Wednesday, February 5, 2025
2/5/2025
Project Summary Relapse to cocaine use, and the underlying failure to inhibit cocaine-seeking behavior, remain significant barriers to the treatment of cocaine use disorder. However, our understanding of the neural pathways and network mechanisms underlying the inhibition of cocaine seeking remain insufficient. Previous studies investigating fear conditioning and drug seeking suggest that, often, the infralimbic cortex (IL) inhibits and the prelimbic cortex (PL) promotes such behaviors. Although downstream projections from these brain regions have been identified in the involvement of regulating fear conditioning and drug seeking, it is unknown what inputs to these regions determine their influence over cocaine-seeking behavior. Evidence from fear conditioning studies suggests that separate subpopulations of basolateral amygdala (BLA) neurons project to the PL vs. IL and oppose each other for control over fear conditioning vs. the extinction thereof. These findings raise the possibility that the BLA is a key region influencing PL and IL activity and determining the degree of cocaine-seeking behavior. Indeed, global manipulations suggest that the BLA promotes cocaine seeking as well as fear conditioning, but more recent reports suggest the BLA may also have a role in extinction and inhibition of drug seeking. However, whether the BLA separately regulates the IL and PL to extinguish or engage in cocaine seeking and how these regions engage in complex network interactions during cocaine seeking has never been investigated. Therefore, the goal of this proposal is to examine BLA→IL and BLA→PL pathways in cocaine extinction learning using optogenetics (Aim 1) and examine network activity in the BLA, IL, and PL simultaneously during cocaine seeking via multi-site electrophysiological recordings (Aim 2). The overall hypothesis is that the BLA-IL system is critical for the extinction of cocaine seeking, whereas the BLA-PL system opposes this effect and that neural activity between these systems during cocaine seeking will reflect the degree of cocaine-seeking behaviors. The findings from these experiments will provide fundamental knowledge regarding the neural systems that regulate cocaine-seeking behaviors. The sponsor (Dr. Ryan LaLumiere) and co-sponsor (Dr. Rainbo Hultman) for this proposal are leaders in the field of drug-seeking behavior and mood disorder, respectively, and have expertise in all techniques needed for the proposed research. Moreover, the University of Iowa and the Psychological and Brain Sciences Graduate Program provide an excellent environment and resources for neuroscience research. The training plan for this work includes training in the technical and conceptual skills for the proposed research along with development of teaching and mentoring skills, networking through neuroscience conferences, scientific writing and presentations. Therefore, the applicant will receive first- rate training that will propel her forward in her career and help to achieve her goals of becoming an independent investigator.
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