Date of Award

Summer 2019

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Pavel I. Ortinski

Abstract

Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. This thesis illustrates effects of dopamine on cultured astrocytes and astrocytes in brain slices (ex vivo). In striatal cultures, extracellular dopamine triggered changes in astrocytic Ca2+ signaling and rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation, but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. To isolate possible mechanisms underlying these structural and functional changes, whole-genome RNA sequencing was used in identifying prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. Specifically, results show that cultured astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. To examine astrocyte response to behaviorally relevant dopamine signals, astrocyte morphological and molecular profiles in ventral striatum (nucleus accumbens core; NAcC) and dorsolateral striatum were characterized following cocaine self-administration training on an extended access schedule. Findings illustrate that extended cocaine experience resulted in decreased numbers of GFAP+ cells and primary process number in the ventral striatum. This was associated with an increase in connexin 30 mRNA, an astrocyte-astrocyte interaction gene. In the dorsolateral striatum, there was an observed increase in length of GFAP+ primary processes and downregulation of SPARC (astrocyte-neuron interaction gene) mRNA.

Rights

© 2019, Ashley L. Galloway

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