Researchers identify potential therapeutic target for management of thirst disorders

CLEVELAND—The cerebellum, often referred to as the ‘little brain’, has captivated researchers for centuries due to its unique structure and cellular complexity, as one of the most ancient brain regions in evolutionary terms. It has traditionally been viewed only as a motor control center; however, recent studies have revealed its involvement in non-motor functions such as cognition, emotion, memory, autonomic function, satiety and meal termination.

In a recent mouse-model study, published in Nature Neuroscience, researchers at University Hospitals (UH), Harrington Discovery Institute at UH, and Case Western Reserve University have now found that the cerebellum also controls thirst, a major function necessary for survival. Specifically, the research team found that a hormone, asprosin, crosses from the periphery into the brain to activate Purkinje neurons in the cerebellum. This leads to an enhanced drive to seek and drink water.

“Asprosin, a hormone our lab discovered in 2016, is known to stimulate food intake and maintain body weight by activating key ‘hunger’ neurons in a part of the brain called the hypothalamus, and works by binding a protein on the neuron surface called a ‘receptor,’” explained Atul Chopra, MD, PhD, senior author on the study, Investigator at Harrington Discovery Institute at UH and Associate Director of the Harrington Rare Disease Program, Attending Medical Geneticist at UH, and Associate Professor of Medicine, and Genetics and Genomics at Case Western Reserve School of Medicine.

A receptor is necessary for a hormone to work, and in the case of asprosin’s ability to control appetite and body weight, that receptor is Ptprd. Besides the hypothalamus, the team found that it is also highly expressed in the cerebellum, although the functional significance of this was unknown.

“At the outset, we wondered whether asprosin action in the cerebellum was to coordinate food intake with the hypothalamus, which turned out to be incorrect. The breakthrough came when Ila Mishra, a postdoctoral fellow in the lab, and now the head of her own lab at the University of Kentucky, discovered that mice generated to lack cerebellar responsiveness to asprosin exhibited reduced water intake. Our intended endpoint was measurement of food intake, not water intake, making this a serendipitous observation.”

These mice also showed reduced Purkinje neuron activity accompanied by hypodipsia (reduced feelings of thirst). Their food intake, motor coordination, and learning remained unaffected. By contrast, mice generated to preclude hypothalamic responsiveness to asprosin show reduced food intake without impacting thirst.

“Our results identified not only a new function of cerebellar Purkinje neurons in the modulation of thirst, but also its independent regulation from their well-established role in motor coordination and learning,” added Dr. Chopra. “It is fascinating that after a century or more of neuroscience, we are still discovering major new functions of parts of the brain long thought to be understood. The broader implication of this discovery lies in its potential to inform the management of thirst disorders like polydipsia (excessive thirst), hypodipsia and adipsia, for which no current treatments exist.”

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Mishra, I., Feng, B., Basu, B. et al. The cerebellum modulates thirst. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01700-9

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 23 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Northeast Ohio Medical University, Oxford University and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.

About Harrington Discovery Institute at University Hospitals
The Harrington Discovery Institute at University Hospitals in Cleveland, OH – part of The Harrington Project for Discovery & Development – aims to advance medicine and society by enabling our nation’s most inventive scientists to turn their discoveries into medicines that improve human health. The institute was created in 2012 with a $50 million founding gift from the Harrington family and instantiates the commitment they share with University Hospitals to a Vision for a ‘Better World’. For more information, visit: HarringtonDiscovery.org.

Case Western Reserve University is one of the country's leading private research institutions. Located in Cleveland, we offer a unique combination of forward-thinking educational opportunities in an inspiring cultural setting. Our leading-edge faculty engage in teaching and research in a collaborative, hands-on environment. Our nationally recognized programs include arts and sciences, dental medicine, engineering, law, management, medicine, nursing and social work. About 6,200 undergraduate and 6,100 graduate students comprise our student body. Visit case.edu to see how Case Western Reserve thinks beyond the possible