CELL TYPES IN ORBITOFRONTAL CORTEX AND THEIR CAUSAL INFLUENCE ON ECONOMIC CHOICE

描述（由申请人提供）：经济选择（EC）是当个人仅基于主观偏好做出选择时观察到的行为-例如在餐厅菜单中。作为一种心理功能，EC需要为可用的选项赋值;然后通过比较这些值来做出决定。几条线索的证据牵连眶额皮质（OFC）作为EC的神经基板。首先，OFC的病变或功能障碍（例如，在额颞叶痴呆和药物成瘾中）通常破坏EC行为。第二，对人类的成像研究表明，当受试者做出选择时，与为他们做出选择时相比，OFC的激活增强。第三，灵长类眶额皮层中的单个神经元对受试者在不同选项之间做出选择时赋予它们的价值进行编码。综上所述，这些因素表明，OFC在EC中发挥作用。然而，OFC中编码的价值观和行为选择之间的因果关系尚未建立。为了开始解决这个基本问题，我们将对现有数据进行二次分析（目标1），并使用电微刺激和药物灭活进行两项试点研究（目标2）。 在我们的实验中，猴子在两种不同数量的果汁中选择。我们之前发现，眶额皮层的神经元对猴子在选择不同果汁时赋予的主观价值进行编码。更准确地说，眶额皮层的神经元反应编码了3个变量：提供价值（两种果汁中的一种的价值）、选择价值（所选果汁的价值）和味道（所选果汁的类型，与数量无关）。在计算的意义上，报价价值反应（在报价后立即流行）似乎编码了做出选择所需的价值。相反，选择的价值反应和品味反应似乎编码了选择过程的结果。因此，我们的工作假设是，选择可能是基于提供价值的反应。为了检验这一假设，并建立一个因果关系之间的编码提供价值和选择，我们将解决三个关键问题。(1)变量是否提供了由不同的，也许是解剖学上聚集的细胞群体编码的价值和选择价值？这个问题将通过对现有数据的二次分析来解决。(2)通过“人工”激活一群编码出价值的神经元，选择会有偏差吗？这个问题将通过电微刺激来解决。具体来说，我们将确定神经元编码特定果汁的报价值的位置，并在猴子选择这种果汁和另一种果汁时注入小电流。(3)选择是否被“沉默”这个神经元群体所破坏？将使用可逆药理学灭活来解决该问题。 证明眶额皮层中的价值编码与选择行为之间的因果关系将是一个重要的突破。因此，这项研究可能会影响我们如何理解EC背后的神经机制以及精神疾病中的功能障碍。 公共卫生相关性：当个体做出选择时-例如在餐馆菜单上的不同菜肴之间-眶额皮层（OFC）的神经元计算不同选项的主观价值。这项研究将测试选择是否确实是由OFC中计算的值引起的。

DESCRIPTION (provided by applicant): Economic choice (EC) is the behavior observed when individuals make choices solely based on subjective preferences - for example out of a restaurant menu. As a mental function, EC entails assigning values to the available options; a decision is then made by comparing these values. Several lines of evidence implicate the orbitofrontal cortex (OFC) as a neural substrate for EC. First, lesions or malfunction of the OFC (e.g., in frontotemporal dementia and drug addiction) typically disrupt EC behavior. Second, imaging studies in humans show enhanced OFC activation when subjects make choices compared to when choices are made for them. Third, individual neurons in the primate OFC encode the value subjects assign to different options when they choose between them. Taken together, these elements suggest that OFC plays a role in EC. However, a causal relationship between values encoded in the OFC and behavioral choices has not yet been established. To begin addressing this fundamental question, we will perform a secondary analysis of existing data (Aim 1) and we will conduct two pilot studies using electrical microstimulation and pharmacological inactivation (Aim 2). In our experiments monkeys choose between two juices offered in variable amounts. We previously found that neurons in the OFC encode the subjective values monkeys assign to different juices while choosing. More precisely, neuronal responses in the OFC encode 3 variables: offer value (the value of one of the two juices), chosen value (the value of the chosen juice) and taste (the chosen juice type, independently of the amount). In a computational sense, offer value responses (which are most prevalent immediately after the offer) seem to encode the values necessary to make a choice. Conversely, chosen value responses and taste responses seem to encode the result of the choice process. Thus our working hypothesis is that choices may be based on offer value responses. To test this hypothesis and establish a causal link between the encoding of offer values and choices, we will address three key questions. (1) Are variables offer value and chosen value encoded by distinct and perhaps anatomically clustered populations of cells? This question will be addressed with a secondary analysis of existing data. (2) Can choices be biased by "artificially" activating a population of neurons encoding the offer value? This question will be addressed using electrical microstimulation. Specifically, we will identify sites where neurons encode the offer value of a particular juice and inject small current as a monkey chooses between that juice and another juice. (3) Are choices disrupted by "silencing" this neuronal population? This question will be addressed using reversible pharmacological inactivation. Demonstrating a causal relationship between the encoding of value in OFC and choice behavior would represent an important breakthrough. Thus this research can potentially shape how we understand the neural mechanisms that underlie EC and that malfunction in mental illness. PUBLIC HEALTH RELEVANCE: When individual make choices - for example between different dishes on a restaurant menu - neurons in the orbitofrontal cortex (OFC) compute the subjective value of the different options. This research will test whether choices are indeed caused by values computed in the OFC.