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 孤独症谱系障碍（ASD）是以社交功能缺陷为特征的神经发育障碍。 交互、重复行为和非典型感觉处理。ASD患者生活质量的变化 主要归因于社会缺陷，这可能与非典型处理有关（甚至由非典型处理触发） 的感官信息。特别是，ASD中的社会接触缺陷可能解释了这种关联， ASD患者社会交往缺陷与触觉超敏反应的关系早期触觉高反应 预测自闭症儿童未来的社会障碍，缺乏触摸可以防止自闭症儿童形成 成年人的社会关系。ASD患者也缺乏情感性社会接触的表征， 躯体感觉脑区在ASD小鼠模型中，触觉敏感性和社交触摸互动也 似乎有联系。尽管如此，关于社会接触的几个重要问题仍然没有得到解决。一是不为人知 自闭症患者首次出现社交接触行为缺陷的时候这些缺陷可能在发育早期出现 当感觉超敏反应首次出现时，或在青春期后期，当社会经验变得更多时， 频繁。第二，很少有人知道社会接触和社会接触的适应不良行为是如何发生的 在自闭症患者的大脑中。相关的大脑区域可能包括初级躯体感觉皮层 (S1)编码社交触觉，并显示ASD小鼠对无害触觉刺激的适应受损 模型，以及基底外侧杏仁核（BLA），这是编码厌恶刺激和突出的社会 信息.为了研究自闭症小鼠模型的社会接触缺陷，我设计了一种新颖的头部固定的 行为分析，在此期间可以测量对社会接触的行为反应。这个实验让我 在空间和时间上控制老鼠之间的社交触摸互动，这样我就可以评估老鼠的行为， 在测试中对自愿（胡须-胡须接触）和强迫（鼻子-鼻子接触）社交接触的反应 当它与一只陌生的老鼠互动时。我的初步数据已经显示脆性X综合征 自闭症动物的母体免疫激活小鼠模型显示出增加的回避行为， 厌恶面部表情（AFE）自愿和强迫社会接触相比，他们的控制， 成年此外，这些适应不良行为在社会接触中比物体接触更突出。 对于这个建议，我将利用这种新的行为分析和体内硅探针电生理记录 （神经像素）为1。研究回避行为和对社会接触的AFE在发育过程中何时出现 （出生后和幼年期）在ASD小鼠和2。确定社交接触和适应不良的行为 它在ASD中触发的反应表示为S1和BLA中的神经动力学。这一提议意义重大 因为它将提供第一个社会接触缺陷的行为表现的特征， 发展和调查神经回路中断这些缺陷在小鼠模型的ASD。