During early brain development, microglial activation can negatively impact long-term neuroimmune and cognitive outcomes. It is well-known that significant alcohol exposure during early gestation results in a number of cognitive deficits associated with fetal alcohol spectrum disorders (FASD). Additionally, microglia are activated following high levels of alcohol exposure in rodent models of FASD. We sought to examine whether moderate prenatal alcohol exposure (70 mg/dL blood alcohol concentration) activates microglia in the fetal rat brain, and whether moderate fetal alcohol exposure has long-term negative consequences for immune function and cognitive function in the rat. We also measured inflammation within the placenta and maternal serum following moderate alcohol exposure to determine whether either could be a source of cytokine production in the fetus. One week of moderate prenatal alcohol exposure produced a sex-specific increase in cytokines and chemokines within the fetal brain. Cytokines were also increased within the placenta, regardless of the sex of the fetus, and independent of the low levels of circulating cytokines within the maternal serum. Adult offspring exposed to alcohol prenatally had exaggerated cytokine production in the brain and periphery in response to lipopolysaccharide (25 μg/kg), as well as significant memory deficits precipitated by this low-level of inflammation. Thus the immune system, including microglia, may be a key link to understanding the etiology of fetal alcohol spectrum disorders and other unexplored cognitive or health risks associated with even low levels of fetal alcohol exposure.

One contribution of 16 to a theme issue 'Multifaceted origins of sex differences in the brain'. Early-life exposure to drugs and alcohol is one of the most preventable causes of developmental, behavioural and learning disorders in children. Thus a significant amount of basic, animal and human research has focused on understanding the behavioural consequences and the associated neural effects of exposure to drugs and alcohol during early brain development. Despite this, much of the previous research that has been done on this topic has used predominantly male subjects or rodents. While many of the findings from these male-specific studies may ultimately apply to females, the purpose of this review is to highlight the research that has also examined sex as a factor and found striking differences between the sexes in their response to early-life opiate and alcohol exposure. Finally, we will also provide a framework for scientists interested in examining sex as a factor in future experiments that specifically examine the consequences of early-life drug and alcohol exposure.

BackgroundIn addition to its classical effects on opioid receptors, morphine can activate glia and stimulate the production of pro-inflammatory immune molecules which in turn counteract the analgesic properties of morphine. We hypothesized that decreased morphine analgesia in females may be the result of exaggerated microglial activation in brain regions critical for analgesia.MethodsMale and female rats were treated with morphine and/or minocycline and morphine analgesia was examined using the hot plate. We also examined the expression of microglial and astrocyte markers in the pain pathway.ResultsMales treated with minocycline, a microglial inhibitor, exhibited a significant increase in acute morphine analgesia as previously shown; however, morphine analgesia was not affected by minocycline pretreatment in female rats. Minocycline decreased the expression of glial activation markers in the male spinal cord and periaqueductal gray as expected; however, these same molecules were upregulated in the female.ConclusionsThese data describe a significant difference between males and females in the behavioral effects following co-administration of morphine and minocycline.

Microglia, the immune cells of the brain, are important and necessary for appropriate neural development; however, activation of microglia, concomitant with increased levels of secreted immune molecules during brain development, can leave the brain susceptible to certain long-term changes in immune function associated with neurological and developmental disorders. One mechanism by which microglia can be activated is via alcohol exposure. We sought to investigate if low levels of prenatal alcohol exposure can alter the neuroimmune response to a subsequent acute dose of alcohol in adulthood. We also used the novel object location and recognition memory tasks to determine whether there are cognitive deficits associated with low prenatal alcohol exposure and subsequent adulthood alcohol exposure. We found that adult rats exposed to an acute binge-like level of alcohol, regardless of gestational alcohol exposure, have a robust increase in the expression of Interleukin (IL)-6 within the brain, and a significant decrease in the expression of IL-1β and CD11b. Rats exposed to alcohol during gestation, adulthood, or at both time points exhibited impaired cognitive performance in the cognitive tasks. These results indicate that both low-level prenatal alcohol exposure and even acute alcohol exposure in adulthood can significantly impact neuroimmune and associated cognitive function.

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