Donita L. Robinson - US grants

DESCRIPTION (provided by applicant): Candidate: Donita L. Robinson, Ph.D., is an Assistant Professor in the Department of Psychiatry and the Center for Alcohol Studies at the University of North Carolina School of Medicine. Her training has been in analytical chemical methodology for brain measurements of dopamine and ethanol in freely-moving animals. Her immediate goal is twofold: (1) to learn multineuron electrophysiological recording in behaving animals and (2) to learn a technique to measure neuronal firing and subsecond dopamine signaling at the same microelectrede in behaving animals. Her long-term goal is to develop a high-quality, independent research program in ethanol neuropharmacology and behavior, funded by independent extramural grants. This Research Career Award will help Dr. Robinson accomplish these goals by providing solid training in the above methods as well as research support to apply these techniques to ethanol studies. Environment: The University of North Carolina provides laboratory space, equipment, and access to faculty and staff that will allow Dr. Robinson to accomplish the training and research proposed herein. The combined electrophysiology electrochemistry technique was developed by Drs. Regina Carelli and Mark Wightman, who are thus best qualified to sponsor this application. The UNC Center for Alcohol Studies contains many well known experts in ethanol pharmacology and self-administration behavior, including Dr. Clyde Hodge. The sponsoring departments and institution are committed and supportive of Dr. Robinson's development of a successful, independent research program at UNC. Research: The nucleus accumbens (NA) is a limbic-motor integrator, assimilating memory and drive input and coordinating responsive behavioral output. Anatomical and pharmacological evidence indicates that the core and shell subregions of the NA perform overlapping but distinct roles in motivated behavior. The proposed experiments will examine NA core and shell functions in ethanol drinking behavior in rats, with particular focus on how dopamine input modulates NA activity on the millisecond timescale. Finding patterns of neurons in the NA core and shell during operant responding for concurrent ethanol and water will be fully characterized using multi-electrode arrays (Specific Aims 1 and 2). Phasic (subsecond) dopamine activity will be evaluated in the NA core and shell during operant responding for concurrent ethanol and water, while simultaneously recording firing patterns of nearby NA neurons (Specific Aims 3 and 4). Finally, opiate modulation of NA cell firing patterns (Specific Aim 2) and phasic dopamine signals (Specific Aim 4) will be assessed with naltrexone administration before the operant session. Together, these experiments will provide new and valuable information on the interaction of physiology, pharmacology and chemistry in the NA during behavior, comparing ethanol to water reinforcement and core to shell. These studies will best train the candidate in a unique and innovative method, and significantly advance our understanding of neural control of ethanol drinking.

[unreadable] DESCRIPTION (provided by applicant): Alcoholism is a chronic disorder, typically spanning several decades. The learning processes underlying habit formation may contribute to continued alcohol drinking and render the behavior resistant to change. The degree to which habits (actions driven by conditioned cues and independent of outcome) versus goal-directed behaviors (actions dependent on the outcome or drug) drive alcohol drinking may influence susceptibility to relapse. Operant conditioning paradigms in rats, which can produce robust goal-directed or habitual behavior, can model the contribution of habit to alcohol drinking and allow direct measurement of brain function during these behaviors. The dorsomedial striatum (DMS) underlies goal-directed behavior while the dorsolateral striatum (DLS) is crucial for habit formation, and both areas are involved in animal models of relapse. Dopamine input is essential to the association between cues and drugs, and has profound and region-specific effects on synaptic plasticity, neuronal activity and behavior. The critical dopamine signal in cue-action habits may be fast changes in dopamine (or transients) that can occur in response to salient stimuli and that can only be measured with fast scan cyclic voltammetry. In addition, medium spiny neurons in the dorsal striatum can encode reward-related cues and actions by short-term changes in firing rates, which may be dopamine- dependent. This proposal will test the overall hypothesis that subsecond dopamine release and ongoing neuronal activity differ in DMS versus DLS, with the DMS preferentially active during goal-directed alcohol reinforcement, and the DLS preferentially active during habitual alcohol reinforcement and cue-induced relapse. We will use state-of-the-art, real-time recording techniques in rats: fast scan cyclic voltammetry to reveal dopamine transients, and extracellular recording at multielectrode arrays to evaluate ensemble activity of MSNs. Moreover, we will make this combination of chemical and physiological measurements during goal- directed and habitual alcohol drinking (Aims 1 and 2) as well as relapse-like behavior (Aims 3 and 4), to provide the most complete picture to date of dorsal striatal encoding of alcohol-related habit formation. Mechanistic studies will investigate the functional role of dopamine release in the physiological events associated with habitual drinking and relapse. The data resulting from these innovative studies will provide important information about how the dorsal striatum differentially encodes goal-directed versus habitual alcohol drinking. Overall, these studies have the potential to identify novel mechanisms by which habitual alcohol drinking leads to changes in brain and behavioral processes that are of fundamental importance to both the development and treatment of alcohol abuse and alcoholism. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Habitual alcohol drinking and cue-induced relapse are major factors to alcoholism. We will examine dopamine release and neural activity in rat models of habitual alcohol drinking and cue-induced relapse. [unreadable] [unreadable] [unreadable]

Absolute ethanol; Affect; Alcohol, Ethyl; Alcoholic; Alcoholism; Alcohols; Animals; Awareness; Awarenesses; Boozer; CPE1; CYP2E; CYP2E1; CYP2E1 gene; CYPE1; Cell Communication and Signaling; Cell Signaling; Cells; Chemical Class, Alcohol; Chromosome 10; Chromosomes, Human, Pair 10; Chronic; Classification; Common Rat Strains; Data; Dependent drinker; ELIG; ETOH; Electrophysiology; Electrophysiology (science); Eligibility; Eligibility Determination; Ethanol; Faculty; Feasibility Studies; Fire - disasters; Fires; Funding; Gene Expression; Genes; Genetic; Goals; Grain Alcohol; Human; Human, General; Hydrogen Oxide; Intracellular Communication and Signaling; Investigation; Investigators; Mammals, Rats; Man (Taxonomy); Man, Modern; Measures; Methods and Techniques; Methods, Other; Methylcarbinol; Monitor; Neurophysiology / Electrophysiology; P450-J; P450C2E; Pathology; Pattern; Pilot Projects; Process; Programs (PT); Programs [Publication Type]; Protocol Screening; R01 Mechanism; R01 Program; RPG; Rat; Rattus; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Research Resources; Research Support; Researchers; Resources; Signal Transduction; Signal Transduction Systems; Signaling; Systematics; Techniques; Translational Research; Translational Research Enterprise; Translational Science; Water; alcohol exposed; alcohol exposure; alcohol research; alcohol response; alcohol sensitivity; base; biological signal transduction; design; designing; ethanol exposed; ethanol exposure; ethanol research; ethanol response; ethanol sensitivity; exposed to alcohol; exposure to alcohol; interest; pilot study; problem drinker; professor; programs; response; response to alcohol; response to ethanol; sensitivity to alcohol; sensitivity to ethanol; success; translation research enterprise

DESCRIPTION (provided by applicant): Disruption of maternal behavior by substance abuse resulting in higher levels of maternal neglect towards infants is well documented in human and animal research, while the associated neural mechanisms remain unclear. Several rodent studies indicate that cocaine-exposed maternal females may be less motivated to spend time with pups compared to non-cocaine exposed mothers. One possibility is that pup stimuli, which are known to promote maternal responding in normal mothers, are perceived as less motivating in cocaine-exposed mothers. Motivated behaviors are modulated by dopamine activity in the mesoaccumbens pathway. Fast dopamine release events in the ventral striatum, i.e. dopamine transients, are neural signals of reward prediction occurring at the detection of salient stimuli and often precede approach to a reinforcer. We hypothesize that dopamine transients in rat mothers are triggered by pup stimuli and facilitate normal pup-directed maternal behaviors, while cocaine-treated mothers have blunted DA release to stimuli from their pups that correlates with less maternal response and is driven by a combination of maternal dopamine alterations to cocaine and altered stimuli produced by the cocaine-exposed pups. We propose to use fast scan cyclic voltammetry to measure dopamine release in an established rodent model of maternal behavior. Thus, we will determine whether maternal cocaine exposure during pregnancy, which reduces pup-directed behaviors, also diminishes maternal dopamine release to pup cues. We will use a two-step approach: we will profile dopamine transients in rodent mothers first as they respond to their litters, and second in response to selected pup cues separately from the whole litter. Together, results from these experiments will (1) determine relationships between specific pup-associated stimuli, normal maternal behavior and dopamine transients, and (2) verify how gestational cocaine use alters these relationships in the mother-infant dyad. The data from these studies will provide a solid foundation for future research concerning the causality and biochemical underpinnings of phasic dopamine signals in maternal behavior and their dysregulation by chronic cocaine and will inform our understanding of human maternal neglect in drug-abusing mothers.

Attentional bias toward drug-related stimuli is commonly reported in substance use disorders and is positively correlated with craving. By capturing attention and facilitating drug-seeking behavior, alcohol-associated stimuli can promote continued drinking and relapse. The goals of this project are to (1) determine the neuromodulatory role of dopamine in attentional bias to alcohol cues in heavydrinking humans, (2) model early aspects of attentional bias to alcohol cues in rats, and (3) use that animal model to mechanistically probe brain circuits mediating attentional bias, by using pharmacology, electrochemistry, and optogenetics. These goals synergize with the overall aim of the Center to understand alcohol induced pathology in brain circuits that regulate alcohol use. Moreover, this project potentially identifies novel therapeutic targets for alcohol use disorders. The proposed studies test the overall hypothesis that projections from the prefrontal cortex to the mesolimbic system regulate Pavlovianconditioned attentional bias towards alcohol cues in heavy-drinking humans and binge-alcohol-exposed rats. To address this hypothesis, two aims manipulate dopamine function in humans and rats to determine the effects of dopamine on attentional bias to alcohol cues, and a third aim translates human measurements of frontolimbic connectivity to rat studies that activate and inactivate particular neural pathways in order to identify brain circuits mediating attentional bias. Together, these highly innovative studies reveal how chronic alcohol exposure alters appetitive responses to alcohol cues. These translational studies examine pathology in frontolimbic circuits associated with chronic alcohol exposure that manifest In altered attention and response to alcohol-associated stimuli. The combination of human behavior and imaging with rodent measures of behavior, dopamine release and selective manipulation of prefrontal cortical projections provides a mechanistic approach to identify how alcohol cues usurp attention and behavior to perpetuate compulsive alcohol use.

DESCRIPTION (provided by applicant): The primary, long-term objective of UNC PREP in the Biological and Biomedical Sciences is to increase the number of highly trained, under-represented (UR) biomedical scientists in leadership positions who can significantly impact the health-related research needs of the nation. The immediate goals of UNC PREP in the Biological and Biomedical Sciences are to equip, encourage, and empower talented UR post-baccalaureates to enter and excel in top biological and biomedical graduate programs. Our program will address each scholar's unique needs and support his or her transition into highly competitive PhD or MD/PhD programs and research careers. This will be accomplished through extensive high-quality research experiences, relevant professional development training, supportive program staff, and the development of a community of like-minded scholars with similar goals. In addition to becoming competitive PhD or MD/PhD candidates, our program will lay the foundation of each trainee's network of mentors who can provide guidance and support success throughout their career. The specific aims for UNC PREP are 1) to provide a unique training experience for each scholar based on his or her specific needs through the use of Individual Development Plans (IDPs). This will form the foundation of each scholar's training and will allow him or her to develop a foundation in all skills critical to success in graduate school and research careers; 2) to have UNC PREP scholars engage in mentored lab research (75% time) as well as professional development activities and graduate level coursework (25% time) so they develop not only critical thinking skills but also critical time management skills needed t balance graduate school expectations; 3) to have 80% of UNC PREP scholars transition into top-tiered, competitive graduate programs with the intent of pursuing a biomedically relevant research career; and 4) to thoroughly integrate early and continuous evaluation into all aspects of UNC PREP. Quantitative and qualitative measures of scholar progress, scholar outcomes, and all program components designed to address these aims will be consistently and thoroughly evaluated and will drive evolution of program components to maximize development of students and positive outcomes in the above aims. In its first three years, 87.5% of PREP scholars have been accepted into top biomedical PhD programs with 100% retention in these programs. Ultimate success of the program will be defined as UNC PREP scholars completing PhD programs and entering high-quality postdoctoral positions, and later, faculty and leadership positions in academia, government, or industry.

Project Summary/Abstract The Information Dissemination Core of the UNC NIAAA Alcohol Research Center (ARC) has a two-fold objective: to disseminate scientific information on alcohol pathology to the public and to equip our trainees and faculty to communicate their science through community engagement. These goals integrate with the educational mission of the Bowles Center for Alcohol Studies (BCAS) as a part of the University of North Carolina at Chapel Hill. To accomplish our goals, we partner with state-wide and nonprofit agencies in three integrated but separate aims. First, we will disseminate current research on the risks of adolescent binge drinking that induce long lasting changes in neurobiology. By partnering with the North Carolina ABC Commission, the North Carolina Governor?s Task Force on Underage Drinking, and the state-wide ?Talk It Out? campaign we will inform both parents and adolescents through multiple approaches. Current and accurate scientific information, is disseminated through the ?Talk It Out? TV and radio announcements and website, as well as the BCAS website. Second, we will provide education on the neurobiology of alcohol use to college students at risk for alcohol use problems. Our two target groups are first-time offenders with alcohol-related charges and UNC sorority/fraternity members. This aim is facilitated by partnering with Carpe Diem, a UNC- affiliated alcohol education program, and the UNC Office of Fraternity & Sorority Life and Community Involvement. Third, we train BCAS scientists ? with a particular focus on graduate students and postdoctoral fellows ? to effectively engage a broad audience in neuroscience outreach. Each year we develop new learning modules that center on an aspect of neuroscience, then provide training and resources to use them. For example, each year Core faculty develop a new interactive module aimed toward children and youth that is showcased during Brain Awareness Week at the local North Carolina Museum of Life and Science, and BCAS scientists are recruited to volunteer at the event. Additional programming aimed at adults focuses on alcohol neurobiology, intoxication and neuropathology. The Museum of Life and Science, as well as the UNC Morehead Planetarium and Science Center, are key partners in these efforts. Overall, these activities maximize the impact of the ARC to promote addiction research, healthy behavior and substance abuse prevention. Collaborative partnerships for the translation and scientific insight on alcohol drinking across the lifespan, including adolescence, will optimize the impact of scientific knowledge on health.