Unveiling Anxiety-Related Brain Circuits in the Hippocampus


Selected as the cover story of Cell Reports in the issue of September 14th 2021, the study led by the Distinguished Professor Cheng-Chang Lien at National Yang Ming Chiao Tung University uncovers an anxiety-related cell, which mediates anxiolytic effects. This study has filled a gap between the brain circuits and behavior and sheds light on the prospect of brain circuit intervention in mental disorders.

Anxiety disorders are common mental disorders and have a striking impact on the global burden of disease. Despite their public health significance, the pathophysiology of anxiety remains unclear. Developing intervention strategies against anxiety disorders is an unmet need. In addition to well-known functions such as navigation and memory, the hippocampus plays a critical role in emotional regulation. In light of this view, Professor Cheng-Chang Lien and his research team have devoted themselves to investigating the relationship between brain circuits and anxiety.

Taking advantage of mouse genetics, the research team reports that activity of mossy cells, a type of glutamatergic neurons located in the hippocampal dentate gyrus, correlates with the anxiogenic factors in the environment. Interestingly, mossy cell activity preferentially increases when mice explore the anxiogenic environment (e.g., in bright and open space). They further employ a chemogenetic approach to manipulate mossy cell activity selectively and find that elevating mossy cell activity decreases animals’ avoidance behavior (anxiety-like behavior).

The information processed in the dentate gyrus is transferred to the hippocampal output region via canonical tri-synaptic circuits. Under the MOST-HAS international collaboration project, the research team collaborates with Dr. Gábor Tamás at University of Szeged, Hungary to record in vivo neuronal activity along the tri-synaptic circuits upon mossy cell activation. They find that mossy cells preferentially activate inhibitory cells in the dentate gyrus, thereby suppressing the hippocampal output. These findings support an anxiolytic role of mossy cells.

The research team further translates their findings from basic research to preclinical studies and demonstrates an anxiolytic effect of mossy cells on fibromyalgia syndrome, a chronic muscle pain disorder with comorbid psychiatric disorders.

This study was supported by the National Health Research Institute and the Ministry of Science and Technology, Taiwan. Dr. Kazu Nakazawa (University of Alabama at Birmingham, USA) provided the transgenic mice. Gábor Tamás (University of Szeged, Hungary) and his research team helped set up the in vivo juxtacellular recording technique.


From the left: Assistant Professor Yu-Huan Tsai of NYCU Institute of Microbiology and Immunology, the artist Mr.Yu-Lin Tsai, Professor Cheng-Chang Lien(Project host)of NYCU College of Life Science,  Ministry of Science and Technology Life Science Department Manager Hong-Chen Chen, Institute of Neuroscience Ph.D. student Kai-Yi Wang(First author), Contracted Part-time Assistant Professor Chun-Chung Chen, Ph.D. student Che-Wei Wu

Related link:https://www.nycu.edu.tw/news/2546/


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