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.

Running is a potent stimulator of cell proliferation in the adult dentate gyrus and these newly generated hippocampal neurons seem to be implicated in memory functions. Here we have used a mouse model expressing activated Ras under the direction of the neuronal Synapsin I promoter (named synRas mice). These mice develop down-regulated proliferation of adult hippocampal precursor cells and show decreased short-term recognition memory performances. Voluntary physical activity reversed the genetically blocked generation of hippocampal proliferating cells and enhanced the dendritic arborisation of the resulting doublecortin newly generated neurons. Moreover, running improved novelty recognition in both wild type and synRas littermates, compensating their memory deficits. Brain-derived neurotrophic factor (BDNF) has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors. This was confirmed here by the identification of doublecortin-immunoreactive cells expressing tyrosine receptor kinase B BDNF receptor. While no difference in BDNF levels were detected in basal conditions between the synRas mice and their wild type littermates, running was associated with enhanced BDNF expression levels. Thus increased BDNF signalling is a candidate mechanism to explain the observed effects of running. Our studies demonstrate that voluntary physical activity has a robust beneficial effect even in mice with genetically restricted neurogenesis and cognition.

Ataxin-2 (ATXN2) is implicated mainly in mRNA processing. Some ATXN2 associates with receptor tyrosine kinases (RTK), inhibiting their endocytic internalization through interaction of proline-rich domains (PRD) in ATXN2 with SH3 motifs in Src. Gain of function of ATXN2 leads to neuronal atrophy in the diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Conversely, ATXN2 knockout (KO) mice show hypertrophy and insulin resistance. To elucidate the influence of ATXN2 on trophic regulation, we surveyed interactions of ATXN2 with SH3 motifs from numerous proteins and observed a novel interaction with Grb2. Direct binding in glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation of the endogenous proteins indicated a physiologically relevant association. In SCA2 patient fibroblasts, Grb2 more than Src protein levels were diminished, with an upregulation of both transcripts suggesting enhanced protein turnover. In KO mouse embryonal fibroblasts (MEF), the protein levels of Grb2 and Src were decreased. ATXN2 absence by itself was insufficient to significantly change Grb2-dependent signaling for endogenous Ras levels, Ras-GTP levels, and kinetics as well as MEK1 phosphorylation, suggesting that other factors compensate for proliferation control. In KO tissue with postmitotic neurons, a significant decrease of Src protein levels is prominent rather than Grb2. ATXN2 mutations modulate the levels of several components of the RTK endocytosis complex and may thus contribute to alter cell proliferation as well as translation and growth.

A large number of endogenous and exogenous factors have been identified to upregulate and downregulate proliferation, differentiation and/or survival of newborn cells in the adult hippocampus. For studying neuronal mechanisms mediating the impact of those factors, we used a transgenic synRas mouse model expressing constitutively activated Valin12-Harvey Ras selectively in differentiated neurons. BrdU injections showed significantly reduced proliferation of new cells within the adult hippocampus of transgenic animals compared with their wild-type siblings. In contrast, the relative survival of newborn cells was increased in synRas mice, although this effect did not fully compensate for diminished proliferation. Inhibition of progenitor cell proliferation and enhancement of cellular survival were more pronounced in males compared with females. Double labelling and doublecortin immunostaining verified that specifically newborn neurons were decreased in synRas mice. Reduced cell generation was observed already 2 h after BrdU pulse injections, identifying an early precursor cell population as target of the inhibitory transgene effect. Differences in proliferation remained stable after 24 h and were specific for the subgranular zone of the dentate gyrus, as subventricular cell generation was not affected supporting a non-cell autonomous effect on neural hippocampal progenitors. Transgene expression only starts with synaptic differentiation and therefore reduced proliferation must represent an indirect secondary consequence of synRas activity in differentiated neurons. This was associated with impaired spatial short-term memory capacities as observed in a radial maze paradigm. Our data suggest that constantly high Ras activity in differentiated neurons downregulates hippocampal precursor cell generation in the neuronal lineage, but is modulated by sex-dependent factors.

Neurogenesis occurs in two neurogenic zones in the adult brain: new neurons are born at the subventricular zone of the lateral ventricles and then migrate to the olfactory bulb, and at the subgranular zone to integrate the granular cell layer of the dentate gyrus. The hippocampus is involved in learning and memory and the generation of new hippocampal neurons has been suggested to be a new form of plasticity implicated in these processes. In the last decades, diverse intrinsic and epigenetic factors have been identified to influence adult neurogenesis but the underlying mechanisms remain unclear. In a recent study, Lafenetre et al. (2010) showed the beneficial influence of physical voluntary activity on adult neurogenesis and cognitive performance in a transgenic mouse, the synRas mouse via brain-derived neurotrophic factor. Here we review how hippocampal neurogenesis can be regulated by environmental factors and the possible role of the newly generated cells in learning and memory.