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）是指个人完全基于主观偏好做出选择时所观察到的行为，例如在餐馆的菜单之外。作为一种心理功能，电子商务需要为可用选项赋值；然后通过比较这些值做出决策。一些证据暗示眶额皮质（OFC）是EC的神经基质。首先，OFC的病变或功能障碍（例如，额颞叶痴呆和药物成瘾）通常会破坏EC的行为。其次，对人类的成像研究表明，当受试者做出选择时，OFC的激活程度比别人为他们做出选择时有所增强。第三，灵长类动物OFC的单个神经元编码了受试者在选择不同选项时分配给不同选项的值。综上所述，这些因素表明OFC在EC中起着重要作用。然而，在OFC中编码的价值观与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），我们将使用电微刺激和药物失活（目标2）进行两项试点研究。在我们的实验中，猴子在两种不同数量的果汁中做出选择。我们之前发现，猴子在选择果汁时，OFC的神经元会对不同果汁的主观价值进行编码。更准确地说，OFC中的神经元反应编码了3个变量：提供值（两种果汁中的一种的值），选择值（选择果汁的值）和味道（选择的果汁类型，与数量无关）。在计算意义上，提供值响应（在提供值之后最普遍）似乎编码了做出选择所需的值。相反，选择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，选择可能基于报价价值反应。为了检验这一假设，并在报价值的编码和选择之间建立因果关系，我们将解决三个关键问题。(1)变量的提供值和选择值是否由不同的、可能是解剖学上聚集的细胞群体编码？这个问题将通过对现有数据的二次分析来解决。(2)通过“人为”激活编码出价的神经元群，选择是否会有偏差？这个问题将通过电微刺激来解决。具体来说，我们将确定神经元对特定果汁的提供值进行编码的位置，并在猴子在这种果汁和另一种果汁之间进行选择时注入小电流。(3)“沉默”这些神经元群会扰乱选择吗？这个问题将通过可逆的药物失活来解决。证明OFC中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和精神疾病中功能障碍背后的神经机制。

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.