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I cannot stop after the first ‘drink’! Alcohol effects on the inhibitory control brain systems

Grant number: 19/01686-0
Support type:Research Grants - Young Investigators Grants
Duration: September 01, 2019 - August 31, 2024
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Karina Possa Abrahão
Grantee:Karina Possa Abrahão
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Decades of scientific studies have collected data on how alcohol (ethanol) can affect the brain. The development of new technologies has made possible the study of the effects of alcohol in specific brain pathways that are associated with the most diverse physiological functions. The lack of control over ethanol consumption is one of the main characteristics of the binge drinking and the relapse during abstinence. However, few studies have focused on how ethanol interferes with the brain sys-tems of inhibitory control. We hypothesized that ethanol itself alters the function of neuronal sys-tems of decision-making and inhibitory control to affect the ability to self-control. To that end, we will study the pattern (microstructure) of ethanol consumption by C57Bl/J6 mice (natural drinkers of high amounts of ethanol) and Swiss mice (outbred mice for the study of behavioral variability), males and females, which will allow a better understanding about the characteristics of the uncon-trolled ethanol consumption. In addition, we will study the physiological effects of ethanol on the synaptic activity of brain regions that are part of the inhibitory control system: cortex and subtha-lamic nucleus, subthalamic nucleus and globus pallidus; and globus pallidus and striatum. Using the Cre-Flox transgenic system, we will use photometry of Ca2+ activity (GCaMP protein) to measure the activity of specific synaptic boutons; and electrophysiology (patch clamp and optogenetics) to measure synaptic activity of each of the synapses of the regions mentioned above. Finally, we will use the chemogenetic (DREADDs) to artificially mimic the effects of ethanol observed in the pho-tometry and electrophysiology experiments. This will allow us to manipulate the specific pathway of the brain in vivo and observe the behavioral consequences (ethanol consumption with the protocol studied in the first stage of this project) of each of the ethanol's effect on the inhibitory control brain systems. The findings of this project will allow a broad understanding of maladaptation of decision making and inhibitory control, which may help in the development of better interventions for patients with problems associated with alcohol use disorders. In addition, the results will help to better understand the brain pathways associated with other neurological and psychiatric diseases. (AU)