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Yale School of Medicine

Cell Stem Cell, May 25, 2026 | https://doi.org/10.1016/j.stem.2026.04.021 Human amygdala-like telencephalic organoids model stress circuitry in assembloid systems

Woo Sub Yang,^1,14Mu Seog Choe,^1,14 Cynthia Lo,¹ Hui-Wen Liu,³ Yoon Mi Cho,¹ Jonghun Kim,¹ Ferdi Ridvan Kiral,¹Michael Scandura,¹ Xiaona Lu,² Kun-Yong Kim,² Kyuhwan Na,⁴ Caihong Qiu,¹ Fan Wu,⁸ Andrew Dirks,⁸Rebecca Mathew,⁹Bilal Cakir,⁹ Hyuk-Jin Cha,¹⁰Sangwon F. Kim,¹¹ Andrew Cox,¹Seok Chung,^3,5,6,7 Yong-Hui Jiang,²Kunyoo Shin,¹² Sang-Hun Lee,¹³and In-Hyun Park ^1,15,*

¹Department of Genetics, Interdepartmental Neuroscience Program, Yale Stem Cell Center, Yale Child Study Center, Wu Tsai Institute, Yale School of Medicine, New Haven, CT 06520, USA
²Department of Genetics, Pediatrics, Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
³School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
⁴Life solution team, Samsung Research, Samsung Electronics, Seoul R&D Campus, 33 Seongchon-gil, Secho-gu, Seoul 06765, Republic of Korea
⁵KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
⁶Absology, Anyang 14057, Republic of Korea
⁷Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
⁸Diagnostic Biochips Inc., Glen Burnie, MD, USA
⁹Data, AI & Genome Sciences, Merck & Co., Inc., Cambridge, MA, USA
¹⁰College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
¹¹Department of Medicine, and Neuroscience, Johns Hopkins University, Baltimore, MD 21224, USA
¹²Institute of Molecular Biology and Genetics, School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea
¹³Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
¹⁴These authors contributed equally
¹⁵Lead contact

^*Corresponding author: correspondence to In-Hyun Park

Abstract

Human emotional and stress responses are orchestrated by subcortical limbic circuits, with the amygdala playing a central role in integrating affective, sensory, and endocrine signals. Despite the urgent need to understand how these circuits develop and contribute to anxiety and stress-related disorders, progress has been hindered by lack of ex vivo human models. Here, we generated human amygdala-like telencephalic organoids (hATOs) that recapitulate cellular composition, region-specific development, and key features of the amygdala. By assembling hATOs with a hypothalamic organoid (hypoTO) with paraventricular nucleus (PVN)-like features, we modeled the amygdala-hypothalamus-like interaction, which enabled circuit-level analysis of stress-responsive signaling. Exposure to cortisol led to robust upregulation of BCYRN1, a primate-specific retrotransposon-derived noncoding RNA, which uncovered a previously unrecognized mechanism of stress hormone signaling to retrotransposon biology and human-specific synaptic regulation. These findings highlight the potential of hATOs to understand molecular features of affective circuitry underlying emotion and the stress response and neuropsychiatric disorders.

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