2000 — 2002 |
Flagel, Shelly Beth |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Postnatal Chronic Stress: Vulnerability to Drug Use @ University of Michigan At Ann Arbor |
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2009 — 2010 |
Flagel, Shelly Beth |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Individual Differences in Incentive Salience Attribution: Relevance to Addiction
DESCRIPTION (provided by applicant): While some individuals are able to casually use a drug without it interfering with their day-to-day activities, others become addicted, unable to shift their thoughts and actions away from drugs and drug-associated stimuli. The factors underlying these individual differences are not yet known, but one plausible explanation is that individual differences in addiction liability are related to the extent to which reward-related cues come to control behavior. The ability of reward-related stimuli to gain control over behavior can be studied in the laboratory using Pavlovian conditioning procedures. When a discrete cue is reliably paired with the receipt of a reward, it not only serves as a predictor of reward, but can also elicit complex emotional and motivational states. Thus, for some animals, goal-trackers, the reward-related cue serves merely as a predictor, eliciting approach directed toward the location of reward delivery;and for others, sign-trackers, the cue attains motivational value, eliciting approach and consummatory behavior directed towards the cue. Sign-tracking behavior is thought to reflect enhanced attribution of incentive salience to reward-related cues and may therefore be especially relevant to the study of addictive behavior and relapse. The working hypothesis then is that sign-trackers may represent individuals with increased vulnerability to addiction;whereas goal-trackers may represent those that are resilient to the disorder. To test this hypothesis, we will utilize a unique genetic animal model-rats selectively bred on the basis of a novelty-seeking trait but known to diverge on a number of traits relevant to addiction. Bred high-responder rats (bHR) are primarily sign-trackers, exhibiting approach to cues associated with both food and drug (cocaine) reward;and bred low-responder rats (bLR) are almost exclusively goal-trackers, approaching the location of reward delivery. Cross-bred intermediate responders (bIR) behave similarly to commercial rats, with almost equal probability of developing either goal-tracking or sign-tracking behavior. Utilizing all three of these lines will provide a continuum in the population, enabling us to examine the relationship between various traits (e.g. novelty-seeking, sign-tracking) and addiction liability. The following indices of substance abuse vulnerability will be obtained: I) escalation of drug intake during prolonged (5-hr) cocaine self-administration sessions;II) the persistence of drug-taking behavior when the drug is no longer available;III) resistance to extinction;and IV) cue-induced reinstatement (i.e. relapse) following a 30-day abstinence period. From these measures of addictive liability it will be determined whether rats that sign-track are more susceptible to the transition to addiction relative to rats that goal-track. Moreover, the use of the selectively bred rat lines provides enormous potential for future studies to investigate the genetic, molecular and behavioral antecedents to traits relevant to addictive behavior. PUBLIC HEALTH RELEVANCE: The proposed project will examine whether individual differences in the extent to which reward-related cues come to control behavior are related to substance abuse vulnerability. Utilizing selectively bred rat lines, these studies may prove to be very informative in understanding the psychological, neurobiological, and genetic mechanisms that contribute to the development of addiction. Moreover, the proposed animal model may allow us to determine what renders some individuals susceptible to addiction and what protects others from developing the disorder.
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2012 — 2016 |
Flagel, Shelly Beth |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core B: Behavioral Core
PROJECT SUMMARY (See instructions): The Behavioral Core will serve all individual Projects proposed in this application. In addition to the supervision of husbandry for all animals to be used in the Projects, there are a number of behavioral test procedures that are common to all Projects and these will be conducted in the Behavioral Core. This includes initial behavioral testing to quantify traits that are thought to contribute to vulnerability to addiction, including the propensity to attribute incentive salience to reward cues (measured by Pavlovian approach to reward cues) and the propensity to make impulsive actions (measured by premature responses on a 2-choice serial reaction time task). In addition, drug self-administration testing will be conducted in the Behavioral Core, when feasible and appropriate. The implementation of the Behavioral Core will insure a level of quality control and standardization that will significantly reduce variance and facilitate the comparison of results across individual Projects.
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2015 — 2019 |
Flagel, Shelly Beth |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dynamic Control of Cue-Driven Behavior Via the Paraventricular Thalamic Nucleus @ University of Michigan At Ann Arbor
? DESCRIPTION (provided by applicant): Stimuli (cues) in the environment associated with reward can motivate normal behavior, bringing one in close proximity to valuable resources (i.e. food, water, mates); but they can also gain inordinate control over behavior, as is the case with addiction. The ability of reward cues to motivate both normal and maladaptive behavior occurs through Pavlovian learning processes. Thus, when a discrete cue is repeatedly paired with presentation of a reward, it can acquire the ability to act as a predictor, but can also acquire incentive motivational properties. For example, in addicts, cues that have been previously associated with the drug- taking experience acquire the ability to maintain drug-seeking behavior and instigate relapse, even when there is a strong desire to stop use. We have recently discovered that in rats there is considerable individual variation in the extent to which food cues are attributed with Pavlovian incentive motivational value (incentive salience) and this variation predicts how avidly they will later seek drugs and the propensity to relapse. Using a Pavlovian conditioning paradigm, rats can be classified as sign-trackers-those that attribute incentive salience to reward cues, or goal-trackers-those that assign only predictive value to reward cues. Thus, this animal model allows us to parse the incentive from the predictive properties of reward-associated cues and to elucidate the neural circuitry underlying these distinct forms of cue-reward learning. In the proposed studies we will exploit this natural variation in the propensity to attribute incentive salience to reward cues, using a uniquely heterogeneous population of rats. Further, we will use a novel molecular-genetic approach that uses viral vectors to express engineered artificial receptors (known as DREADD receptors), to examine how transiently modulating activity of specific brain circuits will alter the propensity to sign-track or goal-track. Specifically, the proposed studies focus on afferent systems to the paraventricular nucleus of the thalamus (PVT), a site that has gained increasing attention in the addiction literature, and has recently been shown to play a role in sign- vs. goal-tracking behavior. We will test the hypothesis that sign-tracking behavior, which is dopamine dependent, is mediated via subcortical processes including dopaminergic projections from the ventral tegmental area (VTA) to the PVT; and that goal-tracking behavior, which is dopamine-independent, is mediated via cortical top-down afferents to the PVT. We will also examine how altering activity in these specific circuits will affect patterns of food- and drug-cue-induced neuronal activity throughout the brain in sign- trackers vs. goal-trackers. This work will lead to better understanding of the neural mechanisms that go awry in psychopathologies like addiction, and has the potential to lead to novel therapeutic interventions.
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2018 |
Flagel, Shelly Beth |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Animal and Human Behavior ? Using Computational Approaches to Build a Two-Way Bridge @ University of Michigan At Ann Arbor
PROJECT SUMMARY/ABSTRACT Translation, i.e. the application of findings from animal experiments to humans, is of central importance for the field of behavioral neuroscience. However, the value of translational research has been challenged by many findings, which show results in animal studies that do not properly replicate in human experiments. Computational psychiatry is a young field that uses computational approaches to advance rigorous mechanistic understanding of the processes that underlie mental health and disease, in part by developing practical applications based on the automated analysis of human data. Computational neuroscience has used a similar approach for animal data. Thus, computational approaches, i.e. quantifying behavioral results in terms of underlying computational models, may have significant utility in translational research. Therefore, we aim to bring together computational researchers with behavioral neuroscience researchers to develop collaborative efforts focused on using computational approaches for translational research. Several important developments have occurred that make this proposed meeting timely: First, clinicians are beginning to recognize the importance of individual differences, brain-behavior relationships and the limitations of traditional means of classifying psychiatric disorders (e.g. DSM). Second, with the advent of new technology, basic researchers are able to better elucidate brain-behavior relationships and knowledge in this regard is increasing at an exponential rate. Nonetheless, there remains a gap between animal models and human behavior, and until that gap is filled, we will continue to make only small strides in identifying successful treatment options for psychiatric illness. The overall goal of this workshop is to identify means to better bridge the gap between animal models of maladaptive behavior and human psychopathology. In order for animal models to provide help with clinical questions, these models will need to have both predictive validity and explanatory power. Some of the key questions that will be addressed are: (1) Can computational approaches be used to develop better ?at risk? animal models? (2) Can computational approaches in animal models be used to disambiguate the contributions of different drugs of abuse to compulsive drug-taking and drug-seeking behaviors? (3) Can computational approaches in animal models improve the predictive validity of novel interventions? The hope is that this workshop will set the stage for future studies to utilize computational methods to bridge the ?translational? gap and thereby improve our strategies for identifying novel therapeutic targets for the successful treatment of addiction and related disorders.
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2018 — 2019 |
Flagel, Shelly Beth |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Identification of Neurochemical Antecedents and Consequences of Distinct Learning Processes Relevant to Addiction Liability @ University of Michigan At Ann Arbor
ABSTRACT Cues or stimuli in the environment can guide behavior in adaptive ways, bringing one in close proximity to valuable resources (i.e. food, water, mates); but they can also elicit maladaptive behavior. For example, in addicts, exposure to cues (e.g. places, paraphernalia) previously associated with drug-taking often leads to relapse, despite the desire to remain abstinent. The ability of such cues to elicit complex emotional and motivational states and gain control over one's behavior occurs via Pavlovian learning mechanisms. Using an animal model that captures individual differences in response to reward cues, we can now study the neural processes underlying aberrant forms of cue-reward learning, bringing us closer to identifying novel targets for the treatment of addiction. When rats are exposed to a Pavlovian conditioning paradigm wherein a discrete cue is repeatedly paired with presentation of a reward, some are ?sign-trackers??those that attribute incentive salience to the cue, and others ?goal-trackers??those that assign only predictive value to the cue. Thus, there is individual variation in the extent to which food cues are attributed with Pavlovian incentive motivational value (?incentive salience?), and this variation predicts the degree to which drug cues will attain control over behavior and the propensity to relapse. Furthermore, this animal model allows us to parse the incentive from the predictive properties of reward cues, and we have used it to demonstrate that distinct neural circuits regulate these different forms of cue-reward learning. In addition, we have shown that dopamine is critical for incentive learning (i.e. sign-tracking), but not predictive learning (i.e. goal-tracking). Most studies to-date, however, have been hampered by the inability to measure neural correlates of these phenotypes prior to learning. That is, rats must first undergo Pavlovian conditioning in order to be characterized as sign- or goal-trackers. Thus, the first Aim of the current proposal is to determine whether there are pre-existing basal differences in neurotransmitter signaling in the nucleus accumbens core that predict those individuals prone to attribute incentive salience to reward cues prior to behavioral testing. To do this, we will use a novel chemical analytical approach (stable-isotope labeling) that will allow us, for the first time, to assess true basal levels of dopamine, norepinephrine, acetylcholine, serotonin, glutamate and GABA in sign- and goal-trackers. The second Aim will use another novel, but different, chemical analytical approach to simultaneously assess up to 50 neurochemicals in the nucleus accumbens core in sign- and goal-trackers. The focus of the second Aim will be on the neurochemical profiles that emerge as a consequence of an individual's associative learning style. Advanced statistical analyses will be applied in order to identify neurochemical profiles that best predict the behavioral phenotypes and to examine the relationship between neurochemicals over the course of learning. This work will highlight specific neural systems that may render an individual more susceptible to control by reward cues and lay the foundation for future studies to identify novel neuromolecular targets for the treatment of addiction.
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2019 — 2020 |
Flagel, Shelly Beth |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Nida Training Program in Neuroscience @ University of Michigan At Ann Arbor
? DESCRIPTION (provided by applicant): This application is a request for continuing support for a predoctoral NIDA Training Program in Neuroscience, which was founded at The University of Michigan (UM) in 1995. The major goal of this Program is to recruit and develop student interest in research related to the neurobiology of substance abuse, and to provide the necessary infrastructure for trainees to pursue these interests as they work towards their doctoral degree in the field of neuroscience. To be eligible for support by the NIDA Training Program students must first gain admittance to an existing UM graduate program in the biological, biomedical or natural sciences, such as the interdepartmental Neuroscience Graduate Program or the Biopsychology Program. Students nominated for support by the NIDA Training Program in Neuroscience are selected on the basis of two criteria: 1) academic qualifications and references (i.e. academic excellence), and 2) the relevance of their program of study and research interests to the NIDA mission. After admission to the NIDA Training Program in Neuroscience, students pursue a program of study in the neurosciences, including a required course on the neuropsychopharmacology of substance abuse and an accompanying seminar series involving the NIDA Training Program faculty. The NIDA Training Program in Neuroscience consists of 18 affiliated faculty, all of whom conduct research related to the biological basis of substance abuse. Most of the faculty is either a principal or co-investigator o a NIDA-funded research grant. The core faculty members have changed since the prior funding cycle, with 7 new faculty replacing those who are no longer conducting relevant research at the University of Michigan. Most of these new faculty members are considered junior investigators; thus, there is a plan in place for more senior faculty to serve as co-mentors for any trainees that join a junior faculty's lab. In addition, the faculty affiliated with this training grant is assistd by over 120 Neuroscience Graduate Program faculty who are also involved in many aspects of the training. The training grant is used primarily to foster interest in students to do research rotatins in a laboratory that studies the neurobiology of substance abuse, and to ultimately choose one of these labs for their dissertation work. In addition, we hope to maintain their interest in substance abuse research throughout their dissertation work with journal clubs, seminar series and social events that will be open to all current and previous trainees supported by this training grant. The NIDA Training Program in Neuroscience is administered by a Director and a Co-Director, and now includes a Director of Student Development in order to enhance the experience of the trainees.
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2021 |
Flagel, Shelly Beth |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Nida Training Program in Neuroscience-Administrative Supplement @ University of Michigan At Ann Arbor
Project Summary (as submitted in 2015 for current funded project) This application is a request for continuing support for a predoctoral NIDA Training Program in Neuroscience, which was founded at The University of Michigan (UM) in 1995. The major goal of this Program is to recruit and develop student interest in research related to the neurobiology of substance abuse, and to provide the necessary infrastructure for trainees to pursue these interests as they work towards their doctoral degree in the field of neuroscience. To be eligible for support by the NIDA Training Program students must first gain admittance to an existing UM graduate program in the biological, biomedical or natural sciences, such as the interdepartmental Neuroscience Graduate Program or the Biopsychology Program. Students nominated for support by the NIDA Training Program in Neuroscience are selected on the basis of two criteria: 1) academic qualifications and references (i.e. academic excellence), and 2) the relevance of their program of study and research interests to the NIDA mission. After admission to the NIDA Training Program in Neuroscience, students pursue a program of study in the neurosciences, including a required course on the neuropsychopharmacology of substance abuse and an accompanying seminar series involving the NIDA Training Program faculty. The NIDA Training Program in Neuroscience consists of 18 affiliated faculty, all of whom conduct research related to the biological basis of substance abuse. Most of the faculty are either a principal or co-investigator on a NIDA-funded research grant. The core faculty members have changed since the prior funding cycle, with 7 new faculty replacing those who are no longer conducting relevant research at the University of Michigan. Most of these new faculty members are considered junior investigators; thus, there is a plan in place for more senior faculty to serve as co-mentors for any trainees that join a junior faculty?s lab. In addition, the faculty affiliated with this training grant are assisted by over 120 Neuroscience Graduate Program faculty who are also involved in many aspects of the training. The training grant is used primarily to foster interest in students to do research rotations in a laboratory that studies the neurobiology of substance abuse, and to ultimately choose one of these labs for their dissertation work. In addition, we hope to maintain their interest in substance abuse research throughout their dissertation work with journal clubs, seminar series and social events that will be open to all current and previous trainees supported by this training grant. The NIDA Training Program in Neuroscience is administered by a Director and a Co-Director, and now includes a Director of Student Development in order to enhance the experience of the trainees
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2021 |
Flagel, Shelly Beth |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Probing the Role of a Hypothalamic-Thalamic-Striatal Circuit in Cue-Driven Behaviors @ University of Michigan At Ann Arbor
PROJECT SUMMARY/ABSTRACT Stimuli (cues) in the environment associated with reward can motivate normal behavior, bringing one in close proximity to valuable resources (e.g. food); but they can also gain inordinate control over behavior, as is the case with addiction. The ability of reward cues to motivate behavior occurs through Pavlovian learning processes. When a discrete cue is repeatedly paired with presentation of a reward, it can acquire the ability to act as a predictor, but can also acquire incentive motivational properties. In individuals with addiction, cues that have been previously associated with the drug-taking experience acquire the ability to maintain drug-seeking behavior and instigate relapse, even when there is a strong desire to stop use. The neurobiological processes by which reward cues gain inordinate control over behavior have proven difficult to discern because cues can simultaneously acquire ?predictive? and ?incentive? properties, and in most studies these two psychological processes are confounded. In the proposed studies we will exploit natural variation in cue-reward learning to identify the neural circuitry specifically responsible for the attribution of incentive motivational value (incentive salience) to reward cues. When rats are exposed to a Pavlovian conditioned approach paradigm, some, termed ?goal-trackers?, attribute predictive value to a discrete food-associated cue; whereas others, termed ?sign-trackers? attribute incentive salience to the cue. Relative to goal-trackers, sign-trackers are more susceptible to behavioral control by discrete food- and drug-paired cues and have a greater propensity for cue- induced reinstatement or relapse. Using this animal model, we have found that the paraventricular nucleus of the thalamus (PVT) plays a critical role in incentive learning processes and in regulating individual differences in relapse propensity. The PVT appears to act as a node that integrates ?top-down? and ?bottom-up? input to regulate cue-driven behaviors, but the subcortical circuitry subserving incentive salience attribution remains to be determined. The central hypothesis to be tested here is that both input to and output from the PVT are necessary and sufficient to promote dopamine-dependent incentive learning. We will use a molecular-genetic approach with viral vectors to selectively express engineered artificial receptors (e.g. DREADD) to determine how transiently altering activity of neurons in select PVT circuits affects the propensity to attribute incentive salience to reward cues. Specifically, we will target inputs to the PVT from the lateral hypothalamus (LH), and outputs from the PVT to the nucleus accumbens shell (NAcSh). We will determine whether the PVT-NAcSh pathway can regulate cue-driven behavior independent of the ventral tegmental area, and how manipulating these subcortical circuits affects neurochemical activity in the NAcSh. In addition, we will determine if the LH- PVT and PVT-NAcSh pathways mediate individual differences in the propensity for cue-induced reinstatement of drug-seeking behavior. This work will identify critical components of the neural circuitry that contribute to addiction liability.
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2021 |
Flagel, Shelly Beth |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
The Glucocorticoid Receptor as a Mechanism of Top-Down Control of Cue-Motivated Behavior @ University of Michigan At Ann Arbor
PROJECT SUMMARY/ABSTRACT The glucocorticoid receptor (GR) is best known for its role in mediating the stress response. Thus, it is not surprising that this receptor has been implicated in the pathophysiology of several psychiatric disorders. Recently, a number of reports have emerged identifying GR-related polymorphisms associated with susceptibility to cocaine use and addiction. Indeed, it has been known for decades that glucocorticoids, via GR, interact with dopamine to produce individual differences in response to drugs of abuse. The mechanism by which this occurs, however, remains to be determined. Importantly, while stress can facilitate dopamine- glucocorticoid interactions, it is not necessary. That is, an individual may be inherently ?wired?, or primed for these interactions to occur, rendering them more susceptible to addiction, even in the absence of stress. The overarching goal of the proposed work is to identify one such priming mechanism. Some individuals may be particularly prone to addiction because they have a tendency to attribute drug cues with excessive incentive motivational value. For these individual exposure to cues (e.g. paraphernalia) previously associated with drug- taking may precipitate relapse, despite a desire to remain abstinent. In rats, we have shown that those with an increase propensity for incentive learning have insufficient ?top-down? cortical control, concurrent with hyperactive subcortical mechanisms. In conjunction, these rats are more impulsive, have deficits in attentional control and are more likely to exhibit cue-induced reinstatement of drug-seeking behavior (i.e. relapse). The neurobehavioral endophenotype captured by the propensity to attribute incentive salience to reward cues, therefore, is reminiscent of individuals with addiction. The central hypothesis to be tested here is that GR function in a ?top-down? cortico-striatal circuit plays a critical role in determining this addiction-related endophenotype. We will take advantage of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas 9-mediated gene-editing technology to selectively manipulate GR in glutamatergic afferents projecting from the prelimbic cortex (PrL) to the nucleus accumbens core (NAcC) - a circuit that we believe has little to do with stress responsivity and more to do with mediating responses to reward-associated cues. We hypothesize that knockdown of GR selectively in this cortico-striatal circuit will attenuate 1) the propensity to attribute incentive motivational value to a reward cue, and 2) cue-induced reinstatement of cocaine-seeking behavior. This exploratory grant has the potential to uncover a novel neural mechanism that contributes to the propensity for relapse. Regardless of the outcome, this research will set a foundation for future studies to further investigate the role of GR in addiction-related behaviors with great neuroanatomical precision.
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