A quantitative analysis of TAAR1-positive cells in whole mouse brain by FDISCO technology

Abstract

Over the past two decades, studies on trace amine-associated receptor 1 (TAAR1), have substantially enhanced our understanding of their critical function in regulating monoamine neurotransmitter transmission. As a result, TAAR1 has emerged as a highly promising therapeutic target for treating psychiatric disorders. However, there is still no systematic analysis or detailed assessment for the distribution of TAAR1-positive cells throughout the brain until now. Herein, by applying CRISPR/Cas9-based approach and genetic labeling strategies, we constructed a TAAR1-Cre transgenic mouse and labeled TAAR1-positive cells with red fluorescence in whole brain. In combination with FDISCO technology, high-resolution imaging and automatic counting of stereoscopic cells, we conducted whole-brain three dimensions (3D) mapping, precise positioning and quantification of the TAAR1-positive cells. We found a diffuse distribution of TAAR1-positive cells throughout the brain. Higher number of TAAR1-positive cells were found in several brain regions including entorhinal area (ENT), sensory related area of medulla (MY-sen), Medial group of the dorsal thalamus (MED), basomedial amygdala (BMA), motor related area of medulla (MY-mot), and Cortical amygdala area (COA), all of which had more than 2,000. Moreover, the BMA and MED had the higher average density of TAAR1-positive cells compared to all of other subregions in the whole brain. In conclusion, this study unprecedentedly performed a systematic and exact whole-brain quantitative analysis of TAAR1-positive cells, providing a foundation for future investigations on the function of TAAR1 and TAAR1-positive cells, as well as delving deeper into the roles they play in the pathogenesis, development and treatment of multiple psychiatric disorders.