A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice

Authors: CAI, XING - Children'S Nutrition Research Center (CNRC); LIU, HAILAN - Children'S Nutrition Research Center (CNRC); FENG, BING - Louisiana State University; YU, MENG - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIANG, CHEN - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); ZHANG, NAN - Children'S Nutrition Research Center (CNRC); WANG, LINA - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); HAN, JUNYING - Children'S Nutrition Research Center (CNRC); YAN, ZILI - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - University Of Illinois; WU, QI - Children'S Nutrition Research Center (CNRC); TONG, QINGCHUN - University Of Texas Health Science Center; HE, YANLIN - Louisiana State University; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Nature Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/24/2022
Publication Date: 5/2/2022
Citation: Cai, X., Liu, H., Feng, B., Yu, M., He, Y., Liu, H., Liang, C., Yang, Y., Tu, L., Zhang, N., Wang, L., Yin, N., Han, J., Yan, Z., Wang, C., Xu, P., Wu, Q., Tong, Q., He, Y., Xu, Y. 2022. A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice. Nature Neuroscience. 25:646-658. https://doi.org/10.1038/s41593-022-01062-0.
DOI: https://doi.org/10.1038/s41593-022-01062-0

Interpretive Summary: This study investigated the interaction between dopamine (DA) and serotonin (5-HT) neurons in the brain and how they regulate feeding behaviors. The researchers found that DA neurons in the ventral tegmental area of the mouse brain can either inhibit or activate 5-HT neurons in the dorsal raphe nucleus, depending on the strength of the stimulation. This interaction was found to be involved in the development of anorexia-like behaviors in a mouse model. Additionally, the researchers found that blocking a specific type of dopamine receptor (DRD1) prevented anorexia and weight loss in the mice. These findings suggest that the interaction between DA and 5-HT neurons may contribute to the development of anorexia nervosa.

Technical Abstract: Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HTDRN neurons, which causes constant activation of these neurons and contributes to AN-like behaviors. Finally, we found that systemic administration of a DRD1 antagonist can prevent anorexia and weight loss in ABA. Our results revealed regulation of feeding behavior by stimulation strength-dependent interactions between DA and 5-HT neurons, which may contribute to the pathophysiology of AN.