自闭症动物模型嗅觉恐惧反应异常的神经环路解析

The innate fear responses to environmental threats play a fundamental role in survival. The scent of predators induces an instinctive fear response in mice that includes behavioral changes, as well as a surge in blood stress hormones that mobilizes multiple body systems to escape impending danger. Clinically, individuals with autism spectrum disorder (ASD) may exhibit olfactory dysfunction and abnormal fear responses. In our preliminary study, we found impaired fear response to predator odor in Shank3B knockout (Shank3B-/-) mice, an ASD animal model. However, the neural mechanism underlying the abnormal olfactory fear processing in ASD is still unclear. To focus on this issue, we employ multidisciplinary techniques including calcium detection, cell-type specific optogenetics, patch clamp and neural circuits tracing to: 1)Identify key nuclei and related neural circuits that are involved in abnormal olfactory fear responses in Shank3B-/- mice; 2)Investigate molecular and structural mechanisms underlying Shank3B deletion-induced impaired functionality of innate olfactory fear circuits.The implementation of this project will deepen our understanding of abnormal fear emotion processing in mental disorders, and also provide potential therapeutic targets, so this project has important scientific and clinical significance.

本能恐惧反应对动物的生存至关重要。当动物探测到捕食者气味时会表现出逃逸或冻结行为以及由交感神经系统的兴奋和应激激素的分泌而引发的生理反应。临床上，自闭症谱系障碍患者存在着嗅觉功能障碍且表现出恐惧异常。我们在初步研究发现，自闭症动物模型Shank3B敲除(Shank3B-/-)小鼠受到捕食者气味刺激时表现出本能恐惧反应异常，然而自闭症中异常嗅觉本能恐惧加工的神经机制并不明确。聚焦这一问题，本项目将通过整合钙信号荧光检测、光遗传学、膜片钳以及神经环路示踪等技术进行以下研究：1）解析Shank3B-/-小鼠发生嗅觉本能恐惧反应异常的关键核团并分析其上下游环路功能变化特征；2）探索Shank3B缺失引发嗅觉本能恐惧神经环路失调的分子和结构机制。本项目的实施将为深入理解精神疾病中恐惧情感信息处理异常的神经环路机制提供重要线索和依据，有望为其在神经环路层面上提供新的治疗靶点，具有重要的科学

嗅觉障碍在自闭症谱系障碍(Autism spectrum disorders, ASD)患者中很常见，其程度与ASD的严重程度密切相关。然而，其神经环路的机制仍不十分清楚。在这里，我们报道了在Shank3B突变ASD小鼠模型中鉴定出先天性嗅觉功能障碍。与野生型小鼠不同，Shank3B-/-小鼠无法对捕食者狐狸尿气味2,5-二氢-2,4,5-三甲基噻唑啉(2,5-dihydro-2,4,5-trimethylthi-azoline, TMT)进行正常的防御行为。通过行为学检测和光纤记录钙信号，我们发现皮质杏仁核(Cortical amygdala, CoA)的神经元兴奋受损，这是先天气味驱动行为的关键节点。神经电生理结果分析揭示了CoA突触传递出现了皮层不同层的特异性损伤。此外，恢复CoA内Shank3的表达可以挽救TMT诱导的Shank3突变小鼠的恐惧反应。这些数据表明，在Shank3突变ASD模型中，CoA的突触功能障碍在先天嗅觉恐惧行为缺陷中起着关键作用。