Astrocyte modulation of striatal neuronal activity and behavioral sensitivity to alcohol

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.

Grant Number: 5F32AA032173-02
NIH Institute/Center: NIH
Principal Investigator: Cherish Ardinger