Single-cell whole brain imaging of nicotine intoxication, dependence, and abstinence

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Abstract In the past 20 years, neuroscientists have focused on circuit-specific manipulations of the brain to identify neuronal pathways controlling nicotine dependence and relapse using bioengineering approaches, such as optogenetics and calcium imaging. These approaches have determined a causal relationship between activation of localized neurons by nicotine and specific nicotine-related behaviors. However, we still have very little understanding of how the brain, as a whole, processes this information because of a technical gap making it difficult to image the whole brain at single-cell resolution. This is a critical problem for the field, as nicotine, pharmacological and behavioral treatments affect the brain as a whole and not just specific circuits. The recent development of single-cell whole-brain imaging of immediate-early genes using light-sheet microscopy on cleared brains (iDisco+) has made the study of brain-wide functional networks at single-cell resolution possible. The overarching hypothesis is that coordinated activation of long-range cholinergic neurons is associated with decreased whole-brain modularity and withdrawal-related behaviors that can be partially normalized using FDA-approved medications. The first goal of this proposal is to identify brain-wide functional networks at single-cell resolution associated with acute nicotine intoxication, chronic nicotine dependence, withdrawal, and protracted abstinence using iDisco+ imaging of immediate-early genes. The second goal is to identify the brain activity patterns that control these states and predict the acute and long-term physiological and behavioral response to nicotine using advanced neural network analyses. The third goal is to test the hypothesis that FDA-approved medications will normalize these network changes. This project will lead to four outcomes that will likely produce a long-lasting impact on the field: 1) Identification of the functional brain networks of acute nicotine, nicotine dependence, acute withdrawal, and protracted abstinence. 2) Molecular phenotyping of the functional network. 3) Identification of the major hub regions that predict withdrawal-related behaviors. 4) Characterization of the brainprints of FDA-approved medications for tobacco use disorder. 5) Testing the theory that coordinated activation of long-range cholinergic neurons is associated with decreased whole-brain modularity and withdrawal-related behaviors.