Exploring neural circuit mechanisms of social contact and social isolation

探索社会接触和社会隔离的神经回路机制

• 批准号: 10159755
• 负责人: Kay Maxine Tye
• 金额: $ 48.39万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159755
• 关键词: Action Potentials; Acute; Affect; Anatomy; Animals; Anxiety; Architecture; Behavior; Behavioral; Biological; Brain Stem; Calcium; Cell Count; Cells; Data; Data Set; Dopamine; Electric Stimulation; Emotional; Exclusion; Feeling; Fiber; Foundations; Glutamates; Heterogeneity; Home; Human; Image; Impairment; Individual; Individual Differences; Lead; Light; Loneliness; Maintenance; Maps; Mediating; Mental Depression; Mood Disorders; Moods; Morphology; Motivation; Mus; Nature; Neurons; Optics; Outcome; Output; Patient Self-Report; Photometry; Physiological; Physiology; Population; Population Dynamics; Positioning Attribute; Property; Psyche structure; Rabies virus; Research Proposals; Rewards; Rodent; Role; Safety; Social Behavior; Social Environment; Social Hierarchy; Social Interaction; Social Perception; Social isolation; Stimulus; Structure; Synapses; System; Techniques; Testing; Therapeutic Intervention; Viral Vector; Well in self; Withdrawal; Work; autism spectrum disorder; base; brain circuitry; design; dopamine system; dopamine transporter; dopaminergic neuron; dorsal raphe nucleus; experience; experimental study; in vivo; individual variation; insight; neural circuit; neuroadaptation; neurobiological mechanism; neuromechanism; neuropsychiatric disorder; new therapeutic target; novel; physical conditioning; relating to nervous system; response; social; social attachment; social deficits; social exclusion; social group; social neuroscience; social situation

Humans possess a fundamental need for social contact, which is essential for survival and mental well- being. Therefore, situations of social isolation, exclusion, or disconnection are highly aversive, and can lead to negative feelings of loneliness. However, we have a poor understanding of the brain circuitry which underlies this emotional state, and how this generates a need to seek social contact. Additionally, in many neuropsychiatric disorders, including depression, anxiety, and autism spectrum disorders social withdrawal and impaired social interaction are defining features. As a first step, we must uncover the neural mechanisms which underlie our inherent drive to seek and engage in social contact, in order to understand how these might go awry in mood disorders. We have recently gathered exciting preliminary data implicating an understudied population of dopamine (DA) neurons in the dorsal raphe nucleus (DRN) in representing the subjective experience of social isolation. We find that these neurons are sensitive to acute periods of social isolation, and manipulations of their activity in vivo can induce or suppress a ‘loneliness-like’ state, in a manner predicted by social rank. We hypothesize that the DRN DA neurons mediate a ‘loneliness-like’ state, and provide the motivational drive to re-establish social contact. With this research proposal, we therefore seek to explore and unravel this largely uncharted territory within the dopaminergic circuit and explore its functional importance for social contact. To achieve this, we will first identify the input-output architecture of this type of neurons. This will generate a neuroanatomical roadmap and the foundation for detailed circuit- and projection-specific analyses. Furthermore, we will test which input and output regions are involved in conveying essential information about the social environment. For this we will examine the naturally-occurring activity within the DRN dopamine neurons, and establish how manipulating their activity affects social behavior. This will provide insight into how the neural dynamics of this population differ in grouped and socially-isolated animals. We will additionally explore the DRN DA system in relation to the establishment and maintenance of social hierarchy. These experiments will unravel the relationship between DRN DA function and social rank, and further our understanding of the neural mechanisms which contribute to individual differences in social behavior. Importantly, we will work with Ian Wickersham and Liqun Luo to be at the forefront of viral vector approaches needed to successfully execute this proposal. Given my lab’s track record, the unique preliminary data set generated by my team, the questions identified and the necessary steps already taken, we are particularly well-suited to execute this study, and are thrilled to drive the field of social neuroscience forward.

人类对社会接触具有根本的需求，这对于生存和心理良好至关重要 存在。因此，社会隔离，排斥或断开连接的情况是高度厌恶的，可以导致 负面的孤独感。但是，我们对脑电路的理解很差 这种情绪状态，以及如何产生寻求社会接触的需求。另外，在许多人中 神经精神疾病，包括抑郁症，动画和自闭症谱系障碍，社交戒断和 社交互动受损是定义特征。作为第一步，我们必须揭示神经机制 这是我们继承寻求和参与社会联系的动力的基础，以了解这些可能如何 心情障碍出现问题。 最近，我们收集了令人兴奋的初步数据，暗示了 在代表社会的主题经验中，多巴胺（DA）神经元（DRN） 隔离。我们发现这些神经元对社会隔离的急性时期敏感，对 他们在体内的活动可以通过社会等级预测的方式诱导或抑制“孤独”状态。我们 假设DRN DA神经元介导了“孤独”状态，并为 重新建立社会接触。因此，通过这项研究建议，我们寻求在很大程度上探索和解开这一 多巴胺能回路中未知的领域，并探讨了其对社会接触的功能重要性。 为了实现这一目标，我们将首先确定此类神经元的输入输出体系结构。这会 生成神经解剖路线图和详细的电路和特定于投影分析的基础。 此外，我们将测试哪些输入和输出区域参与传达有关的基本信息 社会环境。为此，我们将检查DRN多巴胺内的自然活动活性 神经元，并确定操纵活动如何影响社会行为。这将提供有关如何 这种人群分组和社会分离的动物的神经动力学。我们还将 探索与建立和维护社会等级制度有关的DRN DA系统。这些 实验将揭示DRN DA功能与社会等级之间的关系，进一步 理解有助于社会行为个体差异的神经机制。 重要的是，我们将与Ian Wickersham和Liqun Luo合作，在病毒载体的森林中 成功执行此建议所需的方法。鉴于我的实验室的往绩，是独特的初步 我的团队生成的数据集，确定的问题以及已经采取的必要步骤，我们是 特别适合执行这项研究，并为推动社会神经科学领域而感到非常兴奋。