2025年1月15日，美国耶鲁大学医学院Nenad Sestan研究小组在《自然》杂志发表论文，报道了丘脑-杏仁核和古皮层神经元及回路的特性。

研究人员揭示了转录因子SOX4、SOX11和TFAP2D在这些兴奋神经元的发育、特化和前额叶皮层（PFC）连接中的关键作用。有丝分裂后兴奋神经元中的SOX4和SOX11缺失会导致杏仁基底外侧复合体（BLC）、杏仁核（CLA）和PIR的大小明显收缩。这些转录因子通过直接调控Tfap2d的表达来控制BLC的形成。包括人在内的跨物种分析表明，Tfap2d在BLC、CLA、PIR以及额叶、岛叶和颞叶皮层相关过渡区兴奋性神经元中的表达一致。

虽然Tfap2d的缺失和单倍体缺陷会导致学习威胁反应行为发生类似的改变，但不同剂量的Tfap2d会导致不同的表型，尤其是在BLC大小和BLC-PFC连接方面。这强调了Tfap2d剂量在协调BLC-PFC连接性和行为发育转变中的重要性。这些发现共同揭示了一个保守基因调控网络的关键要素，该网络塑造了关键腹外侧古皮层（VLp）兴奋神经元的发育和功能及其与PFC的连接，并为了解它们在神经精神疾病中的演变和改变提供见解。

研究人员表示，丘脑-杏仁核复合体和梨状皮层（PIR，是古皮层的一部分）中的VLp兴奋神经元与PFC形成相互联系，整合认知和感觉信息，从而产生适应性行为。早期破坏这些环路与神经精神疾病的发生有关，这凸显了了解其发育过程的重要性。

附：英文原文

Title: Specification of claustro-amygdalar and palaeocortical neurons and circuits

Author: Kaur, Navjot, Kovner, Rothem, Gulden, Forrest O., Pletikos, Mihovil, Andrijevic, David, Zhu, Tianjia, Silbereis, John, Shibata, Mikihito, Shibata, Akemi, Liu, Yuting, Ma, Shaojie, Salla, Nikkita, de Martin, Xabier, Klari, Thomas S., Burke, Megan, Franjic, Daniel, Cho, Hyesun, Yuen, Matthew, Chatterjee, Ipsita, Soric, Paula, Esakkimuthu, Devippriya, Moser, Markus, Santpere, Gabriel, Mineur, Yann S., Pattabiraman, Kartik, Picciotto, Marina R., Huang, Hao, Sestan, Nenad

Issue&Volume: 2025-01-15

Abstract: The ventrolateral pallial (VLp) excitatory neurons in the claustro-amygdalar complex and piriform cortex (PIR; which forms part of the palaeocortex) form reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that results in adaptive behaviours1,2,3,4,5. Early-life disruptions in these circuits are linked to neuropsychiatric disorders4,5,6,7,8, highlighting the importance of understanding their development. Here we reveal that the transcription factors SOX4, SOX11 and TFAP2D have a pivotal role in the development, identity and PFC connectivity of these excitatory neurons. The absence of SOX4 and SOX11 in post-mitotic excitatory neurons results in a marked reduction in the size of the basolateral amygdala complex (BLC), claustrum (CLA) and PIR. These transcription factors control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including in humans, identified conserved Tfap2d expression in developing excitatory neurons of BLC, CLA, PIR and the associated transitional areas of the frontal, insular and temporal cortex. Although the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat-response behaviours, differences emerge in the phenotypes at different Tfap2d dosages, particularly in terms of changes observed in BLC size and BLC–PFC connectivity. This underscores the importance of Tfap2d dosage in orchestrating developmental shifts in BLC–PFC connectivity and behavioural modifications that resemble symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial VLp excitatory neurons and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.

DOI: 10.1038/s41586-024-08361-5

Source: https://www.nature.com/articles/s41586-024-08361-5