Selected as the cover story of Cell Reports in the issue of September 14th 2021 (https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01149-9), 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 Ministry of Science and Technology, Taiwan, and performed mainly by the PhD student Kai-Yi Wang (first author of this paper) in the laboratory of Professor Lien. 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. Dr. Jen-Kun Cheng (Mackay Memorial Hospital, Taiwan) helped established a chronic muscle pain mouse model. The calcium imaging data were analyzed by Dr. Chun-Chung Chen and the PhD student Jei-Wei Wu. The cover image was designed by Yu-Ling Tsai and Dr. Yu-Huan Tsai.
About the cover: Mossy cells are named for the characteristic moss-like spines found in patches on their proximal dendrites. The cover depicts a mossy cell as a lightning bolt in the night sky. In this issue, Wang et al. define a circuit-based role of how mossy cells regulate dentate granule cell and CA1 pyramidal cell spiking in mice exploring anxiogenic contexts. Image by Yu-Ling Tsai and Yu-Huan Tsai.
Left panel, the research team of Prof. Cheng-Chang Lien reports that activity of mossy cells correlates with the anxiogenic factors in the environments. Increased mossy cell activity (a red cell in the figure) when animals stay in open arms. Right panel, circuit mechanism of the anxiolytic effect underlying mossy cell activation in the hippocampus. Increased mossy cell activity leads to activation of local inhibitory cells in the dentate gyrus, finally resulting in suppression of hippocampal output.
Cheng-Chang Lien MD, PhD
Professor and Dean of the College of Life Sciences of National Yang Ming Chiao Tung University at Taipei, Taiwan.
Prof. Cheng-Chang Lien, MD, PhD
Institute of Neuroscience, College of Life Sciences
National Yang Ming Chiao Tung University
TEL: +886-2-2826-7325 (Lab office) -or- +886-2-2826-7200 (Dean office)
Department of Life Sciences
Ministry of Science and Technology