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

描述（由申请人提供）：动物改变行为以应对环境变化的能力是生存所必需的。神经精神疾病患者，尤其是成瘾性疾病患者，通常在这种行为灵活性方面有困难。我们可以通过强化物贬值任务来衡量动物在结果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（如提示）和特定强化物（如食物奖励）之间形成关联。强化物随后通过选择性饱足（随意提供食物）而“贬值”。贬值后，正常被试在没有新的联想学习的情况下，调整自己的反应，反映强化者的新“价值”。伏隔核（NAc）与其他几个大脑结构（如眶额皮质和基底外侧杏仁核）一起，是通过强化物贬值任务测量的行为灵活性所必需的。然而，目前尚不清楚从腹侧被盖区（VTA）到NAc的DA输入如何在“实时”贬值后编码目标导向的行为，或者如何操纵DA释放来调节这种行为。为了评估这一点，提出了两个具体目标来解决这些问题。Aim 1旨在使用电化学方法（快速扫描循环伏安法）测量NAc核心和壳中的快速DA信号，以奖励奖励贬值后的预测线索和反应。目的2将使用光遗传学操作来人工刺激NAc在获得或表达强化物贬值任务期间释放DA。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有选择性的目标系统提供关键的见解，用于治疗干预具有不适应奖励寻求的个体，这是药物成瘾的标志。

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.