Michael W. Shiflett - US grants

DESCRIPTION:(adapted from applicant?s abstract) This research project examines learning and plasticity in the hippocampus of food-storing birds. The first three experiments address the role of the hippocampus in spatial memory processing, through the use of reversible inactivation or injection of receptor antagonists. The fourth experiment examines factors that may induce seasonal neurogenesis by manipulating experience and hormone levels. This research will contribute to our understanding of the neural basis of learned behaviors in the following ways; first, by studying a natural behavior, we can increase the generality and validity of our current theories on the neural basis of learning and memory. Second, by studying a system with remarkable adult neural plasticity, we may better understand the link between plasticity in the nervous sytem and changes in cognitive function. This in turn may be relevant to therapeutic strategies involving brain repair, by revealing the mechanisms through which adult generated neurons become functionally integrated into the nervous system.

[unreadable] DESCRIPTION (provided by applicant): This proposal explores the neural mechanisms underlying motivational control of reward-seeking behavior by reward-paired stimuli, and their modulation by exposure to drugs of abuse. Specifically, this proposal examines the involvement of the extracellular-signal regulated kinase (ERK) pathway in the Nucleus Accumbens core (NAcc) in cue-controlled behavior, and how exposure to one abused substance, the psychostimulant d-amphetamine, may alter cue-controlled behavior by altering NAcc ERK signaling. It is hypothesized that NAcc ERK signaling is necessary for reward-paired stimuli to motivate reward-seeking behavior. Furthermore, d-amphetamine exposure is hypothesized to enhance cue-controlled behavior by increasing NAcc ERK activation in response to reward-paired stimuli. The proposed experiments use Pavlovian and instrumental learning tasks coupled with intracranial infusions of an ERK antagonist to assess the role of NAcc ERK signaling in cue-induced reward seeking. The effect of d-amphetamine exposure on cue-induced reward seeking and cue-evoked ERK activation will be assessed using Western blot analysis. These experiments may shed light on the mechanisms underlying relapse caused by drug-paired cues. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): A prevalent form of relapse in addiction is caused by exposure to cues or contexts formerly paired with drug delivery. The ability of drug-paired conditioned stimuli (CSs) to increase incentive motivation, or "craving", indicates that the rewarding properties of drug exposure can be associated with CSs predicting their delivery through a Pavlovian incentive learning process. Recent research raises the possibility that, as a consequence of neuroadaptations resulting from repeated drug exposure, the ability of CSs to compel reward-seeking behavior is enhanced among former drug users. To fully explore this hypothesis, a greater understanding is necessary of the motivational processes that underlie Pavlovian influences on reward-seeking behavior generally, as well as the effects of repeated drug exposure on these processes. This proposal examines the effect of drug sensitization on the ability of Pavlovian cues to influence reward-seeking behavior, with the overall goal of characterizing the motivational processes that underlie the enhanced responsiveness to reward-associated CSs in amphetamine-sensitized rats. The proposed experiments make use of Pavlovian-instrumental transfer (PIT) paradigm to assess the role of outcome saliency and general arousal in determining the choice and intensity of instrumental actions during PIT. These experiments are important for understanding the process through which drug exposure alters the influence of reward-predictive cues on reward-seeking behavior, and will serve as the basis for further research into the neural systems and molecular mechanisms underlying Pavlovian incentive processes and their modulation by exposure to drugs of abuse. Furthermore, these studies will be important in devising therapeutic strategies to treat relapse based on an understanding of the relevant factors that underlie Pavlovian influences on reward-seeking behavior. PUBLIC HEALTH RELEVANCE: The proposed research addresses behavioral processes that are central to substance abuse disorders, and thus is highly relevant to public health. Furthermore, the research findings may be useful in devising therapeutic strategies to prevent relapse caused by re-exposure to drug-associated cues.