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

项目摘要 自闭症谱系障碍(Asd)是以社交缺陷为特征的神经发育障碍。 相互作用、重复行为和非典型感觉加工。自闭症患者生活质量的变化 主要归因于社会缺陷，这可能与非典型加工有关(甚至可能由非典型加工引发 感官信息。特别是，ASD中的社交接触缺陷可能解释了这种联系，因为 ASD患者社会交往缺陷与触觉过敏的关系早期触觉高反应性 预测自闭症儿童未来的社交障碍，缺乏触摸可阻止自闭症儿童的形成 成年后的社会关系。自闭症患者也缺乏情感社交接触的表现 体感脑区。在ASD的小鼠模型中，触觉敏感性和社交触摸交互作用也 似乎是有关联的。尽管如此，关于社交接触的几个重要问题仍然没有得到解决。首先，目前尚不清楚 当社交接触行为缺陷首次出现在ASD中时。这些缺陷可能在发育早期就出现了。 当感觉过敏最初发展时，或后来在青春期，当社会经验变得更多时 很频繁。其次，人们对社交接触和社交接触的不适应行为知之甚少 在自闭症患者的大脑中有代表性。相关的大脑区域可能包括初级躯体感觉皮质 (S1)，它编码社交触摸，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)，它对编码厌恶刺激和显著的社会刺激很重要 信息。为了研究自闭症小鼠模型中的社交触摸缺陷，我设计了一种新型的头部固定装置 可以测量对社会接触的行为反应的行为测试。这个化验结果可以让我 在空间和时间上控制小鼠之间的社交触摸交互，以便我可以评估 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 鼠标，因为它与陌生人的鼠标交互。我的初步数据已经表明，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更多的回避行为和 对自愿和强迫社交接触的厌恶面部表情(AFE)与他们的对照组相比 成人期。此外，这些不适应行为在社交接触中比物体接触中更加突出。 对于这项提议，我将利用这种新的行为分析和活体硅探针电生理记录 (神经像素)1.调查在发育过程中何时出现回避行为和社交接触 (出生后和青少年年龄)和2.确定社交接触和不良适应行为 它在ASD中触发的反应在S1和BLA中表现为神经动力学。这项建议意义重大 因为它将首次对社会接触缺陷的行为表现进行描述 发展并研究ASD小鼠模型中这些缺陷背后的神经回路中断。

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.