Divergent and Subnucleus-Specific Gene Expression Responses to Chronic Stress Hormone Exposure in the Amygdala

Shuhei Ueda¹Manami Kakita¹Masahito Hosokawa²Koji Arikawa²Kiyofumi Takahashi²Ryusuke Shiota¹Masaki Kakeyama²Hiroko Matsunaga¹Haruko Takeyama¹Sayaka Takemoto-Kimura^1*

• ¹Nagoya University, Nagoya, Japan
• ²Waseda Daigaku, Shinjuku, Japan

Major depressive disorder (MDD) is one of the most prevalent mental disorders, posing a significant socioeconomic burden worldwide. Its development involves both genetic and environmental factors, among which chronic stress is considered a major contributor. The amygdala, a key brain region for emotional regulation, is critically implicated in MDD pathophysiology. Given its complex subnuclear architecture, it is essential to characterize stress-induced molecular changes at the level of individual subnuclei. To investigate subnucleus-specific molecular adaptations to chronic stress, we performed RNA sequencing on fluorescence-guided micropunch samples from five amygdala-related subnuclei in mice exposed to chronic corticosterone (CORT): the basolateral amygdala (BLA), the lateral and medial central amygdala (CeL, CeM), and the oval and fusiform bed nuclei of the stria terminalis (BNSTov, BNSTfu). Comparative transcriptomic analysis revealed highly divergent and subnucleus-resolved gene expression responses to chronic CORT exposure. Each subregion exhibited unique profiles of differentially expressed genes, implicating alterations in excitatory–inhibitory synaptic balance, glial functions involving oligodendrocytes or astrocytes, and neuropeptide signaling. Our results uncover the molecular heterogeneity of subnucleus-specific responses within the amygdala. These findings highlight the importance of anatomically resolved analyses in elucidating the biological basis of stress-related mental disorders such as MDD, thereby paving the way for more targeted therapeutic strategies.