Neural mechanisms of affective processing in prefrontal-limbic circuits

前额叶边缘环路情感处理的神经机制

• 批准号: 10016795
• 负责人: Peter Rudebeck
• 金额: $ 57.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016795
• 关键词: Acute; Affect; Affective; Amygdaloid structure; Anhedonia; Anterior; Anxiety Disorders; Area; Behavior; Behavioral; Brain; Chronic; Code; Corpus striatum structure; Data; Decision Making; Deep Brain Stimulation; Diffusion; Disease; Electric Stimulation; Event; Failure; Fiber; Foundations; Frequencies; Functional disorder; Goals; Human; Image; Individual; Intervention; Knowledge; Lesion; Light; Limbic System; Magnetic Resonance Imaging; Major Depressive Disorder; Mental Depression; Methods; Monkeys; Mood Disorders; Neurons; Neurosciences; Operant Conditioning; Pathway interactions; Patients; Pattern; Physiological; Prefrontal Cortex; Primates; Process; Randomized Clinical Trials; Research; Rewards; Role; Schizophrenia; Signal Transduction; Site; Specificity; Structure; Testing; Ventral Striatum; Work; base; behavior influence; behavioral response; cingulate cortex; expectation; experience; image guided; imaging modality; imaging study; innovation; mood symptom; neural circuit; neural patterning; neuromechanism; novel; pleasure; relating to nervous system; response; reward expectancy; reward processing; theories; white matter

Project summary Anhedonia is a defining symptom of mood disorders and anxiety disorders and is characterized by a loss of positive affect from rewarding experiences. Current theories of anhedonia emphasize that it consists of two distinct components: one is related to the expectation of reward, the other to the pleasure from receiving rewards. Understanding how the brain processes expected and received rewards at the level of single neurons is therefore a key challenge for basic neuroscience. Imaging studies indicate that one part of the prefrontal cortex, the subcallosal anterior cingulate cortex (ACC) is active when rewards are expected and is altered in individuals with anhedonia. Corroborating this finding, data from studies of monkeys with lesions of the subcallosal ACC indicate that this area is important for behavior related to the expectation, but not the receipt of rewards. However, no approach to date has been able to provide a circuit-level understanding of how the subcallosal ACC influences reward expectation. This level of understanding is important as deep brain stimulation of subcallosal ACC and nearby white matter pathways alleviates anhedonia in some patients. This intervention is hypothesized to work by altering functional interaction between subcallosal ACC and either amygdala or ventral striatum. Which pathway is more important for controlling behavior related to reward expectation or the requisite activity patterns is unknown. Our goal here is to determine the neural mechanisms engaged in the subcallosal ACC-amygdala-VS circuit when rewards are expected and then received. We hypothesize that the role of the subcallosal ACC is to modulate reward encoding within ventral striatum and amygdala during reward expectation, but not receipt. To test our hypothesis we will use an innovative combination of single-neuron recordings, field potential recordings, electrical stimulation, diffusion imaging methods, and chemogenetics analyzing the timing of reward-related neural responses and LFP coherence among the three sites under normal physiological conditions, when neurons in subcallosal ACC are chronically activated using chemogenetic methods, and when acute electrical stimulation is applied both under normal conditions and when the area is chronically activated. Completing these aims will fundamentally advance our understanding of the neural circuits and activity patterns that control reward-related behavioral and neural activity in primates as well as providing a circuit level understanding of how subcallosal ACC influences expected reward processing. This level of understanding has the potential to inform and help refine pathway- specific interventions for all disorders characterized by a loss pleasure from reward, such as depression as well as schizophrenia.

项目概要 快感缺失是情绪障碍和焦虑症的典型症状，其特征是缺乏 来自有益经历的积极影响。目前的快感缺乏理论强调它由两个部分组成 不同的组成部分：一个与奖励的期望有关，另一个与接受的乐趣有关 奖励。了解大脑如何在单个神经元水平上处理预期和收到的奖励 因此，这是基础神经科学的一个关键挑战。影像学研究表明，前额叶的一部分 在预期奖励时，胼胝体下前扣带皮层 (ACC) 会活跃，并会在 快感缺乏的人。对患有脑部损伤的猴子的研究数据证实了这一发现 胼胝体下区 ACC 表明该区域对于与期望相关的行为很重要，但对于与接收相关的行为不重要 的奖励。然而，迄今为止，还没有任何方法能够提供电路级的理解 胼胝体下 ACC 影响奖励期望。这种理解水平对于深层大脑来说很重要 刺激胼胝体下 ACC 和附近的白质通路可减轻某些患者的快感缺失。这 假设干预是通过改变胼胝体下 ACC 和任一者之间的功能相互作用来发挥作用的。 杏仁核或腹侧纹状体。哪种途径对于控制与奖励相关的行为更重要 期望或必要的活动模式是未知的。我们的目标是确定神经机制 当期待并收到奖励时，胼胝体下的 ACC-杏仁核-VS 回路就会参与其中。我们 假设胼胝体下 ACC 的作用是调节腹侧纹状体内的奖赏编码， 杏仁核在奖励期望期间，但没有收到。为了检验我们的假设，我们将使用一种创新的 单神经元记录、场电位记录、电刺激、扩散成像的组合 方法和化学遗传学分析奖励相关神经反应的时间和 LFP 一致性 在正常生理条件下的三个部位中，当胼胝体下 ACC 神经元长期处于 使用化学遗传学方法激活，并且当在正常情况下施加急性电刺激时 条件以及该区域何时被长期激活。完成这些目标将从根本上推进我们的 了解控制奖励相关行为和神经的神经回路和活动模式 灵长类动物的活动以及提供对胼胝体下 ACC 如何影响的电路水平理解 预期奖励处理。这种程度的理解有可能提供信息并帮助完善途径—— 针对所有以奖励丧失快乐为特征的疾病（例如抑郁症）的具体干预措施 以及精神分裂症。