Scientists have discovered that the metabolic molecule acetate enhances the formation of long-term memories – and that these memory-enhancing effects are far more pronounced in female mice. The discovery reveals a stark, but previously unknown, sex difference in the epigenetic mechanisms that support memory formation. The body produces acetate when it breaks down alcohol, glucose, and dietary fibers. It is also a key player in an epigenetic process known as histone acetylation, which is known to contribute to learning and memory formation. In this study, Erica Periandri and colleagues theorized that acetate itself acts as a memory enhancer, independently of its role in the breakdown of alcohol and carbohydrates. Using a combination of behavioral, proteomic, and genomic analyses, the team examined the impact of administering acetate in both male and female mice. Surprisingly, acetate potentiated the formation of long-term memories in female mice when given before tests that assess spatial memory and recognition of novel objects. However, the effects in male mice were far less pronounced. Periandri et al. observed that acetate strengthened memories by reprogramming epigenetic and transcriptional pathways in the dorsal hippocampus – the region of the brain responsible for memory formation. Specifically, acetate administration in females accelerated the acetylation of a histone named H2A.Z and boosted the expression of learning-associated genes during the critical early window of memory consolidation. “Our findings suggest that acetate treatment could be a promising, noninvasive approach to enhance memory, particularly in females, who are disproportionately affected by both age-related cognitive decline and [Alzheimer’s disease],” Periandri et al. speculate.

Cell lines derived from human induced pluripotent stem cells (iPSCs) have the potential to overcome some of the limitations and challenges of animal models in neurodevelopment and disease research. Now, a new study offers insight into the iPSC-derived cell line KOLF2.IJ, which has been proposed as a neuron model for Alzheimer’s disease and related dementia research. In the work, Ying Hao and colleagues analyzed the changes in protein abundance and phosphorylation that occurred during neuronal differentiation of KOLF2.IJ cells. The various stages of differentiation revealed changes in the abundance of proteins related to the function of mitochondria and the activation of proteins involved in cellular structure and motility and molecular transport. This included stage-specific activation (such as CDK-mediated signaling for pluripotency exit and mitochondrial proteins for neuron maturation) and broader, more dynamic changes spanning multiple stages (such as those related to cell metabolism). The team also observed that changes at these translational and posttranslational levels were not universally detectable or predictable from changes at the transcriptional level, particularly those related to the function of axons and RNA transport. These data reveal a “neuronal differentiation kinome” that highlights the role of kinases in these functions during differentiation and neuronal maturation. The findings form a baseline profile to assess changes during neurodevelopment and neurodegeneration in this cell model. “Future advances in single-cell [multi-omic dataset integration] could provide deeper insights into the heterogeneity of neuronal populations and their developmental trajectories,” the authors write.