Human amygdala-like telencephalic organoids model stress circuitry in assembloid systems.

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.