Research shows that important brain proteins can influence the behavior of mice

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

The study, titled “Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive behavior and weakens reward motivation,” was published in Molecular psychiatry.

“This study examines the key regulators of brain activity through different mechanisms. Ultimately, a better understanding of these could lead to new treatments for neurological and psychiatric disorders,” said Weikang Cai, Ph.D., associate professor in the Department of Molecular and Cellular. Biochemistry at the College of Medicine and faculty at Barnstable Brown Diabetes and Obesity Research Center (BBDOC).

Cai is also the principal investigator on a National Institute of Mental Health grant that supported this work. He collaborated 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 examined 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 example, a protein called vesicular nucleotide transporter (Vnut) mediates the release of specific molecules, ATP, that normally provide energy to cells. Researchers wanted to know whether ATP released through 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 that this protein removal did not change brain structure, metabolism, or memory.

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

“We found that loss of Vnut in adult mice led to increased anxiety, depressive behavior and, most importantly, decreased motivation for reward, especially in females,” says Cai.

When tested in the open field, researchers said female mice spent most of their time against walls rather than in open space, indicating an anxious posture.

“The current study shows that the loss of Vnut in astrocytes is sufficient to induce depressive-like behavior in mice,” says Huang. “The same mechanisms that operate here may be involved in depression in humans.”

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

Finally, in assessing reward motivation, the research team trained their mice to poke a device with their noses to obtain food pellets containing sucrose. The sweetened food pellets provide a strong reward for normal mice.

When the difficulty of the task increased, or when more prodding was required to obtain the food, normal females continued to work for the reward pellets. In stark contrast, women who lacked Vnutty gave up on the task more quickly, meaning they were less motivated for reward – often a clinical sign of major depression in humans.

Importantly, Cai’s research group pinned reduced motivation for reward on reduced levels of dopamine, a ‘happy’ molecule in the brain that is crucial for motivational behavior in both rodents and humans.

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

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