Neural mechanisms of accumbens-dependent impulsivity

描述（由申请人提供）：冲动是一种倾向，立即和轻率地回应奖励相关的刺激，因此，放弃潜在的更大的奖励，可能是在考虑替代品。具有冲动性格的人更容易出现药物滥用问题，成瘾者的冲动行为可能导致寻求药物的行为以及不良的财务，个人和其他生活选择。因此，了解驱动冲动行为的神经机制与在神经水平上了解成瘾的目标以及开发有助于成瘾的干预措施高度相关 吸毒成瘾者抵制对与毒品有关的刺激作出反应，并作出更好的选择。不幸的是，不同形式的冲动是不同的行为和神经过程的结果，并且单个动物行为模型捕获了冲动的所有方面。因此，必须单独研究独特的冲动形式，以发现其神经机制。虽然冲动行为（在需要等待的任务中的过早反应）和提高延迟折扣（选择较小的即时奖励而不是较大的延迟奖励）得到了很好的研究，但很少受到关注的冲动的一种形式是空间折扣，选择较小的更接近的奖励，以牺牲在更大的物理距离上获得的更大奖励为代价。最近的研究（例如，Howe等人，Nature 500：575，2013）表明，中纹状体和中脑边缘多巴胺信号随着接近与奖励相关的运动目标而增加，并且当动物非常接近奖励相关的运动目标时，与动物更远时相比，中脑核中的神经元更强烈地被预测奖励的线索激活（McGinty等人，Neuron 78：910，2013）。这些结果表明，经典定义的“奖励系统”（包括丘脑核及其多巴胺输入）有助于空间折扣;然而，这种贡献的性质仍然未知。拟议的实验使用一种新的决策任务的大鼠研究的神经机制的形式冲动定义的陡峭的空间折扣。在这项任务中，受试者与奖励相关杠杆的接近程度在试验中各不相同。试点数据表明，冲动选择杠杆的可能性，提供次优的结果（小奖励）增加与更接近的杠杆。此外，在这项任务中，神经元在神经核编码的接近独立的预期奖励幅度，这表明他们的发射促进接近驱动的冲动的机制独立于预期的结果评价。所提出的实验更详细地探索了这种机制。他们利用了一种独特的方法-记录行为动物中多巴胺神经元的单位活动，同时将多巴胺拮抗剂注入相同的结构-以评估观察到的神经编码是否与接近驱动的冲动有关。研究结果将以前所未有的细节描述多巴胺和丘脑核对决策和冲动的重要贡献。

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.