Cocaine addiction is a multidimensional psychiatric disorder with pathophysiology that seems to involve abnormally strong learned associations. These types of learned associations are thought to be encoding within patterns of sparsely distributed neurons, called neuronal ensembles. During the last decade, research has mostly focused on acquisition and reinstatement of cocaine seeking. However, cocaine self-administration can be rapidly extinguished by omitting the cocaine reinforcer. This extinction learning appears to involve formation of a new memory, rather than an `unlearning' of self-administration because extinguished behaviors can reinstate. Relatively few studies have attempted to delineate the neurobiological underpinnings of extinction of cocaine seeking. Under the primary mentorship of Drs. Bruce Hope and Yavin Shaham, the present Pathway to Independence award will allow me to obtain training in optogenetic and transgenic methodologies that will allow me to probe the role of neuronal ensembles in extinction learning. In the mentored phase of this grant, I will use double transgenic fos-tet-cre rats to label neuronal ensembles associated with self-administration and extinction of cocaine seeking separately. I will design and build an optogenetics system that will then allow me to inhibit these distinct ensembles in vivo in behaving rats to show necessity of neuronal ensembles in extinction of cocaine seeking. In the independent phase, I will determine whether these self-administration and extinction ensembles project to distinct brain regions. I will then use optogenetics methodologies mastered in the mentored phase to inhibit these projections to determine whether the projections are necessary for inhibition of cocaine seeking following extinction of cocaine seeking. Under the mentorship of Drs. Hope and Shaham, I am uniquely situated to combine Dr. Hope's expertise on neuronal ensemble-level manipulations with Dr. Shaham's expertise on behavioral models of drug addiction in an academic setting focused on studying drug addiction. Thus, this proposal will provide novel insights on an understudied, but fundamental aspect of motivation while preparing me to thrive as an independent investigator. Simultaneously, this award will provide me with the tools necessary to establish an independent research program capable of producing high-impact research combining cutting edge neuronal ensemble methods with behavioral models of drug addiction.
Cocaine addiction is a major public health concern in the United States that appears to involve abnormally strong learned associations. In animal models, these memories persist even after repeated extinction sessions. These studies will identify neuronal ensembles underlying extinction of cocaine-self administration, and may reveal prospective therapeutic targets for treating cocaine addiction.