Role of microglia in stress-induced alcohol intake in female and male mice

Rates of alcohol use disorder (AUD) have escalated in recent years, with a particular increase among women. Women are more susceptible to stress-induced alcohol drinking, and preclinical data suggest that stress can increase alcohol intake in female rodents; however, a comprehensive understanding of sex-specific neurobiological substrates underlying this phenomenon is still emerging. Microglia, the resident macrophages of the brain, are essential for reshaping neuronal processes, and microglial activity contributes to overall neuronal plasticity. We investigated microglial dynamics and morphology in limbic brain structures of male and female mice following exposure to stress, alcohol or both challenges. In a modified paradigm of intermittent binge drinking (repeated "drinking in the dark"), we determined that female, but not male, mice increased their alcohol consumption after exposure to a physical stressor and re-exposure trials in the stress-paired context. Ethanol (EtOH) drinking and stress altered a number of microglial parameters, including overall number, in subregions of the amygdala and hippocampus, with effects that were somewhat more pronounced in female mice. We used the CSF1R antagonist PLX3397 to deplete microglia in female mice to determine whether microglia contribute to stress-induced escalation of EtOH intake. We observed that microglial depletion attenuated stress-induced alcohol intake with no effect in the unstressed group. These findings suggest that microglial activity can contribute to alcohol intake under stressful conditions, and highlight the importance of evaluating sex-specific mechanisms that could result in tailored interventions for AUD in women.