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

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Subcortical limbic circuits, particularly the amygdala, are crucial for human emotional and stress responses.
• Understanding the development of these circuits is vital for addressing anxiety and stress-related disorders.
• A lack of suitable ex vivo human models has limited research progress.

Purpose of the Study:

• To generate human amygdala-like telencephalic organoids (hATOs) that mimic the amygdala's cellular and developmental characteristics.
• To model amygdala-hypothalamus interactions using hATOs and hypothalamic organoids (hypoTOs).
• To investigate stress hormone signaling pathways and their impact on retrotransposon biology and synaptic regulation.

Main Methods:

• Generation of human amygdala-like telencephalic organoids (hATOs).
• Co-culturing hATOs with hypothalamic organoids (hypoTOs) to simulate amygdala-hypothalamus circuitry.
• Analysis of gene expression changes, specifically BCYRN1 upregulation, following cortisol exposure.

Main Results:

• hATOs successfully recapitulated key features of the human amygdala, including cellular composition and regional development.
• The integrated hATOs-hypoTO model enabled circuit-level analysis of stress responses.
• Cortisol exposure led to significant upregulation of BCYRN1, a primate-specific retrotransposon-derived noncoding RNA.
• A novel mechanism linking stress hormone signaling to retrotransposon activity and human-specific synaptic regulation was identified.

Conclusions:

• hATOs provide a valuable ex vivo model for studying the human amygdala and its role in affective circuitry.
• This model facilitates the investigation of molecular mechanisms underlying emotion, stress response, and neuropsychiatric disorders.
• The study uncovered a new pathway involving cortisol, BCYRN1, and synaptic regulation relevant to human brain function and evolution.