Adult-born neurons promote cognitive flexibility by improving memory precision and indexing.

Adult neurogenesis in the hippocampal dentate gyrus (DG) is an extraordinary form of plasticity fundamental for cognitive flexibility. Recent evidence showed that newborn neurons differentially modulate input to the infra- and supra-pyramidal blades of the DG during the processing of spatial and contextual information, respectively. However, how this differential regulation by neurogenesis is translated into different aspects contributing cognitive flexibility is unclear. Here, we increased adult-born neurons by a genetic expansion of neural stem cells and studied their influence during navigational learning. We found that increased neurogenesis improved both memory precision and flexibility. Interestingly, each of these gains was associated with distinct subregional patterns of activity and better separation of memory representations in the DG-CA3 network. Our results highlight the role of adult-born neurons in promoting memory precision and indexing and suggests their anatomical allocation within specific DG-CA3 compartments, together contributing to cognitive flexibility.

Author Correction: Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life.

Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain's endogenous reserve of neural stem cells.

The RNA Processing Factor Y14 Participates in DNA Damage Response and Repair.

DNA repair deficiency leads to genome instability and hence human disease. Depletion of the RNA processing factor Y14/RBM8A in cultured cells or Rbm8a haplodeficiency in the developing mouse cortex results in the accumulation of DNA damage. Y14 depletion differentially affected the expression of DNA damage response (DDR) factors and induced R-loops, both of which threaten genomic stability. Immunoprecipitation coupled with mass spectrometry revealed DDR factors as potential Y14-interacting partners. Further results confirmed that Y14 interacts with Ku and several DDR factors in an ATM-dependent manner. Y14 co-fractionated with Ku in chromatin-enriched fractions and further accumulated on chromatin upon DNA damage. Y14 knockdown delayed recruitment of DDR factors to DNA damage sites and formation of γH2AX foci and also led to Ku retention on chromatin. Accordingly, Y14 depletion compromised the efficiency of DNA end joining. Therefore Y14 likely plays a direct role in DNA damage repair via its interaction with DDR factors.

Y14 governs p53 expression and modulates DNA damage sensitivity.

Y14 is a core component of the exon junction complex (EJC), while it also exerts cellular functions independent of the EJC. Depletion of Y14 causes G2/M arrest, DNA damage and apoptosis. Here we show that knockdown of Y14 induces the expression of an alternative spliced isoform of p53, namely p53ß, in human cells. Y14, in the context of the EJC, inhibited aberrant exon inclusion during the splicing of p53 pre-mRNA, and thus prevent p53ß expression. The anti-cancer agent camptothecin specifically suppressed p53ß induction. Intriguingly, both depletion and overexpression of Y14 increased overall p53 protein levels, suggesting that Y14 governs the quality and quantity control of p53. Moreover, Y14 depletion unexpectedly reduced p21 protein levels, which in conjunction with aberrant p53 expression accordingly increased cell sensitivity to genotoxic agents. This study establishes a direct link between Y14 and p53 expression and suggests a function for Y14 in DNA damage signaling.