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: 9137645
• 负责人: Adam Kepecs
• 金额: $ 44.03万
• 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/9137645
• 关键词: Accounting; 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; Health; Human; Impairment; Intuition; Investigation; Knowledge; Lesion; Life; Light; Maps; Mediating; Methods; Morphine; Neurons; Opiates; Outcome; Output; Pathway interactions; Pilot Projects; Primates; Process; Psychophysics; Rattus; Recording of previous events; Rewards; Rodent; Role; 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; extracellular; gain of function; hippocampal pyramidal neuron; improved; loss of function; motivated behavior; neural circuit; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; prevent; research study; 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（由适用提供）：我们调查的长期目标是了解轨道额皮层中的神经回路如何支持健康状态下的决策，以及在慢性药物滥用后的次优选择。我们在本提案中的实验旨在描述OFC表示如何映射到特定的神经回路，以及它们如何受到慢性吗啡暴露的影响。我们的中心假设是，由OFC产生的独特投影 - 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靶标结构，并且滥用药物（例如吗啡）选择性地影响了损害决策的定义途径。为了研究这个问题，我们为啮齿动物开发了定量的心理物理方法，该方法是根据人类和灵长类动物工作的改编而来的，这可以使不同决策变量的行为读数，例如“奖励价值”和“感知不确定性”，在良好的决策任务中。首先，我们将在奖励有偏见的知觉决策任务中记录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，我们将确定如何将这些表示形式映射到特定类的OFC锥体神经元，特别是OFC投影神经元靶向VS，VTA和BLA以实现这一目标，我们开发了一种基于光质学的新技术来开发一种技术，以识别特定的投影细胞类型在行为上：通过使用逆行式培训来鉴定这些逆行性神经元的靶向，我们的投影神经元在靶向这些技术，轻响应。使用这种方法，我们可以检查哪些信息，ofc-> - > vta和ofc-> bla神经元携带的信息。第三，基于有关这些途径何时以及如何激活这些途径的记录，我们将对神经元活动进行双向操纵，以揭示其在影响选择行为中的因果关系。最后，我们将确定吗啡自我给药和撤回如何破坏沿不同OFC输出途径的选择行为，并试图挽救这一障碍。完成这些目标后，我们希望对OFC中如何计算决策变异的方式有了深刻的了解。此外，我们将提供有关OFC内部信息在途径特定方式中如何从其下皮层靶标传输的新信息。我们预计我们的方法将有助于改进的翻译理解滥用药物如何导致决策中有时会带来毁灭性后果的细微损害。