Date of Award

2026-05-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Travis M. Moschak

Abstract

The psychological distress experienced during drug withdrawal can lead individuals with substance use disorder to abandon their goal of abstinence. Numerous human studies demonstrate that an inability to persist in challenging, goal-directed behavior while experiencing psychological distress is associated with multiple stages of substance use, including relapse. This behavioral construct is referred to as low distress tolerance (DT). Rodent models of DT similarly show that low DT predicts elevated cocaine relapse, particularly when DT is assessed following extended abstinence. This abstinence period corresponds with the incubation of craving, a phenomenon characterized by progressively increased cocaine-seeking over time. Importantly, relapse vulnerability is also associated with heightened anxiety and impulsivity, behavioral traits that frequently co-occur with low DT and may interact to increase susceptibility to drug seeking during abstinence. Two brain regions implicated in these processes are the anterior insular cortex (INS) and medial prefrontal cortex (mPFC), which form core nodes of the salience network. Functional connectivity between these regions is thought to support the integration of affective distress with goal-directed control. However, the role of this circuit in DT and relapse vulnerability remains poorly understood. To address this gap, we examined INS-mPFC neural activity during DT performance and its relationship to impulsivity, anxiety-like behavior, and drug-seeking vulnerability. Using in vivo calcium imaging in Long Evans rats, we recorded INS-mPFC activity across drug-naïve, early abstinence, and late abstinence states following cocaine or water self-administration. Cocaine self-administration procedures produced expected behavioral divergence, with water controls decreasing responding across sessions and cocaine-exposed animals maintaining elevated levels of responding. During extinction, cocaine-exposed animals exhibited greater responding during later sessions, consistent with incubation-related increases in drug seeking. Despite these behavioral differences, analyses of impulsivity, distress tolerance, and anxiety-like behavior revealed no significant main effects of drug exposure on overall behavioral performance or mean neural activity. In contrast, robust relationships emerged at the level of neural-behavioral organization. In the drug-naïve state, INS-mPFC activity predicted individual differences in impulsivity and distress tolerance and exhibited structured cross-task encoding. During early abstinence, this organization was largely preserved, although associations with distress tolerance weakened and changes in neural activity tracked changes in impulsivity across animals. By late abstinence, INS-mPFC activity predicted both impulsivity and distress tolerance, with evidence for increased reliance on task-specific (unshared) neural populations under specific experimental conditions. Together, these findings demonstrate that cocaine exposure and abstinence do not produce gross changes in behavioral output but instead reorganize how behavior is encoded within salience network circuitry. This work identifies INS-mPFC circuit dynamics as a key substrate underlying distress tolerance and relapse vulnerability, highlighting the importance of circuit-level organization in shaping individual differences in substance use outcomes.

Language

en

Provenance

Received from ProQuest

File Size

196 p.

File Format

application/pdf

Rights Holder

Marina Alicia Smoak

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