Subsecond modulation of cost/benefit decision making by dopamine

描述(由申请人提供)：我们如何决定做我们所做的事情是理解行为的神经生物学控制的最基本的问题之一。在我们的一生中，每时每刻，我们都在不断地进行成本/收益分析，以生成优化结果的行动计划。在从行为学的角度衡量一个结果的代价时，必须考虑需要多少体力，在提出结果之前需要等待多长时间，结果的确定性以及任何可能的令人厌恶的后果。此外，我们已经进化到尊重社会和财务成本。在处理费用方面的缺陷可能表现为昏昏欲睡、冲动、冒险或强迫--这些特征跨越了精神障碍的诊断类别。多巴胺可能在应对这些成本方面发挥重要作用。例如，多巴胺的拮抗足以降低大鼠的体力努力，或它们等待获得更大回报的时间。多巴胺神经元中的亚秒活动在可获得的奖励范围内对结果值进行编码，这些快速信号可以促使人们做出决定，做出行为以获得奖励。我们认为，这种快速传输为动物获得奖励所应承受的成本提供了一个门槛信号。由于它们编码了预期的奖励幅度，这将促使动物忍受更高的成本，以获得更好的(预期)结果。为了验证这一假设，我们将使用一系列可操作的决策任务，使我们能够评估成本/收益分析并对不同成本进行标准化，同时使用快速扫描循环伏安法测量多巴胺传输。除了研究多巴胺和行为之间的亚秒时间相关性外，我们还将通过电刺激多巴胺神经元来测试在成本/收益决策中快速释放多巴胺的因果关系。首先，我们将使用单选择范式来测试伏隔核中的多巴胺如何编码奖励价值和强加的努力或时间成本。接下来，我们将进一步探讨当动物在奖励大小和(时间或精力)成本不同的两个选项之间进行选择时的信号。最后，我们将在内源性多巴胺信号产生的准确时间--试验开始时的初始刺激时间--通过电刺激多巴胺神经元来唤起多巴胺的释放。这种刺激将增强内源性信号，从而测试在行为期间的关键时刻释放更多多巴胺的效果足以使决策倾向于成本更高的选择。

DESCRIPTION (provided by applicant): How we decide to do what we do is one of the most fundamental questions in understanding the neurobiological control of behavior. From moment to moment throughout our lives, we are constantly making cost/benefit analyses to generate action plans that optimize outcomes. In weighing up the costs of an outcome from an ethological standpoint, one must consider how much physical effort is required, how long a wait will there be before the outcome is presented, the certainty of the outcome and any possible aversive consequences. In addition, we have evolved to respect social and financial costs. Deficits in dealing with costs can be manifested as lethargy, impulsivity, risk taking or compulsion - traits that cross diagnostic categories of psychiatric disorders. Dopamine may play an important role in dealing with these costs. For example, antagonism of dopamine is sufficient to lower the physical effort rats will make, or the amount of time they will wait to obtain greater rewards. Subsecond activity in dopamine neurons encodes the outcome value within a range of available rewards, and these rapid signals can promote decisions to engage in behaviors to obtain rewards. We propose that this fast transmission provides a threshold signal for the costs an animal should endure to obtain a reward. Since they encode the expected reward amplitude, this would drive animals to tolerate a higher cost for better (expected) outcomes. In order to test this hypothesis, we will use a series of operant decision-making tasks that allow us to assess cost/benefit analysis and normalize across different costs, while measuring dopamine transmission with fast-scan cyclic voltammetry. In addition to investigating the subsecond temporal correlation between dopamine and behavior, we will also test causality of rapid dopamine release in cost/benefit decision making by electrically stimulating dopamine neurons. First, we will use a single-choice paradigm to test how dopamine in the nucleus accumbens encodes reward value and imposed effort or time costs. Next we will explore this signaling further when animals are choosing between two options that differ in reward magnitudes and in (time or effort) cost. Finally we will evoke dopamine release by electrically stimulating dopamine neurons at the exact time that an endogenous dopamine signal is generated - at the time of the initial stimulus at the start of the trial. This stimulation will boost the endogenous signal and thus test the effect of releasing more dopamine at the critical time during the behavior is sufficient to bias decision making towards higher-cost options.