Abstract
BackgroundAn excess of exosomes, nanovesicles released from all cells and key regulators of brain plasticity, is an emerging therapeutic target for stress-related mental illnesses. The effects of chronic stress on exosome levels are unknown; even less is known about molecular drivers of exosome levels in the stress response. MethodsWe used our state-of-the-art protocol with 2 complementary strategies to isolate neuronal exosomes from plasma, ventral dentate gyrus, basolateral amygdala, and olfactory bulbs of male mice to determine the effects of chronic restraint stress (CRS) on exosome levels. Next, we used RNA sequencing and bioinformatic analyses to identify molecular drivers of exosome levels. ResultsWe found that CRS led to an increase in the levels of neuronal but not total (not neuronally enriched) exosomes assayed in plasma and the ventral dentate gyrus, whereas CRS led to a decrease in neuronal but not total exosome levels in the basolateral amygdala. There was a specificity of effects as shown by a lack of changes in olfactory bulb exosome levels. In pursuit of advancing translational applications, we showed that acetyl-L-carnitine administration restored a CRS-induced increase in neuronal exosome levels assayed in plasma (the most accessible specimen). Furthermore, CRS-induced transcriptional changes in the ventral dentate gyrus and basolateral amygdala mirrored the opposite pattern of CRS-induced changes in neuronal exosome levels, with β-estradiol signaling as a potential upstream driver of exosome levels. ConclusionsThis study provides a foundation for future studies of new forms of local and distant communication in stress neurobiology by demonstrating specific relationships between peripheral and central neuronal exosomes and providing new candidate targets for the normalization of exosome levels.
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