Neural mechanisms of accumbens-dependent impulsivity

伏隔核依赖性冲动的神经机制

• 批准号: 9066133
• 负责人: SALEEM M NICOLA
• 金额: $ 39.27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066133
• 关键词: Adolescence; Affect; Animal Model; Animals; Attention; Automobile Driving; Behavior; Behavioral; Behavioral Model; Childhood; Cognitive; Cues; Data; Decision Making; Development; Disease; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine Receptor; Drug abuse; Evaluation; Exhibits; Family; Fire - disasters; Genes; Goals; Hand; Health; Home environment; Impulse Control Disorders; Impulsive Behavior; Impulsivity; Infusion procedures; Intervention; Laboratories; Life; Link; Location; Longitudinal Studies; Measures; Modeling; Movement; Nature; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Personality; Pharmaceutical Preparations; Pharmacological Treatment; Process; Public Health; Rattus; Reaction Time; Rewards; Risk; Risk Factors; Running; Signal Transduction; Stimulus; Structure; Substance abuse problem; Sucrose; System; Testing; Time; Ursidae Family; Walking; addiction; base; classical conditioning; design; discounting; drinking; drug seeking behavior; neuromechanism; novel; premature; problem drinker; relating to nervous system; research study; response

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.

描述（由申请人提供）：冲动是一种立即和轻率地对奖励相关刺激的反应的趋势，因此，考虑到替代方案后，可能会获得更大的奖励。具有冲动性格的人面临滥用药物滥用问题的风险，而成瘾者的冲动行为可能会导致寻求毒品的行为以及财务，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理解神经层面成瘾的目标高度相关，并开发有助于帮助的干预措施 吸毒者抵制对药物相关刺激的反应并做出更好的选择。不幸的是，不同形式的冲动性是不同行为和神经过程的结果，而n个单个动物行为模型捕获了所有冲动性的方面。因此，必须单独研究独特的冲动性形式，以发现其神经机制。尽管有冲动的动作（在响应之前需要等待的任务中的过早响应）和延迟折扣的加剧（选择较小的立即奖励而不是较大的延迟奖励）是充分研究的，但一种很少受到关注的冲动性是一种空间折扣，选择较小的更接近的奖励，以更大的物理距离获得更大的奖励。最近的研究（例如Howe等人，自然500：575，2013）表明，中端和中脂糖多巴胺信号随着与奖励的运动靶标相关的接近而增加，而振容核中的神经元的神经元在动物IS的近距离运动中更强烈地激活了奖励（MEC在奖励中，奖励奖励）（MEC）在奖励中的奖励（MEC）更强烈地激活（MEC）在奖励（MEC）上的激活（MEC）在奖励上是奖励（MEC）的奖励（MEC在奖励中，奖励（MEC）是奖励（奖励），而奖励（MEC）是奖励（奖励奖励），而奖励（MEC）在奖励（奖励）奖励（MEC）的奖励（零售方式），而奖励（MEC）是奖励（奖励）。 Neuron 78：910，2013）。这些结果表明，经典定义的“奖励系统”（包括伏隔核及其多巴胺输入）有助于空间折现。但是，这种贡献的性质仍然未知。拟议的实验采用了一项新的决策任务，使大鼠研究由陡峭的空间折现定义的冲动形式的神经机制。在此任务中，受试者与奖励相关的杠杆的距离随着试验而异。飞行员数据表明​​，冲动选择杠杆的可能性（较大的奖励）随着杠杆的距离而增加。此外，在此任务中，伏隔核中的神经元独立于预期奖励幅度编码接近性，这表明它们的放电通过独立于预期结果评估的机制促进了接近性驱动的冲动。提出的实验更详细地探讨了这种机制。他们利用了一种独特的方法 - 记录伏伏神经在行为动物中的单位活性，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是邻近驱动的冲动性的原因。结果将以前所未有的细节描述多巴胺和伏核对决策和冲动的重要贡献。