Dopaminergic and glutamatergic contribution to the formation of decision variables in fronto-parietal brain circuits

我们每天都要做无数的决定。决策需要积累支持或反对某一主张的证据，并最终采取具体行动。但是，仅仅积累证据是不够的，必须对证据进行评价。它有多有用？什么时候才算够？这些决策的许多方面已经在心理学和某种程度上的神经元水平上进行了研究。证据的积累已经在基于价值的决策、社会决策、经济决策、赌博决策、基于记忆的决策以及重要的感知决策的背景下进行了研究。这些研究为解释决策提供了丰富的理论背景，并产生了描述决策中涉及的不同认知成分的工具。在神经元水平上，在不同的皮层和皮层下区域发现了决策的特征。这些区域的神经元随着支持或反对一个命题的证据的收集而逐渐改变其活动，即使证据被删除，它们也保留了积累证据的表征，即证据的记忆痕迹存在。最后，当收集到足够的证据时，或者在紧急情况下，这些神经元中的许多将证据转化为明确的决定。尽管有这些见解，我们目前还不了解参与决策的大脑区域如何交换信息，或者证据积累、证据评估和分类的过程如何成为可能。具体来说，我们不了解哪些大脑化学物质（递质及其相关受体）在实现这些过程中起着关键作用。理解它对于理解机制层面的决策，以及理解决策缺陷是如何在精神障碍（例如精神分裂症、冲动强迫症或帕金森症）中产生的至关重要。我们的目标是在猕猴身上研究这些问题，猕猴是将神经元数据与人类状况联系起来的最合适的动物模型。决策的神经元特征在感知决策领域得到了最好的理解。在实验室里，这是通过让受试者面对嘈杂的感官刺激来研究的，他们必须区分所呈现的刺激。我们将利用已建立的范例，这些范例有助于理解知觉决策中涉及的神经计算，即连贯运动辨别任务的反应时间版本，以及关于可能选择位置的顺序信息必须随时间整合的任务。在相干运动任务中，受试者面对噪声运动刺激，必须决定运动方向。在顺序采样任务中，猴子们会看到不同的符号，这些符号表示给定的选择地点产生奖励的可能性。我们将记录在这些任务的背景下研究的顶叶和额叶皮层的神经元活动。我们有意复制现有的范例，并在基本反应特性描述良好的区域进行记录，因为这允许测试特定的预测，不同的大脑化学物质如何支持决策过程的不同组成部分。我们关注的是多巴胺能和谷氨酸能系统，因为它们与影响决策的不同认知功能障碍（如工作记忆、证据积累、证据评估）有关，但它们在神经元水平上的作用仍知之甚少。我们将确定这些系统如何有助于证据积累、证据评估和阈值设置，以形成明确的决定。这项研究将使人们更好地理解健康和疾病中决策的神经元机制，旨在帮助改进未来的治疗方法。

We make innumerable decisions every day. Decision making requires accumulation of evidence for or against a proposition and ultimately for a specific action. However, it is not sufficient to simply accumulate evidence, the evidence must be evaluated. How useful it is? When is enough enough? Many of these aspects of decision making have been studied at the psychological and, to some extent, the neuronal level. Accumulation of evidence has been studied in the context of value based decisions, social decisions, economic decisions, gambling decisions, memory-based decisions, and, importantly, perceptual decisions. These studies have provided a rich theoretical background within which decision making can be explained, and they have generated tools to delineate the different cognitive components that are involved in decision making. At the neuronal level, signatures of decision making have been found in various cortical and subcortical areas. Neurons in these areas gradually alter their activity as evidence in favor or against a proposition is gathered, and they retain the representation of accumulated evidence even when the evidence is removed, i.e. a memory trace of evidence exists. Finally, many of these neurons convert the evidence into a categorical decision, when sufficient evidence has been gathered, or when urgency so dictates. Despite these insights, we currently do not understand how brain areas involved in decision making exchange information, or how the process of evidence accumulation, evidence evaluation, and categorization is made possible. Specifically we do not understand which brain chemicals (transmitters and their related receptors) are critical in enabling these processes. An understanding thereof is essential to understand decision making at a mechanistic level, and to understand how deficits in decision making come about in mental disorders such as Schizophrenia, Impulsive compulsive disorders, or Parkinson (for example). We aim to study these questions in macaque monkeys, the most appropriate animal model to relate neuronal data to human conditions. Neuronal signatures of decision making are best understood in the domain of perceptual decisions. In the laboratory, this is studied by confronting subjects with noisy sensory stimuli, who have to discriminate what stimulus has been presented. We will exploit well established paradigms which have helped understand the neural computations involved in perceptual decision making, namely a reaction time version of a coherent motion discrimination task, and a task where sequential information about the likely choice location has to be integrated over time. In the coherent motion task the subject is confronted with noisy motion stimuli and has to decide what direction of motion is present. In the sequential sampling task, monkeys are presented with different symbols which indicate a likelihood that a given choice location will yield a reward. We will record neuronal activity in the parietal and the frontal cortex, which have been studied in the context of these tasks. We intentionally copy existing paradigms and record in areas where the basic response properties are well delineated, as this allows to test specific predictions how different brain chemicals support different components of the decision making process. We focus on the dopaminergic and the glutamatergic system, as these have been implicated with different cognitive dysfunctions that affect decision making (e.g. working memory, evidence accumulation, evidence evaluation), but their contribution at the neuronal level remains poorly understood. We will determine how these systems contribute to evidence accumulation, evidence evaluation, and threshold setting to form a categorical decision.The study will generate a better understanding of the neuronal mechanisms of decision making in health and disease, aiming to help improve therapeutic approaches in the future.