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

 描述（由申请人提供）：我们研究的长期目标是了解眶额皮质中的神经回路如何支持健康状态下的决策以及慢性药物滥用后如何做出次优选择。我们在本提案中的实验旨在描述 OFC 表征如何映射到特定的神经回路，以及这些神经回路如何受到长期吗啡暴露的影响。我们的中心假设是，OFC 产生的不同投射神经元类型代表不同的决策变量，这些信号被发送到不同的皮层下目标结构，并且吗啡等滥用药物会选择性地影响特定的途径，从而损害决策。 为了研究这个问题，我们根据人类和灵长类动物的工作，开发了针对啮齿类动物的定量心理物理学方法，该方法能够读取不同决策变量的行为，例如良好控制的决策任务中的“奖励价值”和“感知不确定性”。首先，我们将在奖励偏向的感知决策任务中记录 OFC 神经元，该任务迫使动物在可变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，我们将确定这些表征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。为了实现这一目标，我们开发了一种基于光遗传学的新用途的技术，以识别行为过程中的特定投射细胞类型：通过使用逆行病毒将 ChR2 靶向特定的投射神经元，我们通过光响应在电生理记录中识别这些神经元。使用这种方法，我们可以检查 OFC->NAc、OFC->VTA 和 OFC->BLA 神经元携带哪些信息。第三，根据从记录中收集的有关这些通路何时以及如何激活的信息，我们将对神经元活动进行双向操作，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不同 OFC 输出途径的选择行为，并尝试挽救这种损害。 完成这些目标后，我们希望能够更好地理解 OFC 中决策变量的计算方式。此外，我们将提供有关 OFC 内的信息如何以特定路径方式从皮层下目标传输的新信息。我们希望我们的方法将有助于更好地理解滥用药物如何对决策造成有时微妙的损害，但却会产生毁灭性的后果。

 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.