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: 10005962
• 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/10005962
• 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 environment; 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.

人类拥有社会接触的基本需求，这对生存和精神健康至关重要。 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 消极的孤独感。然而，我们对大脑回路的理解很差， 这种情绪状态，以及这种状态如何产生寻求社会联系的需求。此外，在许多 神经精神障碍，包括抑郁症、焦虑症和自闭症谱系障碍， 社交障碍是特征作为第一步，我们必须揭示 这是我们寻求和参与社会接触的内在动力的基础，为了理解这些可能是如何发生的， 情绪紊乱时会出差错 我们最近收集了令人兴奋的初步数据，表明有一个研究不足的人口， 中缝背核（DRN）中的多巴胺（DA）神经元在代表社会主观体验中的作用 隔离我们发现，这些神经元对社会隔离的急性期和对社会的操纵是敏感的。 它们在体内的活性可以通过社会等级预测的方式诱导或抑制“孤独样”状态。我们 假设DRN DA神经元介导了一种“孤独样”状态，并提供了动机驱动， 重新建立社会联系。因此，通过这项研究提案，我们试图在很大程度上探索和解决这一问题。 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。 为了实现这一点，我们将首先确定这种类型的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参与传达关于以下内容的基本信息： 社会环境。为此，我们将研究DRN多巴胺内自然发生的活动 神经元，并建立如何操纵他们的活动影响社会行为。这将提供洞察如何 该种群的神经动力学在分组和社会隔离的动物中不同。我们还将 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功能与社会等级之间的关系，并进一步研究DRN DA功能与社会等级之间的关系。 理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。 成功执行这一建议所需的方法。根据我实验室的记录， 根据我的团队生成的数据集、确定的问题和已经采取的必要步骤，我们 特别适合执行这项研究，并很高兴能推动社会神经科学领域的发展。