Early-life exercise primes the murine neural epigenome to facilitate gene expression and hippocampal memory consolidation.

Aerobic exercise is well known to promote neuroplasticity and hippocampal memory. In the developing brain, early-life exercise (ELE) can lead to persistent improvements in hippocampal function, yet molecular mechanisms underlying this phenomenon have not been fully explored. In this study, transgenic mice harboring the "NuTRAP" (Nuclear tagging and Translating Ribosome Affinity Purification) cassette in Emx1 expressing neurons ("Emx1-NuTRAP" mice) undergo ELE during adolescence. We then simultaneously isolate and sequence translating mRNA and nuclear chromatin from single hippocampal homogenates containing Emx1-expressing neurons. This approach allowed us to couple translatomic with epigenomic sequencing data to evaluate the influence of histone modifications H4K8ac and H3K27me3 on translating mRNA after ELE. A subset of ELE mice underwent a hippocampal learning task to determine the gene expression and epigenetic underpinnings of ELE's contribution to improved hippocampal memory performance. From this experiment, we discover gene expression - histone modification relationships that may play a critical role in facilitated memory after ELE. Our data reveal candidate gene-histone modification interactions and implicate gene regulatory pathways involved in ELE's impact on hippocampal memory.

An Improved Method for Individual Tracking of Voluntary Wheel Running in Pair-housed Juvenile Mice.

Rodent cages equipped with access to a voluntary running wheel are commonly used to study the effects of aerobic physical activity on physiology and behavior. Notable discoveries in exercise neurobiology, including the key role of brain-derived neurotrophic factor (BDNF) in neural plasticity and cognition, have been made using rodents housed with voluntary running wheels. A major advantage of using home-cage running wheels over treadmills is the elimination of stress potentially associated with forced running. In addition, voluntary wheel running may simulate a more natural running pattern in laboratory mice. Singly housing mice with voluntary running wheels is traditionally employed to obtain exact quantitation of the distance ran; however, social isolation stress is often ignored to obtain precise running distances. Moreover, voluntary exercise studies in adolescent mice must consider the neurodevelopmental implications of isolation stress. In this protocol, we wean 21-day-old mouse pups directly into running wheel-equipped cages and pair-house them to reduce the impact of social isolation and other developmentally specific factors that could adversely affect their behavior or development. Individual running distances are obtained from each mouse in the cage using a radio-frequency identification (RFID) ear tag and a hidden antenna placed directly under the running wheel. We have demonstrated that voluntary running during a specific juvenile-adolescent developmental period can improve hippocampal memory when tested during adolescence ( Ivy et al., 2020 ). Individual exercise tracking of group-housed mice can enable future studies to precisely correlate the amount of exercise with readouts such as cell-specific gene expression, epigenetic mechanisms, serum biomarkers, and behavior, in an intra-individual manner. Graphic abstract: Figure 1.Illustration of the dual RFID and Vital View system for individual mouse running in a pair-housed cage.