A dual-pathway architecture for stress to disrupt agency and promote habit

Jacqueline R. Giovanniello, Natalie Paredes, Anna Wiener, Kathia Ramírez-Armenta, Chukwuebuka Oragwam, Hanniel O. Uwadia, Abigail L. Yu, Kayla Lim, Jenna S. Pimenta, Gabriela E. Vilchez, Gift Nnamdi, Alicia Wang, Megha Sehgal, Fernando MCV Reis, Ana C. Sias, Alcino J. Silva, Avishek Adhikari, Melissa Malvaez and Kate M. Wassum ()
Additional contact information
Jacqueline R. Giovanniello: University of California, Los Angeles
Natalie Paredes: University of California, Los Angeles
Anna Wiener: University of California, Los Angeles
Kathia Ramírez-Armenta: University of California, Los Angeles
Chukwuebuka Oragwam: University of California, Los Angeles
Hanniel O. Uwadia: University of California, Los Angeles
Abigail L. Yu: University of California, Los Angeles
Kayla Lim: University of California, Los Angeles
Jenna S. Pimenta: University of California, Los Angeles
Gabriela E. Vilchez: University of California, Los Angeles
Gift Nnamdi: University of California, Los Angeles
Alicia Wang: University of California, Los Angeles
Megha Sehgal: University of California, Los Angeles
Fernando MCV Reis: University of California, Los Angeles
Ana C. Sias: University of California, Los Angeles
Alcino J. Silva: University of California, Los Angeles
Avishek Adhikari: University of California, Los Angeles
Melissa Malvaez: University of California, Los Angeles
Kate M. Wassum: University of California, Los Angeles

Nature, 2025, vol. 640, issue 8059, 722-731

Abstract: Abstract Chronic stress can change how we learn and, thus, how we make decisions1–5. Here we investigated the neuronal circuit mechanisms that enable this. Using a multifaceted systems neuroscience approach in male and female mice, we reveal a dual-pathway, amygdala–striatal neuronal circuit architecture by which a recent history of chronic stress disrupts the action–outcome learning underlying adaptive agency and promotes the formation of inflexible habits. We found that the projection from the basolateral amygdala to the dorsomedial striatum is activated by rewarding events to support the action–outcome learning needed for flexible, goal-directed decision-making. Chronic stress attenuates this to disrupt action–outcome learning and, therefore, agency. Conversely, the projection from the central amygdala to the dorsomedial striatum mediates habit formation. Following stress, this pathway is progressively recruited to learning to promote the premature formation of inflexible habits. Thus, stress exerts opposing effects on two amygdala–striatal pathways to disrupt agency and promote habit. These data provide neuronal circuit insights into how chronic stress shapes learning and decision-making, and help understanding of how stress can lead to the disrupted decision-making and pathological habits that characterize substance use disorders and mental health conditions.

Date: 2025
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DOI: 10.1038/s41586-024-08580-w

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