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; 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.

项目摘要 感觉感知异常是自闭症谱系障碍个体的普遍特征 （ASD），伴随着核心社会缺陷。自闭症研究中的一个核心挑战是确定 神经生物学机制的基础与感觉感知和社会认知一样与众不同。作为 这样，我们的长期目标是了解感官共享的常见发展和电路机制 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质。这些发现引起了催产素的激动人心但未经测试的可能性 信号传导与触觉处理和社交功能均相关。在我们的初步研究中，我们发现 催产素受体（OXTR）在表达生长抑素的表达中大量和专门表达 发育过程中原发性体感皮质（S1）中的中间神经元（SST INS）。激活Oxtrs 有选择地，强烈地使SST INS取代，而这些神经元中的OXTR缺失导致超极化 在发育中的S1中，静息膜电位并减少了体内网络活性。另外，小鼠 SST INS中有针对性的OXTR缺失显示出受损的纹理歧视和感官敏感性，以及 社会偏爱的赤字。基于这些初步结果，我们假设需要催产素 在发展中的体感皮层中建立适当的突触连通性，并在 催产素信号传导导致触觉感觉异常和社会缺陷。我们将利用我们的小说 纵向2光子成像技术，电生理和遗传学方法鉴定细胞类型 催产素在S1的发展以及在急性社会互动过程中的特定作用通过三个目标。我们 将评估催产素对SST INS的生长和存活的影响以及电路的成熟 开发S1中的连接性（AIM 1）。我们将剖析催产素信号在一般触觉感觉中的作用 处理，并在社会接触期间编码社交线索时（AIM 2）。我们将探索行为成果 催产素信号传导功能障碍及其神经层，并测试发育触觉功能障碍作为 OXTR缺失的结果加剧了社会缺陷（AIM 3）。共同预计结果将揭示常见 感官和社会信息处理的基础神经机制，提供对基本规则的见解 脑电路发展，并确定与ASD和其他心理相关的早期诊断标记 可以指导新型治疗学的疾病。