Protective effects of ovarian hormones: sex-specific differences in tlr4 expression after adolescent alcohol

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PROJECT SUMMARY/ABSTRACT Early onset of alcohol drinking is associated with an increased lifetime risk of alcohol use disorder (AUD) and impairment of cognitive functions dependent on the prefrontal cortex (Jennison, 2004; Townshend and Duka, 2005). Understanding how alcohol impacts the developing adolescent brain can help us identify molecular and cellular pathways to target for therapeutic intervention. Our lab has shown that just two weeks of voluntary alcohol drinking in early adolescence (during pubertal maturation) leads to reduced myelinated fiber density in the prefrontal cortex in males (Vargas et al., 2014), without measurable changes in female rats (unpublished). This sex difference may reflect differential upregulation of toll-like receptor 4 (TLR4), as this receptor has been shown to orchestrate a neuroinflammatory response (Blanco et al., 2010) and mediate myelin damage after heavy or prolonged alcohol exposure (Alfonso-Loeches et al., 2012). In support of this hypothesis, my dissertation research has confirmed that alcohol drinking upregulates TLR4 mRNA in the prefrontal cortex of male, but not female adolescent rats (Aim 1). Gonadal hormones have been shown to have neuroprotective and anti-inflammatory effects (Vegeto et al., 2003), however, their role in alcohol-mediated disruptions, like upregulation of toll-like receptors, remains unknown. Therefore, in the F99 predoctoral phase of this proposal I will test the role of circulating gonadal hormones in protecting females against these effects and identify the glial population involved. After I am done with my dissertation, my goal for the K00 phase is to study how the neuroimmune system adapts after alcohol exposure during adolescence, and how these neuroadaptations may contribute to alcohol abuse and alcohol use disorder later in life. Specifically, I will use RNAseq, transgenic animal models, primary cell cultures, and ChIP, along with mRNA and protein assays learned in the F99 phase, to answer how epigenetic changes induced by alcohol, especially those targeting neuroinflammatory genes, contribute to changes in biological function of different cell types and how this in turn regulates behavior. My ultimate goal for this research is to gain insight into the epigenetic targets of alcohol, which will help identify potential therapeutics for drug addiction and neurodegenerative disorders.