Alcohol consumption and the rate of heavy binge drinking are becoming increasingly more common in adolescents. Data from the Monitoring the Future Survey found that 14% of 10th graders and 25% of 12th graders reported binge drinking (consuming more than four drinks in a row) in the last two weeks. There are several harmful consequences to heavy drinking during adolescence when the brain is still developing. For example, studies show that alcohol abuse during adolescence can lead to cognitive and neurobehavioral deficits. Drinking during adolescence may also increase the prevalence of alcohol use disorders in adulthood. The hippocampus, a brain region involved in learning and memory, has been shown to be highly sensitive to the effects of alcohol in adolescents. Even though several studies have investigated the effects of alcohol on behavior and neural development, few studies have looked at how drinking during adolescence interferes with normal brain function at the synaptic level. Recent studies have suggested the involvement of the chemokine CCL2 in alcohol consumption and alcoholic pathologies. Key brain signal transduction pathways shown to be regulated by CCL2 are also targets of alcohol action, which suggests that CCL2 may affect the actions of alcohol at the molecular level to alter the functional properties and synaptic circuitry of hippocampal neurons. The goal of the current proposal is to better understand how chronic exposure to elevated CCL2 levels as occurs with chronic alcohol use affects the actions of alcohol in the brain and to determine how this interaction affects hippocampal synaptic transmission in adolescent mice, which could help explain the cognitive deficits often seen with adolescent drinking. To study the effects of elevated levels of CCL2 on the actions of alcohol, we will utilize CCL2 transgenic mice, which have elevated CNS expression of CCL2 under the control of the GFAP promoter and their non-transgenic littermate controls. We hypothesize that the overexpression of CCL2 will cause significant alterations in the effects of alcohol on hippocampal synaptic transmission and plasticity as well as affect the behavioral aspects of hippocampal functioning altered by alcohol such as learning and memory. Electrophysiological techniques will be used to determine if chronic in vivo CCL2 exposure alters the effects of alcohol on hippocampal synaptic function in adolescent mice. Several behavioral tests, such as the Y-maze and Barnes maze will be used to determine if chronic in vivo CCL2 alters the effects of alcohol on hippocampal-dependent learning and memory. Achievement of the Specific Aims will enhance our understanding of how elevated levels of CCL2 as observed in the brains of alcoholics may affect the actions of alcohol to alter neuronal and synaptic functions that are critical for normal CNS function and behavior.
Drinking during adolescence can result in serious deficits in both cognitive function and neuronal development. Recent studies have demonstrated that neuroimmune factors are upregulated in the CNS following alcohol use and may contribute to the cognitive deficits often seen with adolescent drinking. Since limited information is available on this topic, the proposed studies will investigate potential alterations in CNS function resulting from elevated levels of neuroimmune factors and their effects on the actions of alcohol during adolescence.
| Bray, Jennifer G; Reyes, Kenneth C; Roberts, Amanda J et al. (2018) Altered hippocampal synaptic function in transgenic mice with increased astrocyte expression of CCL2 after withdrawal from chronic alcohol. Neuropharmacology 135:113-125 |
| Bray, Jennifer G; Roberts, Amanda J; Gruol, Donna L (2017) Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol. Neuroscience 354:88-100 |
