|2006-2012 ||Neurobiology ||University of Chicago, Chicago, IL |
| ||2012-2017 ||Psychology ||University of Michigan, Ann Arbor, Ann Arbor, MI |
| ||2017- ||Life, Health & Chemical Sciences ||Open University, Milton Keynes, England, Kents Hill, England, United Kingdom |
addiction, learning, conditioning, psychostimulant, sensitization
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According to our matching algorithm, Bryan F. Singer is the likely recipient of the following grants.
||Title / Keywords
|2011 — 2012
||Singer, Bryan Frederick
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.).
Neuroadaptations Underlying Drug Conditioning and Sensitization
DESCRIPTION (provided by applicant): Repeated intermittent exposure to amphetamine leads to long-lasting sensitization of its psychomotor stimulant effects, such that re-exposure to the drug weeks to months later produces enhanced locomotor responding and self-administration of the drug. These findings support the proposal that sensitization of the appetitive effects of amphetamine may underlie the transition from casual drug use to drug craving and abuse. The induction of this drug-induced sensitization necessarily involves exposure to the drug in association with a complex of environmental stimuli. Repeated pairings of drugs with environmental stimuli leads to the formation of associations between the two such that these stimuli come to elicit behavioral and biochemical responses similar to those produced by the drug itself. Thus, it can be easy to confound the separate contributions of associative conditioning and non-associative sensitization to the enhanced responding observed following repeated drug exposure. One method for distinguishing between these two processes is to compare the effects of systemic amphetamine exposure to those of amphetamine applied directly to the ventral tegmental area (VTA). Amphetamine is known to act in the VTA to initiate sensitization, but fails to produce conditioning when applied to this site. Thus, by comparing the effects of VTA and systemically administered amphetamine, the associative and non-associative consequences of repeated exposure to the drug can be studied in relative isolation. The experiments in this grant proposal aim to better characterize both the neurochemical and morphological underpinnings of associative conditioning and non-associative sensitization, and will test two main hypotheses. Hypothesis 1: The activity of specific proteins in the nucleus accumbens (NAcc) during drug-conditioning are necessary for the formation of learned associations linking the drug environment to stimuli. Preliminary findings demonstrate, and the proposed experiments will further explore, how inhibition of the protein cyclin-dependent kinase 5 (cdk5) in the NAcc during drug exposure blocks associative conditioning while preserving non-associative sensitization. Furthermore, by comparing other protein changes in the NAcc caused by repeated systemic or VTA amphetamine exposure, we will be able to identify other proteins correlated either with conditioning or sensitization. Hypothesis 2: Specific populations of neurons undergo conditioning-related neuroanatomical plasticity. Using c-Fos as a marker to identify NAcc cells contributing to associative conditioning, we will inject these neurons with the carbocyanine neuronal tracer DiI in order to characterize their dendritic spine morphology using confocal 2-photon microscopy. PUBLIC HEALTH RELEVANCE: Drug addiction is a disease that is uniquely costly to society and affects the health, productivity, and well-being of individuals in various age groups and demographics. Much published research demonstrates how prolonged drug use produces changes in the brain. The proposed experiments extend this approach to study how these changes are regulated at the neuronal level by environmental factors that may encourage drug-seeking. Understanding how drug-paired environments regulate brain processes underlying compulsive drug use may lead to novel therapeutic and pharmacological treatments for the disease.
|2014 — 2015
||Singer, Bryan Frederick
F32Activity Code Description:
To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas.
Individual Variation in Dopamine Encoding of Incentive Salience
DESCRIPTION (provided by applicant): Addictive foods and drugs are never administered in isolation from salient discrete and contextual stimuli. The formation of associative memories allows for the linking of these stimuli to unconditioned rewarding effects, such that these cues obtain the ability to predict future reinforcement. These conditioned stimuli (CS) often become desired themselves and individuals vary in the degree to which this occurs. Recent evidence suggests the magnitude by which a CS is attractive and attributed with motivational meaning may be a function of dopamine (DA) signaling in the brain. We have been studying this in the rat using a conditioning task known as autoshaping. In this task an extendable/retractable lever is the CS that predicts reward. With repeated trials rats develop a conditioned response (CR); the specific CR performed varies across a population. For example, some rats approach and interact with the lever CS instead of approaching the location of food delivery (sign-trackers), while other rats do the opposite (goal-trackers). Antagonizing DA receptors in a region of the ventral striatum known as the nucleus accumbens core (NAcC) reduces this lever-directed behavior, while leaving goal-directed pellet retrieval intact. Therefore, DA signaling in the NAcC is hypothesized to selectively encode the attribution of incentive salience to the lever CS. The proposed research investigates individual variability in DA signaling underlying motivation- and reward-learning using the electrochemical technique Fast Scan Cyclic Voltammetry (FSCV). This technique allows for detecting real-time alterations in DA concentration in the awake-behaving rat. In two aims, the studies will ask (1) whether individual variability in the propensit to attribute motivational meaning to discrete reward-paired cues, such as the lever, is differentially encoded by DA signaling in the ventral and dorsal striatum; and (2) how variability in behavioral performance and DA signaling investigated in Aim 1 are modulated by environmental contexts that are predictive of reward availability or lack-there-of, therefore setting the occasion for pursuit of reward in the autoshaping task. By understanding variability in how reward-predictive stimuli motivate us to seek reinforcement we can better treat addictive disorders with novel cognitive-behavioral and pharmacotherapeutic techniques that are tailored to specific individuals.