expression of mature neuronal marker NeuN is delayed and early dendritic growth is retarded. Thus, the presence of far fewer new granule cells in the aged DG is not due to alterations in the long term survival and phenotypic differentiation of newly generated cells but solely owing to diminished production of new cells. The results also underscore that the capability of the DG milieu to support neuronal fate choice, migration and enduring survival of newly born cells remains stable even during senescence but its ability to promote rapid neuronal maturation and dendritic growth is diminished as early as middle age.

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

“…This finding is surprising in the light of earlier observations in rat models that a dramatic decline in the proliferation of NSCs occurs in the DG between young and old age (Olariu et al 2007;Rao et al 2006), but NSC numbers are preserved in the SGZ during the course of aging (Hattiangady and Shetty 2008). Furthermore, most studies on rodent models point out that proliferation of far fewer NSCs in the aged DG underlies the age-related reduction in net hippocampal neurogenesis (Cameron and McKay 1999;Hattiangady and Shetty 2008;Heine et al 2004;Kuhn et al 1996;McDonald and Wojtowicz 2005;Rao et al 2005;Seki and Arai 1995;Walter et al 2011but see Encinas et al 2011. Consistent with this, other studies have shown that aging in the hippocampus is associated with alterations in NSC proliferation factors such as decreased concentrations of neurotrophic factors that are mitogenic to NSCs Shetty et al 2005;Zeng et al 2011).…”

“…This phenomenon has received widespread attention because of its perceived role in functions such as learning, memory, and mood (Aimone et al 2006;Clelland et al 2009;Drapeau et al 2003;Dupret et al 2007;Eisch et al 2008;Imayoshi et al 2008;Jessberger et al 2009;Kee et al 2007;Kuhn et al 1996;Leuner et al 2006;Sahay and Hen 2007;Santarelli et al 2003). However, the extent of neurogenesis progressively declines with age resulting in~90 % decline in old age (Kuhn et al 1996;Rao et al 2005Rao et al , 2006. As old age is also associated with decreased ability for hippocampaldependent learning and memory function and increased incidence of depression, there is a widespread interest to understand the mechanisms underlying the age-related decrease in neurogenesis and to develop strategies that increase neurogenesis in the aged hippocampus (Bachstetter et al 2008;Bernal and Peterson 2004;Lie et al 2005;Drapeau and Abrous 2008;Hattiangady et al 2007;Jessberger and Gage 2008;Miranda et al 2012).…”

“…Multiple studies have shown that age-related decrease in neurogenesis is a result of proliferation of far fewer NSCs in the SGZ (Hattiangady and Shetty 2008;Kuhn et al 1996;Nacher et al 2003;Olariu et al 2007;Rao et al 2005Rao et al , 2006. Examination of the putative NSCs using markers such as Sox-2, GFAP, and vimentin over the course of aging has revealed no changes in NSC numbers in the rodent SGZ with aging (Aizawa et al 2011; however, see Encinas et al 2011;Hattiangady and Shetty 2008).…”

Adult Neurogenesis and the Ischemic Forebrain

“…The decline is largely attributable to a reduction in proliferation of neuronal precursor cells, although evidence also implicates a decrease in neuronal fate determination (e.g., Kempermann et al, 1998) or slowed maturation of adult-born neurons in senescence (Rao et al, 2005). The age-dependent decline in neurogenesis appears to be mediated by age-related alterations in the cellular microenvironment rather than impaired responsiveness of progenitor cells to neurogenic stimuli.…”

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

“…; Sigma, St. Louis, MO) for 10 consecutive days to label dividing cells. This injection regimen was based on past research designed to capture the impact of a variety of manipulations on cell proliferation and survival in the hippocampus (Kempermann et al, 1997;Lee, et al, 2002a;Rao et al, 2005;Glenn et al, 2007), and to parallel the time point that prenatal choline protects against seizure-induced memory deficits (Yang et al, 2000;Holmes et al, 2002).…”