Neural Mechanisms Linking Sensory Perception and Social Behavior

项目摘要 感觉知觉缺失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识别 这些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共享的共同发育和电路机制， 和社会信息处理。大量的证据表明，神经肽催产素显着 有助于广泛的社会行为，最近，它已被链接到突触可塑性， 在发育过程中的感觉皮层。这些发现提出了一个令人兴奋但未经验证的可能性， 发信号与触觉处理和社会功能两者相关联。在我们的初步研究中，我们发现， 催产素受体（OXTRs）在生长抑素表达的细胞中大量表达， 中间神经元（SST INs）在初级体感皮层（S1）发育过程中。激活OXTRs 选择性地和强烈地去极化SST IN，而这些神经元中的OXTR缺失导致超极化 的静息膜电位和减少在发展中的S1的体内网络活动。此外，老鼠 SST IN中靶向OXTR缺失的患者显示质地辨别和感觉敏感性受损， 缺乏社会偏好。基于这些初步结果，我们假设催产素是必需的， 在发育中的躯体感觉皮层中建立适当的突触连接， 催产素信号传导导致触觉感觉异常和社交缺陷。我们将利用我们的小说 纵向双光子成像技术、电生理学和遗传学方法来识别细胞类型 催产素在S1的发展中的具体作用，并通过三个目标在急性社会交往。我们 将评估催产素对SST INs生长和存活以及回路成熟的影响。 发展中的S1（目标1）的连通性。我们将剖析催产素信号在一般触觉感觉中的作用， 处理，并在社会接触过程中编码社会线索（目标2）。我们将探讨行为结果 催产素信号功能障碍及其神经相关性，并测试发育性触觉功能障碍是否作为一种 OXTR缺失的结果加剧了社会缺陷（目的3）。总的来说，这些结果有望揭示出 感觉和社会信息处理的神经机制，提供了对基本规则的见解， 脑回路发育，以及识别与ASD和其他精神疾病相关的早期诊断标志物， 可以指导新疗法的疾病。

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.