Maturation of somatosensory circuits for social behaviors

社会行为体感回路的成熟

• 批准号: 10460016
• 负责人: Alicia Yue Che
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460016
• 关键词: Address; Adult; Advisory Committees; Affect; Auditory; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Brain; Calcium; Clinical; Cognitive; Communication; Consultations; Development; Disinhibition; Electrophysiology (science); Equilibrium; Faculty; Foundations; Funding; Future; Goals; Image; Imaging Techniques; Infant; Interneurons; Intervention; Investigation; Life; Link; Measures; Mediating; Membrane; Mental disorders; Mentors; Methods; Modality; Monitor; Motor; Neonatal; Neurodevelopmental Disorder; Neurons; Neuropeptides; Noise; Oxytocin; Oxytocin Receptor; Parents; Perception; Play; Positioning Attribute; Process; Prosencephalon; Psychophysics; Research; Research Personnel; Role; Secure; Sensory; Shapes; Signal Transduction; Slice; Social Behavior; Social Development; Social Environment; Social Interaction; Solid; Stimulus; Supervision; Surveys; Synapses; Synaptic Transmission; System; Tactile; Techniques; Testing; Thalamic structure; Therapeutic; Time; Touch sensation; Training; Vibrissae; Visual; Whole-Cell Recordings; Work; autism spectrum disorder; barrel cortex; career; cohort; design; experience; hippocampal pyramidal neuron; imaging genetics; in vivo; individuals with autism spectrum disorder; infancy; insight; mature animal; meetings; mouse genetics; neonatal mice; neonatal period; neurobiological mechanism; neuronal circuitry; neuroregulation; optogenetics; postnatal; pup; recruit; response; sensory input; sensory stimulus; serotonin receptor; skills; social; social communication; social deficits; somatosensory; symptom treatment; temporal measurement; tool; two-photon

Touch contributes powerfully to parent-infant interactions that are fundamental for early social development. Among the most developed sensory modalities when infants are born, touch continues to play a critical role in communication and social interaction throughout development and adult life. Abnormalities in tactile perception are prevalent features in individuals with autism spectrum disorders (ASD), exacerbating the core social deficits. While the relationship between tactile sensory processing and social behaviors have been studied extensively using psychophysical paradigms from clinical perspectives, little is known about the neurobiological mechanisms underlying their link, and how they facilitate the development of one another. Understanding how social features are encoded alongside early tactile sensory inputs will provide valuable insights into the emergence of circuits integrating primary sensory processing and higher-order cognitive features. Through three distinct aims, we propose to leverage longitudinal two-photon imaging, genetic tools and behavioral assays to determine how oxytocin, a neuropeptide critical in a wide range of social behaviors, modulates superficial intraneuronal circuits to facilitate the development of social touch. We choose to focus on the circuits involving L1 reelin-expressing (L1 Re) interneurons due to their unique connectivity and function in restricting pyramidal neuron activation during sensory input in early postnatal days. In Aim 1, we will survey the neuronal types that express oxytocin receptors (OXTRs) in the superficial layers of the barrel cortex and determine the function of oxytocin in modulating circuits involving L1 Re interneurons. In Aim 2, we will examine the in vivo neuronal activity in neonatal mouse pups during dam induced social touch and determine how disruption in oxytocin signaling in L1 Re interneurons affects this activity. In Aim 3, we will extend our investigation on the role of oxytocin in the emergence of social touch to cover the entire developmental time period from neonatal stage to adulthood by performing longitudinal two-photon imaging, completed with long-term behavioral assessment of social interaction over this time span. Together, these aims will reveal how interneurons shape social interaction, providing a framework that can help refine therapeutic directions for treating symptoms of ASD as well as other neurodevelopmental disorders. By addressing these questions and carrying out the proposed work, the candidate will build both technical and professional skills that will provide a solid foundation for a future career as an independent researcher. The co-mentors, Drs. De Marco García and Froemke, will supervise the candidate in formal aspects of conceptual design and experimental methods through regular meetings (see Training Plan) and also advise and support the candidate in the process of securing a faculty position, setting up an independent lab, and securing initial funding. The Advisory Committee, which consists of Drs. Liston, Lee and Rajadhyaksha, who have extensive experience with the methods outlines in the Research Strategy, will provide consultation on both the conduct and interpretation of the research and in navigating the professional landscape of early-stage research in an academic setting.

触摸对父母与婴儿的互动有很大的贡献，而这种互动是早期社会发展的基础。在婴儿出生时最发达的感觉方式中，触摸在整个发育和成年生活中继续在沟通和社会互动中发挥关键作用。触觉感知障碍是自闭症谱系障碍（ASD）患者的普遍特征，加剧了核心社会缺陷。虽然触觉感觉处理和社会行为之间的关系已经从临床角度使用心理物理学范式进行了广泛的研究，但对它们之间联系的神经生物学机制以及它们如何促进彼此的发展知之甚少。了解社会功能如何与早期触觉感官输入一起编码，将为整合初级感觉处理和高阶认知功能的电路的出现提供有价值的见解。 通过三个不同的目标，我们建议利用纵向双光子成像，遗传工具和行为分析，以确定催产素，神经肽在广泛的社会行为中的关键，调节浅表神经元内电路，以促进社会触摸的发展。我们选择专注于涉及L1 reelin表达（L1 Re）中间神经元的电路，由于其独特的连接和功能，在限制锥体神经元激活感觉输入在出生后早期。在目的1中，我们将调查的神经元类型，表达催产素受体（OXTRs）在桶皮层的浅层，并确定催产素的功能，涉及L1 Re中间神经元调制电路。在目标2中，我们将研究在体内的神经元活动在新生小鼠幼崽在大坝诱导的社会触摸，并确定如何中断催产素信号在L1 Re中间神经元影响这种活动。在目标3中，我们将通过进行纵向双光子成像来扩展我们对催产素在社会接触出现中的作用的研究，以涵盖从新生儿阶段到成年的整个发育时间段，并在此时间跨度内完成对社会互动的长期行为评估。总之，这些目标将揭示中间神经元如何塑造社会互动，提供一个框架，可以帮助完善治疗ASD症状以及其他神经发育障碍的治疗方向。 通过解决这些问题并开展拟议的工作，候选人将建立技术和专业技能，为未来作为独立研究人员的职业生涯奠定坚实的基础。De Marco García和Froemke博士将通过定期会议（见培训计划）在概念设计和实验方法的正式方面监督候选人，并在确保教师职位，建立独立实验室和获得初始资金的过程中为候选人提供建议和支持。咨询委员会由Liston博士、Lee博士和Rajadhyaksha博士组成，他们对研究策略中概述的方法拥有丰富的经验，将就研究的进行和解释以及早期研究的专业领域提供咨询。在学术环境中进行研究。