Behavioral compensation in goal-directed action: Long term effects of voluntary methamphetamine taking versus passive exposure

项目摘要 目标可以随着时间的推移而改变，重要的是根据我们当前的目标调整我们的行动。有 广泛的证据表明，长期使用药物会导致涉及目标导向的神经回路功能障碍。 决策的然而，决策障碍在吸毒者中并不总是明显的， 因为药物引起的某些参与决策的大脑区域的功能障碍会导致 大脑重新组织和/或使用不同的策略来维持适当的决策。这 该提案将研究行为策略的变化和神经元处理的改变， 当通常支持决策的大脑区域因以下原因而发生故障时， 自愿吸食甲基苯丙胺或有针对性的干扰。拟议的研究将评估大鼠在一个 贬值任务中，具体的反应和线索预测奖励，然后价值之一， 奖励减少了。以目标为导向的灵活决策将导致以下方面的反应减少： 价值降低的奖励。重要的是，在我们的任务中，导致奖励贬值的行为是 通过特定空间位置中的杠杆上的响应并且利用杠杆上方的特定光提示来发信号， 尽管正常大鼠基于所述位置来指导它们的行为。然而，降低 前边缘皮层（通常需要将特定位置的反应与特定奖励联系起来） 不损害降低与该奖励相关的光化合物反应的能力。之前 我们实验室的研究表明，动物弥补了将位置与位置联系起来的能力的丧失。 与奖励（由于前边缘皮层病变），而不是关联的提示灯以上的杠杆与 奖励，一种由眶额皮层支持的学习。这些前边缘皮层损伤 与眶额皮质神经元活动和中背神经元活动的增加相关 丘脑神经元在学习过程中投射到眶额皮质。先前的研究表明， 精神兴奋剂暴露可导致前边缘皮层和/或外侧眶额功能的改变， 皮质，我将确定长期影响事先甲基苯丙胺自我管理的神经回路 潜在的贬值以及大脑区域之间的补偿是否可以保持完整的贬值 行为此外，先前的研究表明，自愿吸毒会导致不同的神经生物学 和行为变化相比，被动暴露于药物，我将比较被动 甲基苯丙胺暴露于那些自愿吸毒。这项研究与一项 NIDA的使命的一部分，“开发新的和改进的治疗方法，以帮助人们与物质使用 疾病实现并保持有意义和持续的恢复”。我们的发现可能有助于理解 药物使用者如何在药物引起的脑功能障碍后保持适当的决策， 替代的行为策略，可以改善这种决策后，过去的药物使用。

PROJECT SUMMARY Goals can change over time, and it is important to adapt our actions according to our current goals. There is extensive evidence that long-term drug use can lead to dysfunction of neural circuits involved in goal-directed decision-making. However, decision-making impairments are not always apparent in drug users, possibly because drug-induced malfunction in certain brain areas involved in decision-making causes compensation in which the brain reorganizes and/or different strategies are used to maintain adequate decision-making. This proposal will examine changes in behavioral strategy and alterations in neuronal processing that maintain adequate decision-making when the brain areas that normally support decision-making malfunction due to prior voluntary methamphetamine intake or targeted disruption. The proposed studies will assess rats in a devaluation task in which specific responses and cues predict rewards, and then the value of one of the rewards is decreased. Flexible decision-making that is goal-directed would lead to a decrease in responses for the reward with decreased value. Importantly, in our task, the action that leads to the devalued reward is signaled by a response on a lever in a particular spatial location and with a particular light cue above the lever, although normal rats guide their behavior based on the lever-location. However, decreasing the function of prelimbic cortex (usually required to associate a response in a particular location with a specific reward) does not impair the ability to decrease responses on the lever-light compound associated with that reward. Prior research from our lab suggests that animals compensate for the loss of ability to associate the lever-location with the reward (due to prelimbic cortex lesions) by instead associating the cuelight above the lever with the reward, a type of learning that is supported by orbitofrontal cortex. These prelimbic cortex lesions are associated with an increase in neuronal activity in orbitofrontal cortex and in neuronal activity in mediodorsal thalamus neurons projecting to orbitofrontal cortex during learning. As prior research suggests that psychostimulant exposure can lead to alterations in the function of prelimbic cortex and/or lateral orbitofrontal cortex, I will determine long-term effects of prior methamphetamine self-administration on the neural circuits underlying devaluation and whether compensation between brain areas can preserve intact devaluation behavior. In addition, as prior research suggests that voluntary drug-taking causes different neurobiological and behavioral changes than being passively exposed to drugs, I will compare effects of passive methamphetamine exposure to those of voluntary drug-taking. The proposed research is relevant to one component of NIDA’s mission, to “develop new and improved treatments to help people with substance use disorders achieve and maintain a meaningful and sustained recovery”. Our findings may help to understand how drug users may maintain adequate decision-making after drug-induced brain dysfunction, and may identify alternative behavioral strategies that could improve this decision-making after past drug use.