The role of accumbens neural activity and dopamine release in flexible behavior

描述(申请人提供)：动物因环境变化而改变行为的能力是生存所必需的。患有神经精神障碍的患者，特别是成瘾障碍患者，往往难以适应这种类型的行为灵活性。人们可以使用增强剂贬值任务来衡量动物在结果价值改变后改变目标导向行为的能力。在这项任务中，动物在刺激(如线索)和特定增强剂(S)(如食物奖励)之间形成联系。随后，通过选择性的饱食(随意提供食物)，增强剂被“贬值”。在货币贬值后，正常受试者会调整他们的反应，这反映了在缺乏新的联想学习的情况下增强剂的新“价值”。伏隔核(NAC)与其他几个脑结构(如眶前叶皮质和杏仁基底外侧核)结合，对于通过强化贬值任务测量的灵活行为是必要的。然而，从腹侧被盖区(VTA)到NAC的DA输入如何“实时”编码贬值后的目标定向行为，或者DA释放的操纵如何调节这一行为，目前尚不清楚。为了评估这一点，提出了解决这些问题的两个具体目标。AIM 1旨在使用电化学方法(快速扫描循环伏安法)来测量NAC核心和外壳中的快速DA信号，以奖励奖励贬值后的预测性线索和反应。AIM 2将在获得或表达增强剂贬值任务的过程中，使用光遗传操作来人为地刺激NAC中DA的释放。了解灵活的目标导向行为背后的神经回路将有助于阐明神经精神障碍患者的神经损伤。因此，拟议的研究将为潜在的新的和更具选择性的靶标系统提供关键的见解，用于对患有不适应奖赏寻求的个人进行治疗干预，这是毒瘾的一个标志。

DESCRIPTION (provided by applicant): The ability of an animal to alter behavior in response to changes in their environment is necessary for survival. Patients with neuropsychiatric disorders, especially addictive disorders, often have difficulty with this type of behavioral flexibility. One can measure the ability of an animal to alter goal-directed behavior following a change in outcome value using a reinforcer devaluation task. In this task, animals form associations between stimuli (e.g. cue) and specific reinforcer(s) (e.g. food rewards). The reinforcer is subsequently "devalued" by selective satiation (providing the food ad libitum). Following devaluation, normal subjects adjust their responding which reflects the new "value" of the reinforcer in the absence of new associative learning. The nucleus accumbens (NAc), in conconjuction with several other brain structures (e.g., orbitofrontal cortex and basolateral amygdala), is necessary for behavioral flexibly as measured by reinforcer devaluation tasks. However, it is unknown how DA input from the ventral tegmental area (VTA) to the NAc encodes goal-directed behavior following devaluation in "real-time," or how manipulations of DA release can modulate this behavior. In order to assess this, two Specific Aims are proposed to address these issues. Aim 1 is designed to use electrochemical methods (fast scan cyclic voltammetry) to measure rapid DA signaling in the NAc core and shell to reward predictive cues and responses following reward devaluation. Aim 2 will use optogenetic manipulations to artificially stimulate DA release in NAc during acquisition or expression of the reinforcer devaluation task. Understanding the neural circuitry underlying flexible goal-directed behavior will help elucidate neural impairments in patients with neuropsychiatric disorders. As such, the proposed studies will provide critical insight into potentially new and more selective target systems for therapeutic intervention for individuals with maladaptive reward seeking, a hallmark of drug addiction.