Sunday, May 11, 2025
5/11/2025
Astrocyte-mediated regulation of cocaine-generated synapses during cocaine seeking - Abstract: Substance use disorder (SUD) is a complex emotional and motivational disorder with no effective treatment thus far. Currently, the United States is in the midst of a SUD epidemic that defies socioeconomic and generational boundaries. A particularly insidious component of SUD is relapse, which is the strong motivational drive to seek drugs during abstinence. Cue-induced drug seeking is a rodent model of relapse, wherein a drug-associated cue is presented in the absence of the drug to trigger quantifiable seeking behavior. Addiction research attributes drug-seeking behaviors, such as cue-induced drug-seeking following self- administration (SA) of cocaine, to altered function of the nucleus accumbens (NAc). Focusing on the NAc, extensive studies have examined drug-induced adaptations in GABAergic, medium-spiny neurons (MSNs), which are the majority cell type (~90%) and principal functional output of the NAc. In contrast, much less is known about how glial cells, such as astrocytes, shape drug-related behaviors. Astrocytes closely associate with synapses, allowing them to directly monitor and regulate synaptic transmission. The astrocyte-synapse association (referred to as the tripartite synapse) plays a key role in experience-dependent synaptic adaptations associated with learning and memory. Thus, the objective of this application is to characterize how astrocytes regulate synaptic dynamics in the NAc Shell (NAcSh), which, in turn, regulate cue-induced cocaine seeking in the mouse SA model. Prior results show that re-exposure to cocaine-associated cues re-silences cocaine-generated NAcSh synapses, a process which contributes to the destabilization of cue-associated cocaine memories upon cue re-exposure-induced memory retrieval. Preliminary results demonstrate that functional astrocyte activity during withdrawal (WD) is necessary for the cue-induced re-silencing of cocaine- generated synapses in the NAcSh, and that cues associated with cocaine reward increase astrocyte activity in the NacSh. These preliminary results link astrocyte activity to the dynamic state of cocaine-generated silent synapses and lead to my hypothesis that astrocytes regulate the cue-induced synaptic adaptations of cocaine- generated synapses in the NAcSh which, in turn, regulate cue-induced cocaine seeking after cocaine WD. I will test this hypothesis by pursuing two aims. Aim 1 will test the sufficiency of increased astrocyte activity to re- silence cocaine-generated NAcSh synapses during WD. Aim 2 will expand preliminary data, which demonstrates the necessity of functional astrocyte activity during WD for cue-induced synaptic re-silencing, by using pharmacological and viral tools with increased temporal precision to suppress astrocyte activity immediately prior to cue re-exposure. The expected outcome will provide a holistic understanding of how the NAcSh regulates drug-induced behaviors by incorporating astroglia, thus revealing NAcSh astroglia as key cellular substrates targeted by drug experience to reshape behaviors. This potential conceptual expansion may provide novel angles to understand the cellular and circuit mechanisms underlying drug seeking and relapse.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).