Water is crucial to human survival, composing about 60% of the body. It plays a vital role in cellular function, internal temperature regulation and organ health.
Without sufficient water, the body's processes rapidly fail, leading to death within just a few days. Thirst is the brain's warning sign of dehydration. But being consistently thirsty (or not thirsty at all) could be signs of other health problems.
A researcher at the University of Kentucky is among a group of scientists who are some of the first to find a new role for the cerebellum — a brain region traditionally associated with movement and balance — in regulating thirst.
Ila Mishra, Ph.D., an assistant professor in the Division of Endocrinology, Diabetes and Metabolism in the College of Medicine's Department of Internal Medicine, was one of the lead authors on the study recently published in Nature Neuroscience.
This study was led by Atul Chopra, M.D., Ph.D., and his lab at Harrington Discovery Institute at University Hospitals in Cleveland, Ohio, where Mishra previously conducted this research before joining UK in 2023.
"The cerebellum has a unique structure and complex cells," said Mishra. "It's fascinated researchers for centuries because it's one of the most ancient brain regions in evolutionary terms."
Recent studies have expanded understanding of the cerebellum, linking it to cognition, sensation, emotion and autonomic functions. This research highlights the cerebellum's involvement in thirst regulation. Previously, this role was attributed to other brain regions responsible for sensing and regulating internal water balance.
"Our study shows that mice drink more water when the cerebellar neurons called Purkinje neurons, one of the very first neuronal types to be recognized and amongst the largest neurons of the brain, are activated by the hormone asprosin," Mishra explained.
This study reports that activation of these neurons by asprosin resulted in immediate drinking behavior in mice and deletion of the asprosin receptor from these cells reduced water intake.
"Asprosin is a protein hormone that was discovered in 2016. It has been shown to activate the hypothalamic 'hunger' neurons called AgRP neurons," said Mishra. "In 2022, we identified Ptprd as the neural receptor through which asprosin acts to stimulate appetite. It was interesting to see that this receptor, Ptprd is highly expressed in the cerebellum, but we just didn't know what it does there.
"It is fascinating how asprosin affects both appetite and thirst, but via different brain pathways," Mishra said. "While asprosin stimulates appetite via the AgRP neurons, its action on cerebellar Purkinje neurons triggers increased water intake."
Researchers said targeting the Purkinje neuronal asprosin signaling pathway could become a potential therapeutic approach for treating thirst disorders like polydipsia (feeling extremely thirsty) and hypodipsia (not feeling thirst). However, the team said further study is needed to better understand what's going on in the brain during this process.
"Our findings highlight a powerful and clinically relevant neural circuit for the modulation of thirst," said Mishra.
The research team included scientists from the University of Kentucky, Case Western Reserve University, University Hospitals Cleveland Medical Center, Louisiana State University, Baylor College of Medicine, Texas Children's Hospital and the University of Dayton.
