Role of Brain Derived Extracellular Vesicles in Decoding Sex Differences Associated with Nicotine Self-Administration

Authors

Sneh Koul, University of Nebraska Medical CenterFollow
Victoria L. Schaal, University of Nebraska Medical CenterFollow
Subhash Chand, University of Nebraska Medical Center, OmahaFollow
Steven T. Pittenger, University of Nebraska-Lincoln & National Institutes of Health, BethesdaFollow
Neetha Nanoth Vellichirammal, University of Nebraska Medical Center, OmahaFollow
Vikas Kumar, University of Nebraska Medical Center, OmahFollow
Chittibabu Guda, University of Nebraska Medical Center, OmahaFollow
Rick A. Bevins, University of Nebraska-LincolnFollow
Sowmya V. Yelamanchili, University of Nebraska Medical CenterFollow
Gurudutt Pendyala, University of Nebraska Medical Center, OmahaFollow

ORCID IDs

https://orcid.org/0000-0002-2868-389X

https://orcid.org/0000-0002-2072-2743

https://orcid.org/0000-0002-5393-9316

https://orcid.org/0000-0003-1530-0527

Date of this Version

2020

Citation

2020 by the authors

Comments

Cells 2020, 9, 1883; doi:10.3390/cells9081883 www.mdpi.com/journal/cells

Abstract

Smoking remains a significant health and economic concern in the United States. Furthermore, the emerging pattern of nicotine intake between sexes further adds a layer of complexity. Nicotine is a potent psychostimulant with a high addiction liability that can significantly alter brain function. However, the neurobiological mechanisms underlying nicotine’s impact on brain function and behavior remain unclear. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation. To fill in this critical knowledge gap, our current study focused on identifying sex-specific brain-derived extracellular vesicles (BDEV) signatures in male and female rats post nicotine self-administration. Extracellular vesicles (EVs) are comprised of phospholipid nanovesicles such as apoptotic bodies, microvesicles (MVs), and exosomes based on their origin or size. EVs are garnering significant attention as molecules involved in cell–cell communication and thus regulating the pathophysiology of several diseases. Interestingly, females post nicotine self-administration, showed larger BDEV sizes, along with impaired EV biogenesis compared to males. Next, using quantitative mass spectrometry-based proteomics, we identified BDEV signatures, including distinct molecular pathways, impacted between males and females. In summary, this study has identified sex-specific changes in BDEV biogenesis, protein cargo signatures, and molecular pathways associated with long-term nicotine self-administration.