Experience-mediated transcriptional memory correlates with hypoxia resistance in the nervous system of the sea hare .

Current therapeutics for hypoxic/ischemic brain damage can benefit from insights resulting from the study of hypoxia/anoxia resistant organisms. Hypoxia resistance, however, is not a common feature in mammalian models. Being naturally exposed to hypoxic/anoxic conditions, the sea hare could become a very useful model for the study of hypoxia resistance. Here we experimentally exposed two cohorts of , resulting from crosses of adults with different environmental exposure histories, to daily 6h pulses of hypoxic water conditions (<1.8 mgO/ml) for 6 consecutive days. The transcriptional response to hypoxia was evaluated in the abdominal and pleural/pedal ganglia through the exposure, during rapid reoxygenation, and after 12+ hours of recovery. Resistance to hypoxia was observed in the offspring of wild animals, with no significant changes in growth and reflex performance, compared to unexposed controls of the same cohort. Impairments were observed however in the offspring of lab-reared individuals. Transcriptional response to hypoxia was larger in the abdominal ganglia compared to the pleural/pedal for both cohorts, and significant differences between cohorts were observed for both ganglia. Overall, wild-cross animals displayed a significant reduction in the expression of metabolic genes, and an increased expression of genes involved in stress-response and immune system functions compared to the lab-cross cohort, both under control conditions and during hypoxia exposures. The resistant group displayed similar gene-level regulation as that described to be involved in hypoxia/ischemia preconditioning (HPC/IPC) in mammalian models, including the frontloading of HIF1-a orthologs and other neuroprotective genes like VEGF and HSP70.