Norepinephrine modulates medial prefrontal cortex neural ensembles that control cocaine seeking behavior

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PROJECT SUMMARY/ABSTRACT This K01 application aims to prepare Dr. Ali Gheidi for an independent faculty position by providing specialized training in rodent models of drug self-administration (IVSA), chemogenic manipulation of neurons and targeted deletion of neuronal ensembles. Therefore, Dr. Gheidi will work with a carefully selected Training Team of mentors. Training for Dr. Gheidi will consist of courses, meeting with mentors, workshops, scientific meetings, and performing experiments. Dr. Gheidi’s short term goal is to understand the role of norepinephrine (NE) in regulating neuronal ensembles in cocaine seeking behavior. His long-term goal is to gain an independent position as a researcher-educator, where he can study neuromodulators' role in regulating neuronal ensembles to drug abuse. In addition to advancing the career of Dr. Gheidi, this proposal will increase understanding of substance abuse, in general, and cocaine relapse, in particular. Over the past decade, a paradigm shift has occurred in neurobiology, including within the field of drug addiction. In these studies, only a select, distributed, and a sparse group of neurons, known as a neuronal ensemble, thought to code drug taking events is isolated and studied. This selective approach offers new insights over traditional methods, where drug-induced perturbations are usually studied in the whole brain area or cell type. Instrumental to this task is the use of Fos based approaches. These techniques allow the direct manipulation of Fos positive neurons, and by extension neuronal ensembles, without affecting adjacent areas or cell types not involved in the behavior. For example, using the Daun02 neuronal ablation method in this K01, scientists have identified neuronal ensembles in the prefrontal cortex and nucleus accumbens critical to cocaine, heroin, nicotine, and alcohol taking and seeking behaviors. However, missing from this understanding is the contribution of the brain's neuromodulators (e.g., NE) in sculpting neuronal ensembles and inducing relapse to drug taking. Thus, this grant proposal aims to elucidate the role of NE on prefrontal cortical neuronal ensembles involved in cocaine seeking behaviors in female and male rats. The proposed research will utilize state of the art techniques mentioned above. Aim 1 of this K01 proposal will determine the role of NE in the medial prefrontal cortex (mPFC) ensembles control of cocaine seeking. Aim 2 will utilize DREADDs to inactivate the NE-containing locus coeruleus projections that specifically innervate the mPFC to further explore the role of NE in cocaine seeking. A better understanding of how these processes operate in cocaine seeking situations can inform both clinical and basic science as well as inform clinical care. Results will also inform basic scientists on the neuronal underpinnings of learned motivated behaviors, and researchers may also devise clinical strategies to target neuronal ensembles by controlling neuromodulators, including NE, in the human brain that can ease conditions that lead to relapse of cocaine use.