Cortico-amydala circuit dysfunction underlying avoidance behaviors and aversive facial expressions to social touch in mouse models of autism

自闭症小鼠模型中皮质-杏仁核回路功能障碍是回避行为和厌恶社交接触的面部表情的基础

• 批准号: 10387673
• 负责人: Trishala Chari
• 金额: $ 3.77万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-31 至 2025-12-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387673
• 关键词: Address; Adolescence; Adolescent; Adult; Affective; Age; Air; Amygdaloid structure; Animal Model; Animals; Area; Aversive Stimulus; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Brain region; Child; Computer Vision Systems; Data; Development; Disease model; Electrophysiology (science); Emotional; Environmental Risk Factor; Exhibits; Eye; FMR1; Facial Expression; Fibrinogen; Fragile X Syndrome; Functional disorder; Future; Genetic Models; Genetic Risk; Head; Human; Hypersensitivity; Impairment; Individual; Knowledge; Link; Measures; Microelectrodes; Modeling; Monitor; Motion; Mus; Neurodevelopmental Disorder; Neurons; Perception; Polystyrenes; Problem behavior; Quality of life; Research; Resolution; Running; Sensory; Silicon; Social Behavior; Social Controls; Social Interaction; Somatosensory Cortex; Stimulus; System; Tactile; Testing; Touch sensation; Vibrissae; Work; autism spectrum disorder; autistic children; avoidance behavior; base; behavioral response; critical period; design; disorder control; disorder subtype; experience; immune activation; in vivo; individuals with autism spectrum disorder; machine learning algorithm; maladaptive behavior; mouse model; neural circuit; novel; postnatal; pre-clinical; prevent; relating to nervous system; repetitive behavior; sensory stimulus; social; social deficits; social relationships; somatosensory; tactile stimulation; targeted treatment

PROJECT ABSTRACT Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by deficits in social interaction, repetitive behaviors and atypical sensory processing. The change in quality of life in ASD individuals is primarily attributed to social deficits, which can be associated with (or even triggered by) atypical processing of sensory information. In particular, social touch deficits in ASD may explain this association given the strong relationship between social interaction deficits and tactile hypersensitivity in ASD. Early tactile hyperresponsivity predicts future social impairments in ASD children and the absence of touch prevents ASD children from forming social relationships as adults. ASD individuals also lack representations of affective social touch in somatosensory brain regions. In mouse models of ASD, tactile sensitivity and social touch interactions also appear to be linked. Still, several important questions about social touch remain unresolved. First, it is not known when social touch behavioral deficits first emerge in ASD. These deficits may emerge early on in development when sensory hypersensitivity first develops or later in adolescence when social experiences become more frequent. Second, little is known about how social touch and maladaptive behaviors to social touch are represented in the brain of ASD individuals. Relevant brain areas may include the primary somatosensory cortex (S1), which encodes social touch and shows impaired adaptation to innocuous tactile stimuli in ASD mouse models, and the basolateral amygdala (BLA), which is important for encoding aversive stimuli and salient social information. To investigate social touch deficits in mouse models of autism, I have designed a novel head-fixed behavioral assay during which behavioral responses to social touch can be measured. This assay allows me to spatially and temporally control social touch interactions between mice so that I can assess the behavioral responses to both voluntary (whisker-whisker contact) and forced (snout-snout contact) social touch in a test mouse as it interacts with a stranger mouse. My preliminary data already shows that both the Fragile X Syndrome and maternal immune activation mouse models of autism animals display increased avoidance behaviors and aversive facial expressions (AFEs) to both voluntary and forced social touch compared to their controls in adulthood. Furthermore, these maladaptive behaviors are more prominent during social touch than object touch. For this proposal, I will utilize this novel behavioral assay and in vivo silicon probe electrophysiology recordings (Neuropixels) to 1. investigate when avoidance behaviors and AFEs to social touch emerge during development (postnatal and juvenile ages) in ASD mice and 2. determine how social touch and the maladaptive behavioral responses it triggers in ASD are represented as neural dynamics in S1 and BLA. This proposal is significant because it will provide the first characterization of behavioral manifestations of social touch deficits across development and investigate the neural circuit disruptions underlying these deficits in mouse models of ASD.

项目摘要 自闭症谱系障碍 (ASD) 是一种神经发育障碍，其特征是社交能力缺陷 互动、重复行为和非典型感觉处理。 ASD 个体生活质量的变化 主要归因于社会缺陷，这可能与非典型处理有关（甚至由其触发） 的感官信息。特别是，自闭症谱系障碍患者的社交接触缺陷可以解释这种关联，因为 自闭症谱系障碍（ASD）中社交互动缺陷与触觉超敏反应之间的关系。早期触觉过敏 预测自闭症儿童未来的社交障碍，缺乏接触会阻止自闭症儿童形成 成年后的社会关系。自闭症谱系障碍（ASD）个体也缺乏情感社交接触的表征 体感大脑区域。在 ASD 小鼠模型中，触觉敏感性和社交触摸互动也 似乎是链接的。尽管如此，关于社交接触的几个重要问题仍未解决。首先，目前尚不清楚 自闭症谱系障碍（ASD）首次出现社交接触行为缺陷时。这些缺陷可能在发展早期就出现 当感觉过敏首次出现时或在青春期后期当社会经历变得更加敏感时 频繁。其次，人们对社交接触和对社交接触的适应不良行为的影响知之甚少。 代表自闭症谱系障碍（ASD）个体的大脑。相关大脑区域可能包括初级体感皮层 (S1)，编码社交接触，并显示 ASD 小鼠对无害触觉刺激的适应能力受损 模型和基底外侧杏仁核（BLA），这对于编码厌恶刺激和显着的社交非常重要 信息。为了研究自闭症小鼠模型的社交接触缺陷，我设计了一种新颖的头部固定装置 行为测定，可以测量对社交接触的行为反应。该测定使我能够 在空间和时间上控制小鼠之间的社交接触互动，以便我可以评估行为 测试中对自愿（胡须接触）和强迫（口鼻接触）社交接触的反应 鼠标与陌生鼠标交互时。我的初步数据已经表明，脆性 X 综合症 自闭症动物的母体免疫激活小鼠模型表现出更多的回避行为 与对照组相比，对自愿和强迫社交接触的厌恶面部表情（AFE） 成年期。此外，这些适应不良行为在社交接触过程中比物体接触过程中更为突出。 对于这个提案，我将利用这种新颖的行为测定和体内硅探针电生理学记录 (Neuropixels) 1. 调查发育过程中何时出现回避行为和社交接触 AFE 2. 确定自闭症谱系障碍小鼠（出生后和青少年时期）的社交接触和适应不良行为 它在 ASD 中触发的反应在 S1 和 BLA 中表示为神经动力学。这个提议意义重大 因为它将首次描述跨群体社交接触缺陷的行为表现 开发并研究 ASD 小鼠模型中这些缺陷背后的神经回路破坏。