Neural Mechanisms Linking Sensory Perception and Social Behavior

连接感官知觉和社会行为的神经机制

• 批准号: 10717481
• 负责人: Alicia Yue Che
• 金额: $ 42.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717481
• 关键词: Acute; Address; Adult; Behavior; Behavioral; Brain; Clinical; Color; Cues; Data; Development; Discrimination; Down-Regulation; Early Intervention; Early identification; Electrophysiology (science); Functional disorder; Gene Mutation; Genetic; Goals; Growth; Head; Image; Imaging Techniques; Impairment; Interneurons; Knowledge; Life; Link; Measures; Mechanics; Membrane Potentials; Mental disorders; Mus; Neurons; Neuropeptides; Outcome; Oxytocin; Oxytocin Receptor; Pattern; Perception; Process; Prosencephalon; Pyramidal Cells; Receptor Signaling; Reporting; Research; Rest; Risk Factors; Role; Secondary to; Sensory; Sensory Deprivation; Signal Transduction; Social Behavior; Social Functioning; Social Interaction; Somatosensory Cortex; Somatostatin; Structure; Symptoms; Synapses; Synaptic plasticity; Tactile; Testing; Texture; Time; Vibrissae; Work; autism spectrum disorder; behavioral impairment; behavioral outcome; cell type; clinically relevant; comorbidity; diagnostic biomarker; experience; genetic approach; in vivo; individuals with autism spectrum disorder; information processing; insight; mouse model; neural correlate; neurobiological mechanism; neuromechanism; novel; novel therapeutics; preference; sensory cortex; social; social cognition; social communication; social contact; social deficits; translational impact; two-photon

PROJECT SUMMARY Abnormalities in sensory perception are prevalent features in individuals with autism spectrum disorders (ASD), accompanying the core social deficits. A central challenge in autism research is to identify alterations in neurobiological mechanisms that underlie processes as distinct as sensory perception and social cognition. As such, our long-term goal is to understand common developmental and circuit mechanisms shared by sensory and social information processing. Considerable evidence indicates that the neuropeptide oxytocin significantly contributes to a wide range of social behaviors, and more recently, it has been linked to synaptic plasticity in sensory cortices during development. These findings raise an exciting but untested possibility that oxytocin signaling is associated with both tactile processing and social function. In our preliminary studies, we found that oxytocin receptors (OXTRs) are expressed abundantly and specifically in the somatostatin-expressing interneurons (SST INs) in the primary somatosensory cortex (S1) during development. Activating OXTRs selectively and strongly depolarizes SST INs, while OXTR deletion in these neurons leads to hyperpolarization of the resting membrane potential and reduced in vivo network activity in the developing S1. In addition, mice with targeted OXTR deletion in SST INs show impaired texture discrimination and sensory sensitivity, as well as deficits in social preference. Based on these preliminary results, we hypothesize that oxytocin is required for establishing proper synaptic connectivity in the developing somatosensory cortex, and that impairment in oxytocin signaling leads to both tactile sensory abnormalities and social deficits. We will leverage our novel longitudinal 2-photon imaging technique, electrophysiological and genetic approaches to identify the cell-type specific role of oxytocin in the development of S1 and during acute social interactions through three aims. We will assess the effects of oxytocin on the growth and survival of SST INs, as well as the maturation of circuit connectivity in the developing S1 (Aim 1). We will dissect the role of oxytocin signaling in general tactile sensory processing, and in encoding social cues during social contacts (Aim 2). We will explore the behavioral outcomes of oxytocin signaling dysfunction and their neural corelates, and test if developmental tactile dysfunction as a result of OXTR deletion exacerbates social deficits (Aim 3). Together, the results are expected to reveal common neural mechanisms underlying sensory and social information processing, providing insights into basic rules for brain circuit development, as well as identifying early diagnostic markers associated with ASD and other mental disorders that can guide novel therapeutics.

项目概要 感觉知觉异常是自闭症谱系障碍患者的普遍特征 （ASD），伴随着核心社会赤字。自闭症研究的一个核心挑战是确定自闭症的改变 神经生物学机制是感觉知觉和社会认知等不同过程的基础。作为 因此，我们的长期目标是了解感官所共有的共同发育和回路机制 和社会信息处理。大量证据表明神经肽催产素显着 有助于广泛的社会行为，最近，它与突触可塑性有关 发育过程中的感觉皮层。这些发现提出了一种令人兴奋但未经检验的可能性，即催产素 信号传导与触觉处理和社交功能相关。在我们的初步研究中，我们发现 催产素受体（OXTR）在表达生长抑素的细胞中大量且特异地表达。 发育过程中初级体感皮层 (S1) 的中间神经元 (SST IN)。激活 OXTR 选择性地强烈去极化 SST IN，而这些神经元中的 OXTR 缺失会导致超极化 静息膜电位的降低和发育中 S1 体内网络活性的降低。此外，小鼠 SST IN 中的靶向 OXTR 缺失显示纹理辨别力和感官敏感性受损，以及 社会偏好的缺陷。根据这些初步结果，我们假设催产素是 在发育中的体感皮层中建立适当的突触连接，并且损伤 催产素信号传导导致触觉异常和社交缺陷。我们将利用我们的小说 纵向 2 光子成像技术、电生理学和遗传学方法来识别细胞类型 催产素在 S1 发育和急性社交互动过程中通过三个目标的具体作用。我们 将评估催产素对 SST IN 的生长和存活以及电路成熟的影响 发展中的 S1 的连通性（目标 1）。我们将剖析催产素信号在一般触觉中的作用 处理以及在社交接触期间编码社交线索（目标 2）。我们将探讨行为结果 催产素信号传导功能障碍及其神经相关性的研究，并测试发育性触觉功能障碍是否是 OXTR 缺失的结果加剧了社会赤字（目标 3）。总之，结果预计将揭示共同点 感觉和社会信息处理的神经机制，提供对基本规则的见解 脑回路发育，以及识别与自闭症谱系障碍和其他精神疾病相关的早期诊断标记 可以指导新疗法的疾病。