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: 10378660
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378660
• 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 contact; social deficits; social exclusion; social group; social influence; 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.

人类拥有社会接触的基本需求，这对于生存和心理健康至关重要。 存在。因此，社会孤立、排斥或脱节的情况是非常令人厌恶的，并可能导致 孤独的负面情绪。然而，我们对构成其基础的大脑回路了解甚少。 这种情绪状态，以及它如何产生寻求社交联系的需求。此外，在许多 神经精神疾病，包括抑郁症、焦虑症和自闭症谱系障碍、社交退缩和 社交互动受损是其典型特征。第一步，我们必须揭示神经机制 这是我们寻求和参与社会接触的内在动力的基础，以便了解这些接触如何可能 情绪失常。 我们最近收集了令人兴奋的初步数据，表明尚未得到充分研究的人群 中缝背核 (DRN) 中的多巴胺 (DA) 神经元代表社会主观体验 隔离。我们发现这些神经元对急性社会孤立期和对社会的操纵很敏感 它们在体内的活动可以以社会等级预测的方式诱发或抑制“类似孤独”的状态。我们 假设 DRN DA 神经元介导“类似孤独”的状态，并提供动机驱动 重新建立社会联系。因此，通过这项研究计划，我们试图在很大程度上探索和解开这个问题 多巴胺能回路中的未知领域，并探索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架构。这将 生成神经解剖学路线图，并为详细的电路和投影特定分析奠定基础。 此外，我们将测试哪些输入和输出区域涉及传递有关以下内容的基本信息： 社会环境。为此，我们将检查 DRN 多巴胺中自然发生的活性 神经元，并确定操纵它们的活动如何影响社会行为。这将提供有关如何 该群体的神经动力学在分组和社会孤立的动物中有所不同。我们还将另外 探索 DRN DA 系统与社会等级制度的建立和维护的关系。这些 实验将揭示 DRN DA 功能与社会排名之间的关系，并进一步我们 了解导致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，走在病毒载体的最前沿 成功执行该提案所需的方法。鉴于我实验室的记录，独特的初步 我的团队生成的数据集、已确定的问题以及已采取的必要步骤，我们正在 特别适合执行这项研究，并且很高兴能够推动社会神经科学领域的发展。