Specific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory

We utilized an unbiased RNA-sequencing approach to uncover genes in the dorsal hippocampus that are differentially expressed under conditions where exercise benefits are maintained throughout sedentary delay periods and enable the formation of long-term memory and synaptic plasticity. Engagement in different exercise parameters resulted in a diverse transcriptional profile as defined by differences in the number, pattern, and type of genes up and down-regulated. To identify genes that play a critical role in cognitive enhancement, we next focused our attention on exercise groups that enable robust long-term memory formation under inadequate subthreshold acquisition sessions of the hippocampus-dependent object location memory task. By intersecting up regulated genes when exercise facilitated learning, we identify potential regulators of learning and targets for memory enhancement. We identify a gene coding for a type 1 membrane receptor and kinase for the TGF-β family of signaling molecules, Acvr1c as one of few genes showing upregulation in conditions where exercise enabled the formation of long-term memory, indicating a gate-type role for Acvr1c in memory consolidation. In addition to overall gene expression levels, we identify potential regulators upstream of gene targets within the window for cognitive enhancement. Additionally, we use three complementary analyses to examine the mechanisms responsible for maintaining the ‘molecular memory window’ for exercise utilizing up regulated differentially expressed genes compared to sedentary controls. These analyses include: gene coexpression network analysis to identify potential hub genes for each exercise condition, predicted pathways altered by exercise, and gene ontology enrichment analysis of cellular components altered by exercise. Together, results identify Acvr1c as one of few genes up regulated only under conditions where exercise enabled the formation of long-term memory and synaptic plasticity, suggesting a role for Acvr1c in facilitation of memory consolidation. Follow up experiments manipulating ACVR1C function, find that it serves as an essential bidirectional regulator of long-term memory formation capable of alleviating impairments in hippocampus-dependent memory and synaptic plasticity associated with age and Alzheimer’s Disease. We employed genome-wide RNA-sequencing to analyze transcriptional profiles underlying exercise-enhanced learning in the hippocampus. Adult male mice underwent different periods of exercise including: initial exercise (2 weeks), a sedentary delay period (1-2 weeks), and a brief 2-day period of reactivating exercise, followed by 3 min subthreshold training in an object location memory (OLM) task. We utilized these exercise parameters to examine effects of exercise on gene expression in the hippocampus occurring during memory consolidation, 1 hour following acquisition in a subthreshold version of the object location memory task (OLM). Exercise Parameters (days of: initial exercise-sedentary delay-exercise re-introduction) Harvest Cohort 1 or 2 (within 4 hour window, separated by 24hrs)