Neural mechanisms of accumbens-dependent impulsivity

伏隔核依赖性冲动的神经机制

基本信息

批准号：
9268725
负责人：
SALEEM M NICOLA
金额：
$ 39.66万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
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/9268725
关键词：
Adolescence Affect Animal Model Animals Attention Automobile Driving Behavior Behavior Therapy Behavioral Behavioral Model Childhood Cognitive Cues Data Decision Making Development Disease Dopamine Dopamine Agonists Dopamine Antagonists Dopamine Receptor Drug abuse Evaluation Exanthema Exhibits Family Fire - disasters Genes Goals Hand Home environment Impulse Control Disorders Impulsive Behavior Impulsivity Individual Infusion procedures Intervention Laboratories Life Link Location Longitudinal Studies Measures Movement Nature Neurobiology Neurons Nucleus Accumbens Outcome Personality Pharmaceutical Preparations Pharmacological Treatment Pharmacology 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 cost design discount discounting drug seeking behavior experimental study neuromechanism novel premature problem drinker public health relevance relating to nervous system response

项目摘要

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）：冲动是一种对与奖励相关的刺激立即做出鲁莽反应的倾向，因此放弃在考虑替代方案后可能获得的更大奖励。具有冲动性格的人出现药物滥用问题的风险更大，而成瘾者的冲动行为可能会导致寻求药物的行为以及糟糕的财务、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帮助的干预措施高度相关。成瘾者会抵制与毒品相关的刺激，并做出更好的选择。不幸的是，不同形式的冲动是不同行为和神经过程的结果，而单一动物行为模型涵盖了冲动的所有方面。因此，必须单独研究冲动的独特形式，以发现其神经机制。尽管冲动行为（在需要等待才能做出反应的任务中过早做出反应）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）已得到充分研究，但很少受到关注的一种冲动形式是空间折扣，选择更小的、更近的奖励，以牺牲在更远的物理距离处可获得的更大的奖励为代价。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，并且伏隔核中的神经元被预测奖励的线索更强烈地激活当动物距离奖励相关的运动目标较近时，与距离较远时相比（McGinty 等人，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）有助于空间折扣；然而，这种贡献的性质仍然未知。所提出的实验使用大鼠的一种新颖的决策任务来研究由陡峭的空间贴现定义的冲动形式背后的神经机制。在此任务中，受试者与奖励相关杠杆的接近程度在不同试验中有所不同。试点数据表明，冲动选择提供次优结果（小奖励）的杠杆的可能性随着距离杠杆的距离的增加而增加。此外，在这项任务中，伏隔核中的神经元独立于预期奖励大小对接近度进行编码，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驱动的冲动。所提出的实验更详细地探索了这种机制。他们利用一种独特的方法——记录行为动物伏隔神经元的单位活动，同时将多巴胺拮抗剂注入到同一结构中——来评估观察到的神经编码是否与接近驱动的冲动有关。结果将以前所未有的细节描述多巴胺和伏隔核对决策和冲动的重要贡献。