Dopaminergic modulation of cost/benefit decision making during aging

描述（由申请人提供）：我们如何权衡潜在结果的成本和收益来指导选择对我们的日常运作至关重要。在做出这些经济决策时，人们必须考虑成本，如体力劳动、结果出现之前的延迟、结果的确定性和可能的不良后果，以及社会和财务成本。多巴胺在处理这些代价方面扮演着重要的角色：多巴胺的拮抗作用足以降低大鼠为获得更大奖励而付出的体力努力，或者它们等待获得更大奖励的时间。多巴胺也与冒险有关。多巴胺神经元的亚秒活动编码了一系列可获得奖励的结果值，这些快速信号可以促进决策参与获得奖励的行为。这种快速传递可能提供了一个阈值信号，表明动物为获得奖励所应承受的代价。因为它们编码了预期的奖励幅度，这应该会驱使动物忍受更高的成本来获得更好的（预期的）结果。然而，在正常衰老过程中，多巴胺能系统发生了一些变化，包括纹状体多巴胺受体表达减少和纹状体释放多巴胺的生物能力下降。这引发了一系列问题：1)多巴胺释放能力的减弱是否反映在经济决策过程中释放的多巴胺量上？这些与年龄相关的影响是否有助于经济决策的改变？为了解决这些问题，成年大鼠（6个月大）和老年大鼠（24个月大）将被研究，同时它们通过按杠杆来“购买”食物选择。首先，我们将探讨不同年龄群体在经济决策中潜在的行为差异。研究人员将测试老鼠为了获得更大的奖励和更小但更便宜的奖励而放弃的成本的数量差异。在一组实验中，强制成本的货币将是体力劳动，动物将被要求进行更多次数的杠杆按压以获得更大的奖励。在另一组实验中，将通过让老鼠在较小的奖励和较大但不确定的奖励之间进行选择，来测试冒险行为。接下来，将测量成年或老年大鼠在经济决策过程中腹侧纹状体（伏隔核）的多巴胺释放。使用快速扫描循环伏安法以亚秒分辨率监测多巴胺。使用单一选择范例，当奖励是通过努力或概率成本获得时，多巴胺编码奖励价值的方式将被测试。最后，多巴胺调节成年和老年大鼠经济决策的能力将通过在内源性多巴胺信号正常产生的任务时间内电刺激多巴胺神经元来测试。这种诱发的多巴胺释放将增强内源性信号，从而测试多巴胺克服努力或概率成本的能力。总的来说，这些实验将为经济选择中与年龄相关的变化、决策过程中的多巴胺传递及其相互作用提供独特的见解。

DESCRIPTION (provided by applicant): How we weigh up the costs and benefits of a potential outcome to guide choice is paramount to our everyday functioning. In making these economic decisions one must consider costs such as physical effort, the delay before the outcome is presented, the certainty of the outcome and possible aversive consequences, as well as social and financial costs. Dopamine plays an important role in dealing with these costs: 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. Dopamine is also implicated in risk-taking. 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. This fast transmission may provide a threshold signal for the costs an animal should endure to obtain a reward. Since they encode the expected reward amplitude, this should drive animals to tolerate a higher cost for better (expected) outcomes. However, during normal aging, there are several changes in dopaminergic systems, including a reduction in the expression of striatal dopamine receptors and in the biological capacity for striatal dopamine release. This raises a number of questions: 1) Is the diminished capacity for dopamine release reflected in the amount of dopamine released during economic decision making? 2) Do these age-related effects contribute to a change in economic decision making? To address these questions, adult (6-month-old) and aged (24-month-old) rats will be studied while they perform decision making to "purchase" food options by lever pressing. First potential behavioral differences in economic decision making between age groups will be probed. Quantitative differences in the cost the rats will forgo to obtain a larger reward offered concurrently with a smaller but cheaper reward will be tested. In one set of experiments, the currency of the imposed cost will be physical effort, where animals will be required to make a higher number of lever presses to receive the larger reward. In another set of experiments, risk-taking behavior will be tested by allowing rats to choose between smaller rewards and larger, but uncertain, rewards. Next, dopamine release will be measured in the ventral striatum (nucleus accumbens) of adult or aged rats during economic decision making. Dopamine will be monitored with subsecond resolution using fast-scan cyclic voltammetry. Using a single-choice paradigm, the way in which dopamine encodes reward value when reward is available for effort or probabilistic costs will be tested. Finally, the capacity of dopamine to modulate economic decision making in adult and aged rats will be tested by electrically stimulating dopamine neurons at the time within the task that an endogenous dopamine signal is normally generated. This evoked dopamine release will boost the endogenous signal and thus test the capacity of dopamine to overcome effortful or probabilistic costs. Collectively these experiments will provide unique insight into age-related changes in economic choice, dopamine transmission during decision making and their interaction. Cognitive, emotional and physical capabilities change during aging, in part by age-related changes in brain motivational systems. How these changes impact economic choices is unknown. The proposed work will use behavioral and neurochemical methods to study age-related changes in economic decision making in rats.