Role of Oxytocin in the Amygdala-Prefrontal Network During Social Decision-Making

描述(申请人提供)：神经肽对社会认知至关重要，正被积极用作治疗具有明显社会缺陷的疾病的治疗剂，如自闭症谱系障碍(ASD)、精神分裂症和精神变态。催产素(OT)是一种进化保守的神经肽，参与多种物种的社会加工。尽管催产素诱导的社会行为有大量的例子，但催产素如何调节参与社会决策的神经元网络仍不清楚。使用涉及捐赠者和接受者的奖励捐赠任务，我们报告说，当选择奖励他人和不奖励任何人时，吸入催产素会增强捐赠者的替代强化，而当选择奖励自己和另一个人时，它会放大自我强化。在这项任务中，Ot还会在奖励捐赠后加强对接受者的注视行为。与共情相关的加工可能是由一组涉及杏仁核、前扣带回(ACC)和眶前皮质(OFC)的网络介导的。在奖赏捐赠任务中，我们还发现ACC神经元主要代表传递给他人的奖赏，而OFC神经元主要代表传递给自己的奖赏。杏仁核含有大量的催产素受体，起着调节情感和社会加工的作用。杏仁核，特别是基底外侧区，与ACC和OFC相互联系，参与评估积极和消极的奖励。OT直接控制杏仁核与其他结构的信息处理，并影响人类社会评估过程中杏仁核的激活。关键的是，ASD的OT受体风险等位基因携带者在社交情绪任务中表现出杏仁核激活的改变。鉴于这些观察，我们试图通过利用奖赏捐赠任务来阐明以下几点：1)单个杏仁核神经元在奖赏分配决策过程中的活动；2)杏仁核神经元中OT诱导反应的神经机制；以及3)杏仁核通过OT介导的过程对ACC和OFC神经元的特异性调制。我们假设杏仁核包含替代信号和自我强化信号，这两种信号都被吸入催产素放大。我们进一步假设，局部向杏仁核神经元传递OT增强了OFC的自我奖赏信号和ACC的替代奖赏信号。我们的结果有可能促进我们对有社会缺陷的神经精神疾病的了解，以及我们对基于OT的疗法的理解。 与公共健康相关：尽管行为的表型变化广泛，但自闭症谱系障碍(ASD)患者在社交方面有共同的核心缺陷。在这里，我们提出ASD的社会功能障碍的部分原因是从他人那里获得替代奖赏的问题，这一过程可能依赖于神经肽催产素，这一神经肽与各种社会过程有关。我们将使用我们的替代奖赏动物模型来发现催产素是如何调节大脑中的社会处理，并发现它在大脑功能障碍中的作用。催产素是一种潜在的自闭症治疗方法。

DESCRIPTION (provided by applicant): Neuropeptides are critical for social cognition, and are actively being pursued as a therapeutic agent for treating diseases with marked social deficits, such as autism spectrum disorders (ASD), schizophrenia, and psychopathy. Oxytocin (OT) is an evolutionarily conserved neuropeptide involved in social processing in multiple species. Despite numerous demonstrations of OT-induced social behavior, it remains unclear how OT modulates networks of neurons involved in social decision-making. Using the reward donation task involving donor and recipient monkeys, we reported that inhaled OT enhances vicarious reinforcement of the donor when the choice is between rewarding another and no one, whereas it amplifies self reinforcement when the choice is between rewarding himself and another. OT in this task also enhances the looking behavior at the recipient following reward donations. Empathy-related processing might be mediated by a cohort of networks involving amygdala, anterior cingulate (ACC), and orbitofrontal cortices (OFC). In the reward donation task, we also found that ACC neurons predominantly represent rewards delivered to another, whereas OFC neurons predominantly represent rewards delivered to self. Amygdala contains a high number of OT receptors, and mediates affective and social processing. Amygdala, especially the basolateral portion, is reciprocally connected with ACC and OFC, and is involved in evaluating both positive and negative rewards. OT directly gates information processing in amygdala with other structures, and influences amygdala activations during social evaluations in humans. Critically, OT receptor risk allele carriers for ASD show altered amygdala activations in social emotional tasks. Given these observations, we seek to elucidate the following by capitalizing upon the reward donation task: 1) activity of single amygdala neurons during reward allocation decisions; 2) neural mechanisms of OT-induced responses in amygdala neurons; and 3) specific modulations of ACC and OFC neurons due to OT-mediated processes by amygdala. We hypothesize that amygdala contains both vicarious and self reinforcement signals, and these are both amplified by inhaled OT. We further hypothesize that local OT delivery to amygdala neurons enhances self reward signals in OFC and vicarious reward signals in ACC. Our results have a potential to advance our knowledge on neuropsychiatric diseases with social deficits, and our understanding of OT-based therapeutics. PUBLIC HEALTH RELEVANCE: Despite a broad continuum of phenotypic variation in behavior, individuals with autism spectrum disorders (ASD) share core deficits in social interaction. Here we propose that social dysfunction in ASD results, in part, from problems in deriving vicarious reward from others, and that this process may depend on neuropeptide oxytocin, which is implicated in various social processes. We will use our animal model of vicarious reward to discover how oxytocin, a potential therapy for ASD, mediates social processing in the brain, and discover its role in brain dysfunction.