Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China.
Institute of Information Science, Academia Sinica, Taipei, Taiwan, Republic of China.
PLoS Biol. 2024 Jul 16;22(7):e3002646. doi: 10.1371/journal.pbio.3002646. eCollection 2024 Jul.
Autism spectrum disorders (ASDs) are considered neural dysconnectivity syndromes. To better understand ASD and uncover potential treatments, it is imperative to know and dissect the connectivity deficits under conditions of autism. Here, we apply a whole-brain immunostaining and quantification platform to demonstrate impaired structural and functional connectivity and aberrant whole-brain synchronization in a Tbr1+/- autism mouse model. We express a channelrhodopsin variant oChIEF fused with Citrine at the basolateral amygdala (BLA) to outline the axonal projections of BLA neurons. By activating the BLA under blue light theta-burst stimulation (TBS), we then evaluate the effect of BLA activation on C-FOS expression at a whole brain level to represent neural activity. We show that Tbr1 haploinsufficiency almost completely disrupts contralateral BLA axonal projections and results in mistargeting in both ipsilateral and contralateral hemispheres, thereby globally altering BLA functional connectivity. Based on correlated C-FOS expression among brain regions, we further show that Tbr1 deficiency severely disrupts whole-brain synchronization in the absence of salient stimulation. Tbr1+/- and wild-type (WT) mice exhibit opposing responses to TBS-induced amygdalar activation, reducing synchronization in WT mice but enhancing it in Tbr1+/- mice. Whole-brain modular organization and intermodule connectivity are also affected by Tbr1 deficiency and amygdalar activation. Following BLA activation by TBS, the synchronizations of the whole brain and the default mode network, a specific subnetwork highly relevant to ASD, are enhanced in Tbr1+/- mice, implying a potential ameliorating effect of amygdalar stimulation on brain function. Indeed, TBS-mediated BLA activation increases nose-to-nose social interactions of Tbr1+/- mice, strengthening evidence for the role of amygdalar connectivity in social behaviors. Our high-resolution analytical platform reveals the inter- and intrahemispheric connectopathies arising from ASD. Our study emphasizes the defective synchronization at a whole-brain scale caused by Tbr1 deficiency and implies a potential beneficial effect of deep brain stimulation at the amygdala for TBR1-linked autism.
自闭症谱系障碍（ASD）被认为是神经连接障碍综合征。为了更好地理解 ASD 并发现潜在的治疗方法，了解并剖析自闭症状态下的连接缺陷至关重要。在这里，我们应用全脑免疫染色和定量平台来证明 Tbr1+/-自闭症小鼠模型存在结构和功能连接受损以及全脑同步异常。我们在基底外侧杏仁核（BLA）中表达了一种融合了 Citrine 的通道视紫红质变体 oChIEF，以勾勒出 BLA 神经元的轴突投射。通过在蓝光 theta 爆发刺激（TBS）下激活 BLA，我们然后评估 BLA 激活对整个大脑水平 C-FOS 表达的影响，以代表神经活动。我们发现 Tbr1 杂合不足几乎完全破坏了对侧 BLA 轴突投射，并导致同侧和对侧半球的靶向错误，从而全局改变了 BLA 的功能连接。基于大脑区域之间的相关 C-FOS 表达，我们进一步表明，Tbr1 缺乏严重破坏了没有明显刺激时的全脑同步。Tbr1+/-和野生型（WT）小鼠对 TBS 诱导的杏仁核激活表现出相反的反应，降低了 WT 小鼠的同步性，但增强了 Tbr1+/-小鼠的同步性。全脑模块组织和模块间连接也受到 Tbr1 缺乏和杏仁核激活的影响。在 TBS 激活 BLA 后，Tbr1+/-小鼠的整个大脑和默认模式网络（与 ASD 高度相关的特定子网）的同步性增强，暗示杏仁核刺激对大脑功能具有潜在的改善作用。事实上，TBS 介导的 BLA 激活增加了 Tbr1+/-小鼠的鼻对鼻社交互动，增强了杏仁核连接在社交行为中的作用的证据。我们的高分辨率分析平台揭示了 ASD 引起的跨和半球内连接病变。我们的研究强调了 Tbr1 缺乏引起的全脑同步缺陷，并暗示了深部脑刺激在杏仁核治疗 TBR1 相关自闭症方面的潜在有益作用。
