Role of exosomes in ethanol-induced neurotoxicity

Project Details

Description

Fetal alcohol spectrum disorders (FASD) include a range of maladies caused by chronic alcohol exposure during pregnancy. It is documented that approximately 2% to 5% of children born in the United States have FASD. Clinical studies have shown children and adults with FASD often show hyperresponsiveness to stress and are vulnerable to psychiatric disorders, particularly mood disorders. The neurobiology of these emotional disturbances are not well understood, but studies utilizing animal models of fetal alcohol exposure have shown that prenatal or early-postnatal ethanol exposure in laboratory rats and mice disrupts the hypothalamic- pituitary-adrenal axis function and its physiological response to stress and promotes anxiety-like behaviors. Both prenatal ethanol exposure and postnatal ethanol exposure induce hypothalamic proopiomelanocortin neuronal death and reduce levels of proopiomelanocortin and its peptide product ?-endorphin, as well as the ?- endorphin peptide's inhibitory control of the hypothalamic-pituitary-adrenal axis function. Replenishment of ?- endorphin neurons via neuronal transplantation prevents stress and behavioral problems in fetal alcohol- exposed animals, indicating that ?-endorphin deficiency is a significant contributor to the stress and behavioral abnormalities in these animals. The mechanism by which ?-endorphin neurons experience apoptosis following fetal alcohol exposure is not well understood. There are several preclinical and clinical evidences that suggest microglia, one of the immune cells in the central nervous system, play a major role in the regulation of alcohol-induced neuronal damage. Recent studies show that inflammatory cytokines can be released in association with small extracellular vesicles, called exosomes, from microglia. These exosomes are comprised of a lipid bilayer, transmembrane proteins, and cytosolic components derived from their host cells. However, the role of microglial exosomes in alcohol-induced neurotoxicity has not been well studied. In this proposal, we propose to determine if microglia use exosomes to induce ethanol-induced ?-endorphin neuronal death and stress axis functions. We also propose to use proteomic and genomic measurements to identify if ethanol treatment during the postnatal period increases levels of chemokines, complements, and microRNAs in microglial exosomes. Additionally, we propose to identify the exosome biomolecules that have apoptotic effects on ?-endorphin neurons. Together these studies should establish how prenatal ethanol modifies contents of proteins and genes within exosomes to induce ?-endorphin neuronal apoptosis that may lead to stress axis hyperresponsiveness and increased anxiety behavior. Additionally, the proposed studies may identify a novel therapeutic approach to prevent some of the neurological problems that occur in FASD patients.
StatusActive
Effective start/end date9/1/218/31/22

ASJC

  • Neuroscience(all)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.