Lucas Sjulson, MD, PhD - US grants

DESCRIPTION (provided by applicant): My long-term goal is to establish an independent research program aimed at investigating the underlying pathophysiology of addictive disorders and using this information to guide development of novel treatments. To accomplish this, I plan to model cocaine addiction in rodents and use a combination of genetic, behavioral, and neurophysiological techniques to determine underlying mechanisms and identify candidate therapeutic strategies. The immediate goal of this research proposal is to determine the physiological firing patterns and functional importance of GABAergic interneurons of the nucleus accumbens in addiction-related behaviors such as cocaine conditioned place preference and cocaine self-administration with cue-induced reinstatement. To complement my prior experience with animal behavior and genetic approaches for targeted manipulation of neural activity, the training plan contains several major components. The first of these includes formal training in complex behavioral models of addiction and in vivo neurophysiology/optogenetics techniques used to monitor neuronal activity of specific interneuron types in behaving animals. These training components are necessary not only to carry out the research plan as proposed, but also as skills required for future studies in my own independent laboratory. This will be complemented by training aims designed to expand my knowledge of general neurophysiology and the neurobiology of addiction, as well as a training aim designed to prepare me for practical aspects of laboratory management. Research Project Description: The nucleus accumbens (NAc) is a brain region known to be central to the pathophysiology of cocaine addiction, but its internal operations are poorly understood. Investigating these mechanisms requires studying the NAc at the level of each of its constituent neuronal subtypes. GABAergic interneurons (gINs) represent the subtype of neuron in the NAc that is perhaps most poorly understood in the context of addiction, despite the fact that these cells play key functional roles in other parts of the brain and are thought to be affected in multiple neuropsychiatric disorders. We first propose to test the hypothesis that identified gIN populations in the NAc play important functional roles i addiction-related behaviors by manipulating activity in each of the major gIN subclasses and measuring the effect on mouse behavioral models of cocaine addiction and relapse. We additionally propose to gain further understanding of gIN function by recording neuronal activity from gINs during addiction-related behaviors. These studies will advance our understanding of NAc function in addiction and may lead to the identification of novel therapeutic targets. Title of proposal: Functional roles of GABAergic interneurons of the nucleus accumbens in cocaine addiction Specific Aims: Aim 1: To test the hypothesis that identified GABAergic interneuron subpopulations in the medial nucleus accumbens shell play functional roles in context-dependent cocaine addiction-related behaviors Aim 2: To determine the physiological firing patterns of each GABAergic interneuron subpopulation in the nucleus accumbens during cocaine self-administration, extinction, and context-induced reinstatement

Project Summary Recent advances in single-cell transcriptomic methods have revealed an incredible diversity of neuronal subtypes. This presents a challenge for understanding substance use disorders because these subtypes can only be identified in post mortem brain tissue, but substance use disorders occur only in living humans. One of the key unsolved problems is how to link these numerous transcriptomically-defined neuronal subtypes to their functional roles in drug addiction in the intact brain. In this proposal, we take first steps toward bridging this gap. First, we will use innovative optogenetic and electrophysiological techniques to record neuronal activity from genetically identified cell types in the nucleus accumbens during oral opioid self-administration in mice. We will also take the converse approach, using innovative optical methods to label neuronal subpopulations that are active during different phases of opioid self-administration, then identifying their transcriptomic profiles post mortem using a novel in situ sequencing method. We also describe plans to extend these techniques for compatibility with advanced in vivo multiphoton imaging and single-cell transcriptomic and epigenomic studies. We expect this project will open new lines of exploration in substance use disorders and contribute broadly to understanding the relationship between neuronal gene regulation and functional roles in opioid addiction, which may identify new therapeutic targets.