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theses

Fetal alcohol exposure has many detrimental effects on the developing brain and can cause fetal alcohol spectrum disorders (FASDs). Many FASDs patients show lifelong stress response abnormalities, demonstrated by an augmented response to stress hormones such as adrenocorticotropin and corticosterone (Lee et al., 2000), which are likely driven by alterations the hypothalamic-pituitary-adrenal (HPA) axis function (Zhang et al., 2005). Using a rat animal model, we have shown that postnatal ethanol exposure reduces the number and function of stress regulatory β-endorphin producing neurons in the hypothalamus, inducing a hyper-stress response (Sarkar et al., 2007; Logan et al., 2015). Microglia are one of the innate immune cells in the CNS and can be categorized as activated or ramified. Activated microglia are associated with an increase in proinflammatory responses and phagocytosis while ramified microglia are associated with maintaining homeostasis through dynamic communication, remodeling of neuronal synapses, and surveying the environment (Bell-Temin et al., 2013). How β-endorphin neurons communicate with microglia to maintain normal homeostasis has yet to be addressed. β-endorphin can also bind to both mu- and delta-opioid receptors and may serve as a form of communication between β-endorphin neurons and microglia. Exosomes are small vesicles (30-150 nm) that play an important role in local and distant communication between cells. They carry unique cargo (proteins, mRNA, miRNA, and other non-coding RNAs) from the cells they originate from that can affect the recipient cell’s homeostasis and induce apoptosis. Additionally, complement proteins, generally known for their role to opsonize foreign pathogens and support phagocytosis of dying cells may also play a role in ethanol-induced β-endorphin neuronal cell death. Here I demonstrate that ethanol-induced apoptosis of β-endorphin neurons is caused by activation of microglia to release proinflammatory cytokines, pro-apoptotic exosomes, and C1q. Furthermore, mu-opioid receptors activation is critical to ethanol-induced activation of microglia to induce apoptosis of β-endorphin neurons and antagonism of mu-opioid receptors attenuated the ethanol effect. Delta-opioid receptors antagonism did not have an effect on ethanol-induced β-endorphin neuronal cell death.

ETD_9338

doi:10.7282/T3KW5KNS

Ph.D.

Includes bibliographical references

by Miguel Alexander Cabrera

ETD doctoral

The author owns the copyright to this work.