Functions of distinct orbitofrontal cell-types and pathways in decision making

 描述(申请人提供)：我们研究的长期目标是了解眼眶前额叶皮质的神经回路如何在健康状态下支持决策，以及在长期药物滥用后如何做出次优选择。我们在这项提议中的实验旨在描绘OFC表征如何映射到特定的神经回路，以及这些回路如何受到慢性吗啡暴露的影响。我们的中心假设是，来自OFC的不同投射神经元类型代表不同的决策变量，这些信号被路由到不同的皮质下靶结构，并且滥用药物，如吗啡，选择性地影响特定的通路，以损害决策。为了研究这一问题，我们根据人类和灵长类动物的工作，开发了啮齿动物的定量心理物理方法，使行为读出不同的决策变量，如在控制良好的决策任务中的“奖赏价值”和“知觉不确定性”。首先，我们将记录OFC神经元在一个偏向于奖励的感知决策任务中，迫使动物在不同的奖励大小和可能性的背景下做出选择，并将不同的决策变量映射到单个神经元。其次，我们将确定这些表示如何映射到特定类别的OFC锥体神经元-特别是分别针对VS、VTA和BLA的OFC投射神经元。为了实现这一点，我们开发了一种基于光遗传学的新技术来识别行为过程中特定的投射细胞类型：通过使用逆行病毒将ChR2定位到特定的投射神经元，我们通过电生理记录中的光反应来识别这些神经元。利用这种方法，我们可以研究Fc-&gt；NAC、OFC-&gt；VTA和OFC-&gt；BLA神经元携带的信息。第三，基于从录音中收集的关于这些通路何时以及如何被激活的信息，我们将对神经元活动进行双向操纵，以揭示它们在影响选择行为中的因果作用。最后，我们将确定吗啡自我给药和戒断如何扰乱OFC不同输出通路上的选择行为，并试图挽救这种损害。在完成这些目标后，我们期望对OFC中如何计算决策变量达成更好的理解。此外，我们还将提供有关OFC内的信息如何以特定路径的方式从其皮质下靶点传递到其皮质下靶点的新信息。我们预计，我们的方法将有助于更好地从翻译上理解滥用药物如何在决策中造成有时微妙的损害，而这些损害仍然具有毁灭性的后果。

 DESCRIPTION (provided by applicant): The long-term goal of our investigation is to understand how neural circuits in the orbitofrontal cortex support decision-making in the healthy state and how suboptimal choices after chronic drug abuse. Our experiments in this proposal are designed to delineate how OFC representations are mapped to specific neural circuits and how these are impacted by chronic morphine exposure. Our central hypotheses are that distinct projection-neuron types arising from OFC represent different decision-variables and these signals are routed to different subcortical target structures, and that drugs of abuse such as morphine selectively affect defined pathways to impair decision-making. To study this issue, we have developed quantitative psychophysical methods for rodents, adapted from human and primate work, which enables the behavioral readout of different decision variables, such as "reward value" and "perceptual uncertainty" in a well-controlled decision task. First, we will record OFC neurons in a reward-biased perceptual decision task that forces animals to make choices in the context of variable reward size and likelihood, and map distinct decision-variables to single neurons. Second, we will determine how these representations map onto specific classes of OFC pyramidal neurons - in particular, OFC projection neurons targeting VS, VTA, and BLA respectively. To achieve this we developed a technique based on a novel use of optogenetics to identify specific projection cell-types during behavior: by targeting ChR2 using retrograde viruses to specific projection neurons we identify these neurons in electrophysiological recordings by their light-responses. Using this approach we can examine what information OFC->NAc, OFC->VTA and OFC->BLA neurons carry. Third, based on information gleaned from recordings about when and how these pathways are activated, we will perform bidirectional manipulations of neuronal activity to reveal their causal roles in impacting choice behavior. Finally, we will determine how morphine self-administration and withdrawal disrupts choice behavior along different OFC output pathways and attempt to rescue this impairment. Upon completion of these aims, we expect to reach an improved understanding of how decision-variables are computed in the OFC. In addition, we will provide new information about how information within OFC is transmitted in a pathway-specific manner from to its subcortical targets. We expect that our approach will contribute to an improved translational understanding how drugs of abuse can cause the sometimes subtle impairments in decision-making that nevertheless have devastating consequences.