Alcohol abuse is common among adolescents. Unfortunately, alcohol abuse during this vulnerable period of brain development can lead to long-term molecular and behavioral changes. A growing body of research suggests a role for microglia - the resident macrophages of the brain - in the detrimental effects of alcohol. This proposal outlines experiments to determine the long-term effects of adolescent alcohol on microglia and the role of microglia in the long-term effects of adolescent alcohol. Microglia normally exist in a resting state, but in response to insults can undergo activation. There are multiple types of microglial activation, each with different functional outcomes that range from destructive to reparative. Activation is frequently associated with increases in microglial markers, although this does not always indicate what functional changes have taken place. Previous studies find that adolescent alcohol treatment increases levels of microglial marker CD11b, an integrin component involved in process reorganization. However, increased CD11b does not indicate what functional changes - either toxic or healing - AIE has caused in the microglia.
Aim 1 will investigate the long- term effects of adolescent intermittent ethanol (AIE) treatment on microglial functional changes. Rats will be treated with AIE and microglia will be isolated during adulthood. Techniques such as flow cytometry, RT-PCR and ELISA will be used to assess changes in microglial markers and expression of pro-inflammatory and anti- inflammatory cytokines.
Aim 2 will investigate the long-term effects of AIE on the microglial response to activating stimuli. Increased microglial markers such as CD11b are indicative of a phenomenon known as priming. When microglial are primed, they exhibit an enhanced response to activating stimuli. Various stimuli, such as stress and systemic inflammation, can activate microglia. Rats will be treated with AIE and challenged with either acute stress or systemic inflammation during adulthood. Immunohistochemistry will be used to examine the long-term effects of AIE on the microglial response to these activating stimuli. Lastly, Aim 3 will determine the role of microglia in the long-term effects of AIE. A microglial inhibitor, ibudilast, will be administered during AIE treatment. Molecular and behavioral changes caused by AIE, such as increased brain neuroimmune proteins, increased anxiety, and decreased cognitive function will be examined during adulthood. These studies will address important unanswered questions about the consequences of adolescent alcohol abuse. Very little is known about the long-term effects of adolescent alcohol on microglia or the contributions of microglia to the long-term effects of adolescent alcohol. The results have potential to change the way we think about the neurobiology of adolescent alcohol abuse. Given the widespread extent of adolescent alcohol abuse, these studies could help guide preventative strategies, or provide potential targets for pharmacotherapy.
Adolescent alcohol abuse is common, and microglia, the immune cells of the brain, may be involved in the detrimental effects of excessive alcohol use. However, very little is known about adolescent alcohol abuse and microglia. This work will study how adolescent alcohol impacts microglia and how microglia contribute to the effects of adolescent alcohol, thereby providing important insight into the neurobiology and consequences of alcohol abuse during this period.
| Walter, Thomas Jordan; Vetreno, Ryan P; Crews, Fulton T (2017) Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects. Alcohol Clin Exp Res 41:2066-2081 |
| Walter, T Jordan; Crews, Fulton T (2017) Microglial depletion alters the brain neuroimmune response to acute binge ethanol withdrawal. J Neuroinflammation 14:86 |
| Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan et al. (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56-73 |
| Vetreno, Ryan P; Patel, Yesha; Patel, Urvi et al. (2017) Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise. Brain Behav Immun 60:333-345 |
| Crews, Fulton T; Walter, T Jordan; Coleman Jr, Leon G et al. (2017) Toll-like receptor signaling and stages of addiction. Psychopharmacology (Berl) 234:1483-1498 |
