Neural mechanisms of accumbens-dependent impulsivity

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DESCRIPTION (provided by applicant): Impulsivity is a tendency to respond immediately and rashly to reward-associated stimuli and, as a consequence, forego potentially greater reward that may be available after consideration of alternatives. People with impulsive personalities are at greater risk for developing problems with drug abuse, and impulsive behavior in addicts may contribute both to drug-seeking behavior and to poor financial, personal and other life choices. Understanding the neural mechanisms that drive impulsive behavior is therefore highly relevant to the goal of understanding addiction at a neural level, and to developing interventions that help addicts resist responding to drug-related stimuli and make better choices. Unfortunately, different forms of impulsivity are the result of dif- ferent behavioral and neural processes, and n single animal behavioral model captures all facets of impul- sivity. Therefore, unique forms of impulsivity must be studied individually to discover their neural mechanisms. Although impulsive action (premature responses in tasks that require waiting before responding) and heightened delay discounting (choosing a smaller immediate reward rather than a larger delayed reward) are well-studied, one form of impulsivity that has received little attention is spatial discounting choosing a smaller more proximate reward at the expense of larger reward available at greater physical distance. Recent studies (e.g., Howe et al, Nature 500:575, 2013) indicate that the mesostriatal and mesolimbic dopamine signals increase with proximity to a movement target associated with reward, and neurons in the nucleus accumbens are more strongly activated by cues that predict reward when the animal is in close proximity to the reward- associated movement target than when the animal is farther away (McGinty et al, Neuron 78:910, 2013). These results suggest that the classically-defined "reward system" (including the nucleus accumbens and its dopamine input) contribute to spatial discounting; however, the nature of this contribution remains unknown. The proposed experiments use a novel decision-making task for rats to investigate the neural mechanisms underlying the form of impulsivity defined by steep spatial discounting. In this task, the subject's proximity to a reward-associated lever varies across trials. Pilot data show that the likelihood of an impulsive choice of a lever that delivers suboptimal outcome (small reward) increases with greater proximity to the lever. Moreover, in this task neurons in the nucleus accumbens encode proximity independently of expected reward magnitude, suggesting that their firing promotes proximity-driven impulsivity by a mechanism independent of expected outcome evaluation. The proposed experiments explore this mechanism in more detail. They take advantage of a unique approach - recording the unit activity of accumbens neurons in behaving animals while infusing dopamine antagonists into the same structure - to assess whether the observed neural encoding is causal to proximity-driven impulsivity. The results will describe, in unprecedented detail, an important contribution of dopamine and the nucleus accumbens to decision-making and impulsivity.