David N. Linsenbardt - US grants

DESCRIPTION (provided by applicant): Environmental stimuli such as the taste, smell, and sight, of a favorite alcoholic drink can become salient cues that increase craving for alcohol and lead individuals to continue to drink to the point of intoxication (or well beyond). These same cues can also cause craving and relapse in individuals who have abstained from alcohol for long periods of time. Because continued excessive alcohol intake and relapse following abstinence are both hallmarks of alcoholism, understanding the brain regions and processes that regulate cue-evoked alcohol seeking are critical to develop effective treatment strategies for these alcoholic individuals. Interestingly, neural activity within an area of the brain known as th prefrontal cortex (PFC) is now known to be critically involved in regulating how alcohol associated cues elicit craving, alcohol seeking, and intake. However, the exact changes in neural activity that mediate continued excessive alcohol intake and/or craving and relapse are poorly understood. We also have only a very limited understanding of how populations with genetic risk for developing alcoholism might exhibit abnormal neural processing regimes in the PFC, which make them more vulnerable to cue-related craving. We hypothesize that neural networks in the PFC will be more robustly effected by alcohol-paired cues in vulnerable populations than non-vulnerable. We also hypothesize that PFC neuronal networks are more resistant to re-mapping in genetically vulnerable populations during periods of abstinence from alcohol. These abnormal neuronal network processes might contribute to heightened cue-evoked craving and drive both continued excessive alcohol intake, as well as relapse following periods of abstinence. Our broad, long-term objective is to develop a comprehensive understanding of how neuronal networks (ensembles) within the PFC are altered by alcohol associated cues. We will accomplish this by using state-of-the-art electrophysiological recording and analysis techniques of large populations of cells in the awake behaving rodent to determine, for the first time, how instantaneous shifts in PFC ensemble activity evoked by alcohol paired cues: 1) contribute to the maintenance of binge- drinking and are modified during extinction, and 2) initiate relapse-like behavior. We will evaluate these effects in a rat population genetically predisposed to excessive alcohol consumption (Indiana alcohol preferring P rats) and in a rat population with average genetic susceptibility to excessive alcohol consumption (Wistar rats). Determining the neurobiological/neurophysiological causes and consequences of excessive alcohol consumption as well as the role of genetic vulnerability to excessive alcohol intake are directly relevant to the mission of the NIAAA. Specifically, the proposed studies will reveal the neurobiological origins of why genetically vulnerable populations respond to alcohol, and alcohol-paired cues, differently. This will lead us to a better understanding of why and how alcohol can cause addiction and will help us develop strategies to prevent and treat excessive drinking.

The primary objective of the first two years of the K99/R00 award is to provide the candidate with bioinformatics training in the identification and analysis of brain gene expression networks in preparation for an academic research career in the neurophysiological genetics of alcoholism. The candidates specific goal for the K99 phase of the project is to identify gene networks (and key genes regulating these networks) recruited by repeated binge alcohol consumption within brain areas thought to be involved in loss of control over alcohol consumption - the medial Prefrontal Cortex (mPFC) and the ventral Striatum (vSTR; i.e. nucleus accumbens). The candidate will undertake an intensive training regimen to obtain the necessary skills and expertise to analyze and interpret next-generation sequencing data. He will further his career development by completing semester-long didactic coursework in both next-generation sequencing and bioinformatics, and also by attending intensive short courses on the genetics of addiction, statistical genetics, and network analysis. His career development will also be furthered by attending relevant seminars and seminar series offered through the Indiana University Alcohol Research Center (IARC) and Center for Computational Biology and Bioinformatics (CCBB), and by publishing his research findings, attending scientific conferences, and interviewing for independent faculty positions. The proposed mentoring team includes, Drs. Christopher Lapish, Tatiana Foroud, Yunlong Liu, and Howard Edenberg. These individuals collectively are experts in systems and computational electrophysiology, statistical and bioinformatics analyses, and medical/population genomics and genetics. The long-standing collaborative research environment at IUPUI, in particular the IARC, will provide the candidate the necessary resources to complete the aims as outlined in this proposal. At the start of the 3rd year during the R00 phase of the award, the candidate will establish his new role as an independent faculty researcher where he will continue his research on identifying, validating, and characterizing genes and gene networks regulating the brain circuits associated with repeated excessive alcohol consumption, and genetic risk for such consumption. This will be accomplished by combining newly acquired skills in bioinformatics with his current expertise in behavioral physiology and behavioral genetics. Determining the genetic and neurophysiological causes and consequences of excessive alcohol consumption are directly relevant to the mission of the NIAAA in understanding the neurobiology of alcoholism. Specifically, the proposed studies will reveal how the coordinated activity of networks of genes mediates the physiological functioning of a key brain reward circuit to facilitate repeated excessive alcohol consumption. This will result in a better understanding of why and how alcohol use leads to addiction and will help us develop strategies to prevent and treat excessive drinking.