Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) affects over 16 million Americans, contributes to millions of preventable deaths, and causes enormous financial and societal burdens. Therefore, gaining a better understanding of the neurobiological mechanisms underlying AUD would provide insight for developing improved therapeutic strategies. Alcohol (ethanol) dependence is a hallmark of AUD that is characterized by excessive alcohol intake, somatic withdrawal symptoms, and negative mood. The central nucleus of the amygdala (CeA) is a key brain structure involved in ethanol dependence. For example, synaptic transmission is dysregulated in the CeA following chronic ethanol exposure and CeA activity is required for escalated ethanol drinking and withdrawal symptoms during dependence. Accumulating evidence suggests that astroglial cells are essential regulators of synaptic transmission and behavior, however, we lack a basic understanding regarding the role of astrocytes in in ethanol dependence. Two particularly important questions are 1) how does chronic ethanol exposure affect astrocyte-neuron interactions and 2) do astrocytes have a causal role in regulating the consequences of ethanol dependence and withdrawal. The proposed studies will begin to address these questions by testing the overarching hypothesis that chronic ethanol exposure alters astrocyte-synapse proximity in the CeA and the astrocytic GABA transporter, GAT3, mediates ethanol withdrawal and dependence-escalated ethanol intake. The experimental approach utilizes a rat model of chronic intermittent ethanol (CIE) exposure by vapor inhalation and ethanol drinking in combination with super resolution confocal microscopy and three-dimensional astrocyte morphology analysis. The overarching hypothesis will be tested in the following two specific aims. Aim 1 will test the hypothesis that chronic ethanol exposure modulates astrocyte-neuron interactions in the CeA. Astrocyte- synapse proximity will be assessed following CIE exposure to determine the temporal properties of changes in astrocyte plasticity. Astrocyte-synapse proximity will also be assessed following ethanol access during withdrawal to determine how voluntary ethanol drinking modulates astrocyte plasticity in dependent and non- dependent rats. Aim 2 will test the hypothesis that astrocytic GAT3 in the CeA regulates dependence-escalated ethanol intake and somatic withdrawal. A morpholino antisense oligonucleotide strategy will be used to knockdown GAT3 in the CeA to determine whether GAT3 is necessary for the expression of escalated ethanol intake and somatic withdrawal during ethanol dependence. In contrast, a viral overexpression strategy will be used to increase astrocytic GAT3 expression in the CeA to determine whether GAT3 is sufficient to modulate escalated ethanol intake and withdrawal. The consequences of GAT3 manipulation on astrocyte plasticity will also be assessed. Together, these studies will provide novel insight into the role of astrocytes in ethanol dependence and advance our understanding of potential neural substrates amenable to intervention for the treatment of AUD.
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