ROLE OF CORTICOTROPIN-RELEASING FACTOR IN COCAINE-MEMORY RECONSOLIDATION

Jobe Ritchie

doi:10.7273/000006519

Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of cocaine-associated contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Manipulations that interfere with memory reconsolidation can reduce stimulus control over cocaine craving in clinical populations and attenuate relapse-like behaviors in animal models. As such, experimental manipulations that target memory reconsolidation are promising from an anti-relapse treatment perspective. However, a deeper understanding of the mechanisms underlying cocaine-memory reconsolidation is required to inform the development of effective therapeutic approaches. The basolateral amygdala (BLA) is a critical brain region for the reconsolidation of emotionally salient memories, including cocaine memories. Corticotropin-releasing factor receptor type 1 (CRFR1) is densely expressed in the BLA. CRFR1 stimulation can activate intra-cellular signaling cascades that mediate memory reconsolidation in the BLA. However, the role of CRF, or specific CRF circuits, in memory reconsolidation was not ascertained previously, and is the focus of this dissertation. Chapter one provides detailed background information for the studies in Chapters 2-4. Chapter two details investigations into the necessity and sufficiency of CRF signaling in the BLA for cocaine-memory reconsolidation. Chapter three describes experiments that test whether the functional integrity of the dorsal raphe (DR) is necessary for cocaine-memory reconsolidation, as the DR is a potential source of CRF to the BLA based on its neurochemistry and connectivity. Chapter four outlines experiments that build on the results of the prior two chapters by testing if signaling through the DR CRF to BLA circuit is required for memory reconsolidation and assessing the cell type of the BLA-projecting DR CRF neurons that are activated during cocaine-memory reconsolidation. Finally, Chapter five contains a summary of the key findings of the prior chapters, a discussion of overarching themes, and identifies several future directions of research. The experiments detailed in this dissertation are the first to investigate the contributions of specific CRF circuitry to cocaine-memory reconsolidation and provide novel insight into the mechanisms that maintain strong cocaine-associated memories that elicit drug craving and relapse. Overall, the findings suggest that CRF signaling in the BLA, and particularly CRF input from the DR to the BLA, is critical for the maintenance of cocaine memories. These findings provide impetus for future investigations into the contributions of CRF circuitry to memory processes and may help to inform the development of anti-relapse therapeutic strategies.

ROLE OF CORTICOTROPIN-RELEASING FACTOR IN COCAINE-MEMORY RECONSOLIDATION

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