Increased miR-181a-5p Expression Improves Neural Stem Cell Activity, Learning, and Memory in Old Mice

Neurogenesis occurs throughout life to support the changes in neural structure inherent in learning and memory. It also provides some resilience to brain injury, when it comes to maintaining and restoring function. In the process of neurogenesis, new daughter neurons are generated by neural stem cells, and then mature and integrate into existing neural networks in brain tissue. This is all largely studied in mice, due to the difficulties inherent in obtaining access to living human brains, but despite some debate it is reasonable to assume that learning and memory in our species are similarly supported by ongoing neurogenesis throughout life.

Unfortunately, stem cell populations decline in activity with advancing age. This is in part the result of intrinsic damage to the cells themselves, but also a response to altered signaling and dysfunction in stem cell niches. The chronic inflammation of aging, for example, appears to have a strongly negative impact on stem cell function. Thus the pace of neurogenesis is much reduced in old individuals, and experiments in mice indicate that this is an important part of the loss of memory function that occurs with aging. Given this, there is some interest in finding ways to boost neurogenesis, to override the reaction of stem cells to the aged tissue environment, and reduce age-related memory dysfunction. Today's open access paper is one example of this sort of research.

MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice

The hippocampus is a brain region closely related to spatial learning and memory. Adult neural stem cells (NSCs), which are located in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, play important roles in the function of the hippocampus. NSCs have the ability to proliferate, either generating two NSCs to maintain NSC pools through symmetric division or generating one NSC and one neural progenitor cell (NPC) through asymmetric division. NPCs then further differentiate into particular cell types, such as neurons or astrocytes. Studies on rodents have shown that proliferation and neurogenesis of NSCs persist throughout the lifespan; however, adult neurogenesis decreases with age, and this decrease is involved in cognitive and memory declines, indicating that abnormalities in hippocampal NSCs are one of the main causes of age-related deterioration in hippocampus-dependent cognition.

Proliferation and neurogenesis of NSCs are exquisitely regulated by extrinsic and intrinsic factors, including secreted molecules, neurotransmitters, transcription factors, and epigenetic regulators. Among these, miRNAs, which are enriched in the brain, have been shown to be widely involved in the regulation of NSC proliferation and differentiation. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes.

The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.