Microglia and Adolescent Susceptibility to Developing an Alcohol Use Disorder

Nearly 14% of the U.S. population meets diagnostic criteria for an alcohol use disorder, more commonly called alcoholism. Alcohol use and abuse often begins in adolescence where many factors collide to promote excessive intake. Most striking though is that those who drink during adolescence - specifically before age 15 - are four times more likely to develop an alcohol use disorder in adulthood. This suggests that alcohol impacts the adolescent brain in such a way to make it more susceptible to developing an alcohol use disorder. Indeed, the adolescent brain is susceptible to brain damage due to alcohol. Therefore, when considering what alcohol exposure changes long term in the adolescent brain, the effect of alcohol a cell type intricately involved in neurodegeneration caught our attention. Microglia are one of the three types of non-neuronal, glia cells in the brain. Microglia act as the brain’s immune system by actively sampling the local environment such that they are the first cells to respond to even the slightest change in ion balance. Microglia response to change or microglia activation is a hallmark of inflammation, but their role in the alcohol use disorders is not well understood. Recent theories have emerged detailing that microglia may become activated or “primed” by some event, then upon subsequent challenge they may aggressively over-respond. Microglia priming is also proposed in the early life stress programming literature, where early life exposure to stress or infection has long-term consequences on adult outcomes. Indeed, similar effects clearly occur here with the insult of excessive alcohol intake during adolescence and the long-term consequence of greater likelihood to develop an alcohol use disorder in adulthood. Thus, the underlying hypothesis of this proposal is that initial binge exposure during adolescence primes microglia, an effect that is long term, such that the brain has a greater reaction to alcohol in adulthood. This hypothesis will be tested across three specific aims that (1) examine how little alcohol it takes to activate microglia (2) test whether these activated microglia are primed and overrespond to challenge in adulthood and (3) whether greater damage and behavior deficits result. The emerging body of literature that early effects on the immune system i.e. microglia can change the inflammatory state of the organism such that it is primed for an aggressive inflammatory response in adulthood has intriguing implications for why many alcohol use disorders start in adolescence. Microglia can be primed by a variety of stimuli such as stress, pain, infection, or damage, which appears to explain, in part, why AUDs emerge in diverse populations – stress, depression, adolescent drinking, repeated damaging alcohol intake – all of these events may prime microglia. Hopefully, by understanding the events that prime the adolescent brain to be susceptible to developing an alcohol use disorders, better interventions and treatments can be developed so that we can reduce the incidence of alcohol use disorders.