Researchers at the University of Kentucky were part of a team that discovered a key protein in the brain that can regulate motivation for reward in mice.

The study, titled “Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward,” was published earlier this year in Molecular Psychiatry, a journal in the prestigious Nature Portfolio.

“This study explores the important regulators of brain activity through various mechanisms. Ultimately, understanding this better could lead to new treatments for neurological and psychiatric conditions,” said Weikang Cai, Ph.D., an associate professor in the Department of Molecular and Cellular Biochemistry in the College of Medicine and faculty in the Barnstable Brown Diabetes and Obesity Research Center (BBDOC).

Cai is also the principal investigator of a grant from the National Institute of Mental Health that supported this work. He worked with Qian Huang, Ph.D., a research assistant professor in the Department of Molecular and Cellular Biochemistry and first author of this paper.

The team of scientists investigated astrocytes, a type of cell in the brain that supports the central nervous system. These cells are known to release molecules to communicate with neurons and are necessary for proper brain function. For instance, a protein called Vesicular Nucleotide Transporter (Vnut) mediates the release of specific molecules, ATP, which usually provide energy to cells. Researchers wanted to learn if ATP released via Vnut is important for any brain function.

To investigate the functional significance of Vnut, researchers removed this protein from the astrocytes in their mouse model and then analyzed the mice’s behavior. Researchers found this protein deletion did not alter brain structure, metabolism or memory.

The team also looked at the loss of Vnut on anxiety and depression-like behavior in the mice through open field tests and a reward test.

“We found the loss of Vnut in adult mice led to increased anxiety, depressive-like behaviors and, more importantly, decreased motivation for reward, especially in females,” said Cai.

In open field tests, researchers said female mice spent most of their time against the walls instead of the open area, which is indicative of an anxious demeanor.

“The present study demonstrates that loss of Vnut in astrocytes is enough to induce depressive-like behavior in mice,” said Huang. “The same mechanisms working here could be implicated in depression in humans.”  

Scientists marked changes in behavioral variables in the mice, specifically a lack of interest and increased immobility during swimming tests.

Finally, when assessing motivation for reward, the research team trained their mice to poke a device with their nose to obtain food pellets that contain sucrose. The sweetened food pellets provide strong reward to normal mice. When the task difficulty was increased, or when more pokes were needed to obtain the food, normal females continued to work for the reward pellets. In stark contrast, females who lacked Vnut gave up faster on the task, meaning they have reduced motivation for reward — often a clinical sign for major depression in humans.

Importantly, Cai’s research group pinpointed the reduced motivation for reward to the reduced level of dopamine, a “happy” molecule in the brain critical for motivational behavior in both rodents and humans.

The findings from this study suggest that Vnut is a key protein in the regulation of dopamine signals in the brain, mood and motivation, loss of which results in functional consequences including anxiety, depressive-like behavior and a reduction in the motivation for reward.

“This discovery helps us understand how specific proteins in certain brain regions influence emotions and behavior, providing new approaches for future research about mood disorders,” said Cai.

This study brought together a team of researchers from New York Institute of Technology College of Osteopathic Medicine, New York Medical College, Tufts University School of Medicine in Boston, Harvard Medical School, and Zhongshan Hospital and Fudan University in Shanghai.

Research reported in this publication was supported by the National Insitute of Mental Health of the National Institutes of Health under Award Number R01MH125903 and by the National Institute of Aging of the National Institues of Health under Award Number R03AG083363. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.