Mice Exposed to Combined Chronic Low-Dose Irradiation and Modeled Microgravity Develop Long-Term Neurological Sequelae

Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model, simulated microgravity via hindlimb unloading (HLU) and/or low-dose irradiation (LDR) for 21-days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in whole brain samples during readaptation were analyzed by DESeq2 and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression alterations at 4-months within single treatment conditions of HLU and LDR. Following combined HLU+LDR, gene ontology and methylation analyses showed multiple altered pathways involved in neurogenesis and neuroplasticity, regulation of neuropeptides and cellular signaling. In brief, neurological readaptation following combined chronic LDR and HLU is a dynamic process that impacts brain structure and function and may lead to late onset neurological sequelae