How stress rewires the brain: insights into anxiety and depression—and paths to healing

Anxiety disorders and depression are among the most prevalent and disabling mental health conditions worldwide, profoundly affecting both individual well-being and societal productivity.

“Our review shows that over the past two decades, the prevalence of anxiety and depression has continued to rise. In 2021 alone, nearly 700 million people were affected globally. Together, these disorders account for more than 90 million years of healthy life lost each year,” says Prof. Wei-Hua Yue, dean of the Peking University Sixth Hospital, and one of the corresponding authors of the review. “The COVID-19 pandemic further fueled this trend, adding tens of millions of new cases in 2020. The numbers are truly alarming.”

Prof. Yue emphasized that current treatments, while helpful, remain far from ideal. “Not all patients respond well. Side effects such as weight gain and emotional blunting are common, and effective options for treatment-resistant cases or older adults are limited,” she noted. “This reality makes it essential to explore the underlying biological mechanisms of these disorders, which will be crucial for advancing precision psychiatry and tailoring interventions to individual needs.”

The newly published review offers a comprehensive analysis of the pathological mechanisms of anxiety and depression, covering neurotransmitter imbalances, neural circuit dysfunction, neuroendocrine disturbances, neuroinflammation, genetic vulnerabilities, and brain-body interactions. Of these, the focus on abnormal neural circuits represents one of the most significant advances in neuroscience in recent years.

“We think of neural circuits as the brain's intricate wiring system—networks of neurons that communicate to regulate specific functions, such as processing emotions or making decisions. Rather than studying brain regions in isolation, this approach examines how different regions connect and work together dynamically, much like an electrical grid powering a city. By studying neural activity at the single-cell and population levels, and by experimentally modulating circuit function, we can link brain networks to behavior and symptoms.” explained Prof. Bing-Xing Pan, dean of Institute of Biomedical Innovation, Nanchang University, the lead researcher of the newly published study. “For instance, we recently identified that the hyperactivity in the prefrontal-amygdala circuit is strongly linked to anxiety-like behaviors, while reduced function in the hippocampus-nucleus accumbens circuit is associated with anhedonia, a core symptom of depression. Moreover, overactivation of the lateral habenula, often called the brain’s ‘anti-reward center,’ can significantly drive depression-like behaviors. These insights not only expand our understanding of emotional disorders but also highlight new targets for neuromodulation and circuit-based therapies.”

Looking ahead, the researchers stress the importance of bridging basic neuroscience with clinical application. “Future studies should integrate cutting-edge technologies with clinical practice, accelerate the discovery of reliable biomarkers, and support the development of cross-diagnostic treatments” said Prof. Qi-Gang Zhou, of Nanjing Medical University and co-corresponding author of the study. “These efforts will be vital for building more precise, effective, and comprehensive strategies to manage mental health disorders.”