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

项目总结 目标可以随着时间的推移而改变，根据当前的目标调整我们的行动是很重要的。的确有 大量证据表明，长期使用药物会导致参与目标导向的神经回路功能障碍 决策。然而，决策障碍在吸毒者中并不总是明显的，可能 因为参与决策的某些大脑区域的药物引起的故障会导致补偿 大脑重新组织和/或使用不同的策略来维持适当的决策。这 该提案将检查行为策略的变化和神经元处理的变化 当正常支持决策的大脑区域因 事先自愿服用甲基苯丙胺或有针对性的干扰。拟议的研究将评估老鼠在一个 贬值任务，在这项任务中，特定的反应和线索预测奖励，然后 奖励减少了。以目标为导向的灵活决策将导致以下方面的响应减少 价值递减的奖励。重要的是，在我们的任务中，导致报酬贬值的行动是 通过在特定空间位置处的操纵杆上的响应和操纵杆上方的特定灯光提示来发出信号， 虽然正常大鼠根据杠杆位置来指导它们的行为。然而，降低 大脑皮层(通常需要将特定位置的反应与特定的奖赏联系起来)起作用。 不会削弱降低与该奖励相关的杠杆-轻化合物反应的能力。之前 我们实验室的研究表明，动物可以弥补失去联系杠杆位置的能力。 奖赏(由于大脑皮层损伤)，而不是将操纵杆上方的角光灯与 奖赏，一种由眼眶额叶皮质支持的学习。这些大脑皮层损伤是 与眶前皮质神经元活动增加和背内侧神经元活动增加有关 丘脑神经元在学习过程中投射到眶前皮质。正如先前的研究表明的那样 精神刺激剂暴露可导致前额叶皮质和/或外侧眶前叶功能改变 大脑皮层，我将确定甲基苯丙胺自我给药对神经回路的长期影响 潜在贬值和脑区之间的补偿是否能保持完整的贬值 行为。此外，正如先前的研究表明，自愿吸毒会导致不同的神经生物学 与被动接触毒品相比，我会比较被动的影响 自愿吸毒者接触甲基苯丙胺。这项拟议的研究与一项 NIDA使命的一部分，即开发新的和改进的治疗方法，以帮助有药物使用的人 疾病可以实现并保持有意义的、持续的复苏“。我们的发现可能有助于理解 吸毒者如何在药物引起的脑功能障碍后保持适当的决策，并可能识别 替代的行为策略，可以在过去吸毒后改善这种决策。

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.