Specification of claustro-amygdalar and palaeocortical neurons and circuits

Navjot Kaur, Rothem Kovner, Forrest O. Gulden, Mihovil Pletikos, David Andrijevic, Tianjia Zhu, John Silbereis, Mikihito Shibata, Akemi Shibata, Yuting Liu, Shaojie Ma, Nikkita Salla, Xabier Martin, Thomas S. Klarić, Megan Burke, Daniel Franjic, Hyesun Cho, Matthew Yuen, Ipsita Chatterjee, Paula Soric, Devippriya Esakkimuthu, Markus Moser, Gabriel Santpere, Yann S. Mineur, Kartik Pattabiraman, Marina R. Picciotto, Hao Huang and Nenad Sestan (nenad.sestan@yale.edu)
Additional contact information
Navjot Kaur: Yale School of Medicine
Rothem Kovner: Yale School of Medicine
Forrest O. Gulden: Yale School of Medicine
Mihovil Pletikos: Yale School of Medicine
David Andrijevic: Yale School of Medicine
Tianjia Zhu: Children’s Hospital of Philadelphia
John Silbereis: Yale School of Medicine
Mikihito Shibata: Yale School of Medicine
Akemi Shibata: Yale School of Medicine
Yuting Liu: Yale School of Medicine
Shaojie Ma: Chinese Academy of Sciences
Nikkita Salla: Yale School of Medicine
Xabier Martin: PRBB
Thomas S. Klarić: Yale School of Medicine
Megan Burke: Yale School of Medicine
Daniel Franjic: Yale School of Medicine
Hyesun Cho: Yale School of Medicine
Matthew Yuen: Yale School of Medicine
Ipsita Chatterjee: Yale School of Medicine
Paula Soric: Yale School of Medicine
Devippriya Esakkimuthu: Yale School of Medicine
Markus Moser: Techical University of Munich
Gabriel Santpere: Yale School of Medicine
Yann S. Mineur: Department of Psychiatry
Kartik Pattabiraman: Yale School of Medicine
Marina R. Picciotto: Yale Child Study Center
Hao Huang: Children’s Hospital of Philadelphia
Nenad Sestan: Yale School of Medicine

Nature, 2025, vol. 638, issue 8050, 469-478

Abstract: 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 behaviours1–5. Early-life disruptions in these circuits are linked to neuropsychiatric disorders4–8, 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.

Date: 2025
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DOI: 10.1038/s41586-024-08361-5

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