Habenula Circuitry, Smoking, and Genomics

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

PROJECT SUMMARY Cigarette smoking is a leading global health problem, and limited success of even the most successful treatments for Tobacco Use Disorder (TUD) leaves a pressing need for novel treatments. Elucidating the neural circuitry linked to smoking and the genetic influences on it can facilitate development of such advances, possibly using brain-based and precision medicine approaches. Animal research has identified the habenula (Hb) and its circuitry as essential to the effects of nicotine, including aversion and withdrawal. The Hb is part of the brain’s “anti-reward” system, containing neurons that respond to aversive stimuli, representing negative emotional value through inhibitory actions on dopaminergic nuclei. These effects can contribute to nicotine avoidance and nicotine-induced anxiety, and to reinstatement of nicotine self-administration. The Hb also is functionally linked to the Salience Network, a large-scale brain network related to withdrawal and nicotine dependence. Yet, study of human Hb function with respect to TUD and other psychiatric disorders has been severely limited because available neuroimaging methodologies have precluded precise localization of this small epithalamic structure and separating it from neighboring tissue. Recent advances in higher-resolution scan protocols combined with analytic strategies to optimize localization allow more precise measurement of Hb function. Large, publicly available datasets, such as the UK Biobank, can provide robust neuroimaging results, offering unprecedented opportunity to perform functional neuroimaging studies without the problems of replicability associated with small sample size studies. Inclusion of genomic data in the data repository also allows examination of the effects of genomic variation on neuroimaging phenotypes. This study will use the UK Biobank neuroimaging dataset to examine Hb functional connectivity with the Salience Network and ventral tegmental area, and the influence of genomic variations on this connectivity. We will compare Hb functional connectivity in the resting state between participants who smoke regularly and those who never did, examining the relationship of functional connectivity with heaviness of smoking and lifetime exposure to smoking among people who smoke regularly. Given the importance of negative reinforcement in maintaining TUD and the association between Hb and negative emotional states, we will also study relationships between Hb functional connectivity with self-reported negative affect and amygdala activation during a negative affect-induction task. Finally, we will conduct a genome-wide association study of Hb function to create polygenic risk scores (PRSs) to identify novel relationships between Hb function and TUD (and other psychiatric disorders), and for hypothesis-testing in non-imaging datasets. PRSs can also be used to provide causal evidence using Mendelian randomization and associations with other phenotypes using phenome-wide association studies. The results can have wide-ranging implications beyond the scope of TUD, given the role of the Hb in other psychiatric conditions, including Major Depressive Disorder and Anxiety Disorders.