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

不同眶额细胞类型和决策途径的功能

• 批准号: 9528543
• 负责人: Adam Kepecs
• 金额: $ 43.28万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9528543
• 关键词: Advisory Committees; Affect; Amygdaloid structure; Animal Behavior; Animals; Area; Behavior; Behavioral; Brain; Choice Behavior; Chronic; Data; Decision Making; Disease; Drug Addiction; Drug abuse; Electrophysiology (science); Glean; Goals; Human; Impairment; Intuition; Investigation; Knowledge; Lesion; Life; Light; Maps; Mediating; Methods; Morphine; Neurons; Opioid; Outcome; Output; Pathway interactions; Pilot Projects; Primates; Process; Psychophysics; Rattus; Recording of previous events; Rewards; Rodent; Role; Route; Self Administration; Sensory; Signal Transduction; Structure; Techniques; Testing; Uncertainty; Ventral Striatum; Ventral Tegmental Area; Virus; Virus Diseases; Withdrawal; Work; base; behavior change; behavior influence; behavioral response; brain circuitry; cell type; design; designer receptors exclusively activated by designer drugs; drug of abuse; experimental study; extracellular; gain of function; hippocampal pyramidal neuron; improved; loss of function; motivated behavior; neural circuit; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; prevent; public health relevance; response

 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.

 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的次优选择。我们的实验旨在描述眶额皮层的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慢性吗啡暴露的影响。我们的中心假设是，由眶额皮层产生的不同投射神经元类型代表不同的决策变量，这些信号被路由到不同的皮层下目标结构，滥用药物（如吗啡）选择性地影响定义的通路，以损害决策。 为了研究这个问题，我们已经开发了定量的心理物理学方法的啮齿动物，适应人类和灵长类动物的工作，这使得不同的决策变量，如“奖励值”和“知觉不确定性”在一个良好的控制决策任务的行为读出。首先，我们将记录OFC神经元在奖励偏向的知觉决策任务，迫使动物在可变的奖励大小和可能性的背景下做出选择，并映射不同的决策变量到单个神经元。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新用途的技术，以识别行为期间的特定投射细胞类型：通过使用逆行病毒将ChR 2靶向特定投射神经元，我们通过其光反应在电生理记录中识别这些神经元。利用这种方法，我们可以检查OFC->NAc，OFC->VTA和OFC->BLA神经元携带的信息。第三，基于从记录中收集到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是如何沿着不同的OFC输出通路破坏选择行为的，并试图挽救这种损伤。 在完成这些目标后，我们期望能够更好地理解OFC中的决策变量是如何计算的。此外，我们将提供新的信息如何在眶额皮层内的特定途径的方式从其皮层下的目标传输。我们希望我们的方法将有助于提高翻译的理解如何滥用药物可能会导致有时微妙的决策障碍，但具有破坏性的后果。