Champroux, A.; Sadat-Shirazi, M.; Chen, X.; Yang, Y.; Feig, L.

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induces stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not understood. Here we describe evidence for astrocyte-derived exosomes (A-Exos) containing miR-34c mediating how chronic social instability (CSI) stress suppresses levels of miR-34c in sperm that we showed previously contributes to how this stress protocol leads to elevated anxiety and defective sociability in their female offspring, as well as reduced sperm miR-34c in their male offspring. In particular, we found that CSI stress decreases the miR-34c content in A-Exos isolated from the prefrontal cortex and amygdala, as well as blood of CSI-stressed males. Strikingly, miR-34c content is also reduced in A-Exos isolated from these tissues of their F1 male offspring, who also display reduced sperm miR-34c levels despite never being directly exposed to stress and transmit these stress related traits to their offspring. In addition, restoring the blood A-Exos miR-34c content of CSI-stressed males by IV injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal a surprising role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.