No abstract

Cognitive impairment is a consequence of the normal aging process that effects many species, including humans and rodent models. Decline in hippocampal memory function is especially prominent with age and often reduces quality of life. As the aging population expands, the need for interventional strategies to prevent cognitive decline has become more pressing. Fortunately, several major lifestyle factors have proven effective at combating hippocampal aging, the most well-known of which are environmental enrichment and exercise. While the evidence supporting the beneficial nature of these factors is substantial, a less well-understood factor may also contribute to healthy cognitive aging: social engagement. We review the evidence supporting the role of social engagement in preserving hippocampal function in old age. In elderly humans, high levels of social engagement correlate with better hippocampal function, yet there is a dearth of work to indicate a causative role. Existing rodent literature is also limited but has begun to provide causative evidence and establish candidate mechanisms. Summed together, while many unanswered questions remain, it is clear that social engagement is a viable lifestyle factor for preserving cognitive function in old age. Social integration across the lifespan warrants more investigation and more appreciation when designing living circumstances for the elderly.

To manipulate target gene function in specific adult cell populations, tamoxifen (TAM)-dependent CreER T2 is widely used to drive inducible, site-specific recombination of loxP flanked sequences. In studies of cell autonomous target gene function, it is common practice to combine these CreER T2-lox systems with a ubiquitously expressed stop-floxed fluorescent reporter gene to identify single cells supposedly undergoing target gene recombination. Here, we studied the reliability of using Cre-induced recombination of one gene to predict recombination in another gene at the single-cell level in adult hippocampal neural stem and progenitor cells (NSPCs). Using both probabilistic predictions in a generic experimental paradigm, as well as a mouse model with two separate stop-floxed reporters plus a Nestin promoter-driven CreER T2 , we found that, in individual cells, recombination of one gene was a poor predictor of Significance Statement We investigate the reliability of a widely used transgenic mouse model in studies of adult neural stem and progenitor cells (NSPCs). Ligand-dependent Cre recombinases, such as the CreER T2 model, are a fundamental tool for inducible gene modification used to investigate gene function in many cell populations. It is common practice to combine NSPC-specific CreER T2-lox systems with a ubiquitously expressed stopfloxed fluorescent reporter gene to identify single cells undergoing target gene recombination in studies of cell autonomous gene function. Our probabilistic predictions and experimental data suggest that use of stop-floxed reporters to investigate cell autonomous gene function in NSPCs may lead to false conclusions because recombination in separate genes can show poor concordance in individual cells.

Review of Kawai et al. The adult brain of most mammalian species retains distinct areas of neurogenesis that potentially contribute to the proper functioning of neural circuits. One of these niches, the subependymal zone (SEZ), also commonly referred to as subventricular zone, harbors neural stem cells (NSCs) that, in rodents, generate new neurons that migrate to the olfactory bulb under physiological conditions (Kriegstein and Alvarez-Buylla, 2009; Gage and Temple, 2013). To optimally contribute to the function of neural circuits, NSCs must be able to sense signals arising locally within the SEZ niche or from distant brain regions and respond by adjusting the balance between proliferation and quiescence. Quiescent NSCs lay dormant, but poised for cell division, until transitioning to activated NSCs, which generate transitamplifying progenitors. Transient-amplifying progenitors undergo several rounds of proliferation before differentiating into neuroblasts, which, in turn, become immature neurons (Doetsch et al., 1999). Maintenance of stem cell pools and therefore normal neural function depends on

To manipulate target gene function in specific adult cell populations, tamoxifendependent CreER T2 is widely used to drive inducible, site-specific recombination of LoxP flanked sequences. In studies of cell autonomous target gene function, it is common practice to combine these CreER T2 -lox systems with a ubiquitously-expressed stop-floxed fluorescent reporter gene to identify single cells supposedly undergoing target gene recombination. Here, we studied the reliability of using Cre-induced recombination of one gene to predict recombination in another gene at the single cell level in adult hippocampal neural stem and progenitor cells. Using two separate stopfloxed reporters plus a Nestin promoter-driven CreER T2 , we found that, in individual cells, expression of one reporter was a poor predictor of expression of the other. These findings imply that use of stop-floxed reporters to investigate cell autonomous gene function is likely to lead to false conclusions because recombination in separate genes shows poor concordance in individual cells.