State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325027, Zhejiang, People's Republic of China.
School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China.
Mol Autism. 2023 Sep 11;14(1):34. doi: 10.1186/s13229-023-00567-0.
Many children and young people with autism spectrum disorder (ASD) display touch defensiveness or avoidance (hypersensitivity), or engage in sensory seeking by touching people or objects (hyposensitivity). Abnormal sensory responses have also been noticed in mice lacking ASD-associated genes. Tactile sensory information is normally processed by the somatosensory system that travels along the thalamus to the primary somatosensory cortex. The neurobiology behind tactile sensory abnormalities, however, is not fully understood.
We employed cortex-specific Foxp1 knockout (Foxp1-cKO) mice as a model of autism in this study. Tactile sensory deficits were measured by the adhesive removal test. The mice's behavior and neural activity were further evaluated by the whisker nuisance test and c-Fos immunofluorescence, respectively. We also studied the dendritic spines and barrel formation in the primary somatosensory cortex by Golgi staining and immunofluorescence.
Foxp1-cKO mice had a deferred response to the tactile environment. However, the mice exhibited avoidance behavior and hyper-reaction following repeated whisker stimulation, similar to a fight-or-flight response. In contrast to the wild-type, c-Fos was activated in the basolateral amygdala but not in layer IV of the primary somatosensory cortex of the cKO mice. Moreover, Foxp1 deficiency in cortical neurons altered the dendrite development, reduced the number of dendritic spines, and disrupted barrel formation in the somatosensory cortex, suggesting impaired somatosensory processing may underlie the aberrant tactile responses.
It is still unclear how the defective thalamocortical connection gives rise to the hyper-reactive response. Future experiments with electrophysiological recording are needed to analyze the role of thalamo-cortical-amygdala circuits in the disinhibiting amygdala and enhanced fearful responses in the mouse model of autism.
Foxp1-cKO mice have tactile sensory deficits while exhibit hyper-reactivity, which may represent fearful and emotional responses controlled by the amygdala. This study presents anatomical evidence for reduced thalamocortical connectivity in a genetic mouse model of ASD and demonstrates that the cerebral cortex can be the origin of atypical sensory behaviors.
许多自闭症谱系障碍（ASD）儿童和青少年表现出触觉防御或回避（超敏反应），或者通过触摸人或物体来进行感觉寻求（低敏反应）。缺乏 ASD 相关基因的小鼠也表现出异常的感觉反应。触觉感觉信息通常由沿着丘脑传递到初级体感皮层的体感系统处理。然而，触觉感觉异常的神经生物学机制尚不完全清楚。
本研究采用皮质特异性 Foxp1 敲除（Foxp1-cKO）小鼠作为 ASD 模型。通过粘附物去除试验测量触觉感觉缺陷。通过胡须骚扰试验和 c-Fos 免疫荧光分别进一步评估小鼠的行为和神经活动。我们还通过高尔基染色和免疫荧光研究了初级体感皮层的树突棘和桶形成。
Foxp1-cKO 小鼠对触觉环境的反应延迟。然而，与野生型相比，cKO 小鼠在反复胡须刺激后表现出回避行为和过度反应，类似于战斗或逃跑反应。与野生型不同，c-Fos 在基底外侧杏仁核中被激活，但不在 cKO 小鼠的初级体感皮层 IV 层中被激活。此外，皮质神经元中的 Foxp1 缺失改变了树突发育，减少了树突棘的数量，并破坏了体感皮层中的桶形成，这表明体感处理受损可能是异常触觉反应的基础。
丘脑皮质连接的缺陷如何导致过度反应仍不清楚。未来需要进行电生理记录实验，以分析丘脑皮质杏仁核回路在自闭症小鼠模型中去抑制杏仁核和增强恐惧反应中的作用。
Foxp1-cKO 小鼠有触觉感觉缺陷，同时表现出过度反应，这可能代表由杏仁核控制的恐惧和情绪反应。本研究为 ASD 遗传小鼠模型提供了减少丘脑皮质连接的解剖学证据，并表明大脑皮层可能是异常感觉行为的起源。
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