PROJECT SUMMARY / ABSTRACT Human clinical work indicates that the stimulant and sedative responses to alcohol (ethanol; EtOH) represent risk factors for the development of alcohol use disorder (AUD). Human neuroimaging studies and preclinical work both implicate the dorsal striatum as an important regulator of EtOH’s stimulant and sedative effects. Balanced activity in the direct and indirect striatal pathways is thought to confer resiliency against maladaptive EtOH-related behaviors, but the underlying mechanism of how this balance is maintained remains unclear. Astrocytes are anatomically and functionally well-poised to play a role in regulating this neural activity balance, but the mechanism warrants further research. The current proposal uses simultaneous in-vivo recording of striatal astrocyte calcium activity and direct or indirect pathway neuronal activity to determine if and how astrocytes modulate neural activity balance to produce the stimulant and sedative effects of EtOH. Additionally, molecular genetic tools will be used to manipulate astrocyte calcium levels to further assess if there is a causal role for astrocytes in these EtOH-related behaviors. Aim 1 will determine the relationship between striatal astrocyte calcium activity and the stimulant and sedative responses to EtOH. Aim 2 assesses how astrocyte modulation of direct and indirect pathway neuronal activity regulates the stimulant and sedative responses to EtOH. Previous research and our preliminary data support the overall hypothesis that DLS astrocytes limit maladaptive stimulant and sedative responses to EtOH by facilitating balanced direct and indirect pathway activity. AUD is a multi-faceted disorder with few FDA-approved treatment options available. Current FDA- approved pharmacotherapies for AUD target neuronal mechanisms to reduce EtOH intake. However, EtOH impacts neurons and non-neuronal glia cells including astrocytes. Identification of the role of striatal astrocytes in modulating the stimulant and sedative responses to EtOH has the potential to provide crucial insight for the development of future therapies for AUD.

PROJECT NARRATIVE Understanding the neurobiological mechanisms of known risk factors for alcohol use disorder (AUD) provides one avenue for developing potential therapeutics. An individual’s response to the stimulating and sedating effects of alcohol represents known risk factors for the development of AUD. The proposed studies use mouse models of alcohol-induced stimulation and sedation to explore the role of striatal astrocytes in modulating neuronal activity to produce these behaviors.