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 de 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; Nenad Sestan

doi:10.1038/s41586-024-08361-5

Specification of claustro-amygdalar and palaeocortical neurons and circuits

Nature. 2025 Jan 15. doi: 10.1038/s41586-024-08361-5. Online ahead of print.

Authors

Navjot Kaur¹, Rothem Kovner¹, Forrest O Gulden¹, Mihovil Pletikos¹, David Andrijevic¹, Tianjia Zhu^{2

3}, John Silbereis¹, Mikihito Shibata¹, Akemi Shibata¹, Yuting Liu¹, Shaojie Ma⁴, Nikkita Salla^{1

5}, Xabier de Martin⁶, Thomas S Klarić¹, Megan Burke¹, Daniel Franjic¹, Hyesun Cho¹, Matthew Yuen^{1

5}, Ipsita Chatterjee¹, Paula Soric¹, Devippriya Esakkimuthu^{1

5}, Markus Moser⁷, Gabriel Santpere^{1

6}, Yann S Mineur⁸, Kartik Pattabiraman^{1

5

9}, Marina R Picciotto^{5

8

10}, Hao Huang^{2

11}, Nenad Sestan^{12

13

14

15

16

17

18

19}

Affiliations

¹ Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
² Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁵ Yale Child Study Center, New Haven, CT, USA.
⁶ Neurogenomics Group, Hospital del Mar Research Institute, PRBB, Barcelona, Spain.
⁷ Institute of Experimental Hematology, School of Medicine, Techical University of Munich, Munich, Germany.
⁸ Department of Psychiatry, New Haven, CT, USA.
⁹ Wu Tsai Institute, Yale University, New Haven, CT, USA.
¹⁰ Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA.
¹¹ Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹² Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. [email protected].
¹³ Yale Child Study Center, New Haven, CT, USA. [email protected].
¹⁴ Department of Psychiatry, New Haven, CT, USA. [email protected].
¹⁵ Wu Tsai Institute, Yale University, New Haven, CT, USA. [email protected].
¹⁶ Department of Comparative Medicine, Yale University, New Haven, CT, USA. [email protected].
¹⁷ Department of Genetics, Yale University, New Haven, CT, USA. [email protected].
¹⁸ Kavli Institute for Neuroscience, Yale University, New Haven, CT, USA. [email protected].
¹⁹ Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA. [email protected].

PMID: 39814878
DOI: 10.1038/s41586-024-08361-5

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 behaviours^1-5. Early-life disruptions in these circuits are linked to neuropsychiatric disorders^4-8, 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.