Integrating GABA and dopamine signals to regulate meal initiation

"It's well known that serotonin, a neurotransmitter in the brain, can suppress food intake. This finding led to the development of drugs that interact with serotonin or its receptors to regulate food consumption and obesity," said corresponding author Dr. Yong Xu, professor of pediatrics -- nutrition and associate director of basic sciences at the USDA/ARS Children's Nutrition Research Center at Baylor. "However, some of these drugs have unwanted side effects, and they are no longer offered to patients. There is a need to better understand how the brain regulates food intake to improve drug design."

The Xu lab and colleagues have been studying the role of serotonin on feeding control for quite a long time. In this study, they focused on a little-known component of the serotonin regulation of food intake. They looked for brain circuits and neurotransmitters that regulate the activity of serotonin-producing neurons, activating or inhibiting them at the appropriate periods to reach balanced food consumption. "We asked, how can we leverage this system to regulate feeding?" Xu said.

Serotonin is primarily synthesized by neurons in the dorsal Raphe nucleus (DRN) in the midbrain. Serotonin neurons in the DRN project to numerous brain regions, including the arcuate of the hypothalamus (ARH). The team showed that the ARH circuit and two neurotransmitters, GABA and dopamine, play a key role in meal initiation.

"Working with animal models, we found that when the animals are hungry, serotonin-producing neurons in the DRN are inhibited by GABA and dopamine. This reduces the levels of serotonin in the brain, which allows the initiation of a meal," Xu explained. "As the animals feed and reach satiety, the inhibitory signals on serotonin neurons are reduced and more serotonin is produced to inhibit feeding via projections to the ARH."

"What's unique about this is that GABA and dopamine act synergistically - when both are present, serotonin neurons appear to be more inhibited than when only one of the neurotransmitters is present," Xu said.

This work is important because it improves our understanding of how the brain manages body weight and feeding, specifically the roles of neurotransmitters in a specific phase of feeding behavior, meal initiation. This knowledge can inform the development of improved obesity drugs.

"Looking forward, we are interested in identifying signals that regulate the other phases of feeding," Xu said.

Other contributors to this work include Kristine M. Conde, Huey Zhong Wong, Shuzheng Fang, Yongxiang Li, Meng Yu, Yue Deng, Qingzhuo Liu, Xing Fang, Mengjie Wang, Yuhan Shi, Olivia Z. Ginnard, Yuxue Yang, Longlong Tu, Hesong Liu, Hailan Liu, Na Yin, Jonathan C. Bean, Junying Han, Megan E. Burt, Sanika V. Jossy, Yongjie Yang, Qingchun Tong, Benjamin R. Arenkiel, Chunmei Wang and Yang He. The authors are affiliated with Baylor College of Medicine or the University of Texas Health Science Center at Houston.

This work was supported by USDA/CRIS (grants 51000-064-01S, 3092-51000-062-04(B)S), National Institutes of Health (grants R01DK120858, F32DK134121, R01DK131446) and American Heart Association (grant 23POST1030352).