Fetal alcohol exposure induces neurotoxic effects on β-endorphin neurons through microglial activation
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Cabrera, Miguel Alexander.
Fetal alcohol exposure induces neurotoxic effects on β-endorphin neurons through microglial activation. Retrieved from
https://doi.org/doi:10.7282/T3KW5KNS
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TitleFetal alcohol exposure induces neurotoxic effects on β-endorphin neurons through microglial activation
Date Created2018
Other Date2018-10 (degree)
Extent1 online resource (xv, 135 pages : illustrations)
DescriptionFetal 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.
NotePh.D.
NoteIncludes bibliographical references
Noteby Miguel Alexander Cabrera
Genretheses, ETD doctoral
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.