Role of nucleus accumbens in effort-based decision-making

描述(申请人提供)：上瘾有时被描述为一种决策障碍。为了做出适当的决定，人和动物必须权衡可用选择的好处和成本。然而，吸毒者很难评估与吸毒相关的成本，并将花费不成比例的体力和精神努力来获得毒品。为了理解这是如何发生的，我们必须首先研究努力是如何在大脑中被表示的，以及这种表示如何有助于做出寻求的决定 奖励。伏隔核(NAC)--尤其是NAC核心中的多巴胺(DA)信号--长期以来一直与努力获得奖赏有关。然而，目前尚不清楚NAC中的神经信号如何支持做出努力的决定。尽管许多单独的NAC神经元对奖赏预测线索做出反应，但这些神经元如何编码与线索和选择相关的努力尚不清楚，特别是在动物决定是否追求努力选项的时刻。此外，目前尚不清楚DA对NAC的输入如何对努力相关信号做出贡献。为了解决这些问题，将训练大鼠执行一项任务，在这项任务中，它们在与不同努力水平(所需杠杆按压次数)和/或不同数量的蔗糖奖励相关的两个选项(杠杆)之间做出决定。当大鼠做出这些决定时，我们将记录NAC中单个神经元的放电活动。我们假设，NAC神经元将以这样一种方式编码奖励和努力水平，即它们的活动可能有助于权衡选项和/或执行结果决定。接下来，我们将向NAC核心微量注射DA受体阻滞剂，并观察其对大鼠选择的影响。我们预计，这些药物将扰乱基于努力的决策，以至于大鼠将变得不愿付出更多努力来获得更多回报。最后，使用一种创新的技术，我们将向NAC内微量注射DA受体阻滞剂，同时记录NAC神经元的神经活动。我们假设，阻断DA受体将扰乱NAC神经元对努力信息的表达。综上所述，这些实验将阐明NAC及其多巴胺能输入在构成正常大脑决策过程的电路中的作用。这是了解成瘾大脑中这些回路如何出错的关键一步，可能会为开发或改进药物成瘾疗法开辟一条道路。

DESCRIPTION (provided by applicant): Addiction is sometimes described as a disorder of decision-making. To make appropriate decisions, people and animals must weigh both the benefits and the costs of the available options. Addicts, however, have difficulty assessing the costs associated with drug use, and will expend a disproportionate degree of physical and mental effort to obtain drug. To understand how this happens, we must first investigate how effort is represented in the brain, and how this representation contributes to the decision to seek rewards. The nucleus accumbens (NAc) - and especially dopamine (DA) signaling in the NAc core - has long been implicated in the exertion of effort to obtain reward. However, it remains unknown how neural signals in the NAc might support the decision to exert effort. Although many individual NAc neurons respond to reward- predictive cues, it is unclear how these neurons encode the effort associated with cues and choices, especially in the moment when the animal decides whether to pursue an effortful option. Moreover, it is not known how DA input to the NAc contributes to effort-related signaling. To address these issues, rats will be trained to perform a task in which they decide between two options (levers) that are associated with different levels of effort (number of required lever presses) and/or different amounts of sucrose reward. While rats are making these decisions, we will record the firing activity of individual neurons in the NAc. We hypothesize that NAc neurons will encode both reward and effort levels in such a way that their activity may contribute to the weighing of options and/or the implementation of the resulting decision. Next, we will microinject DA receptor blockers into NAc core and observe the effect on rats' choices. We expect that these drugs will disrupt effort-based decision-making such that rats will become unwilling to exert more effort to obtain more reward. Finally, using an innovative technique, we will microinject DA receptor blockers into the NAc while simultaneously recording the neural activity of NAc neurons. We hypothesize that blocking DA receptors will disrupt the representation of effort information by NAc neurons. Taken together, these experiments will clarify the role of the NAc and its dopaminergic inputs in the circuits that underlie decision-making processes in the normal brain. This is a key step towards understanding how these circuits might go awry in the addicted brain, potentially opening a path towards developing or improving therapies for drug addiction.