Summary: A new study has identified a brain protein, vesicular nucleotide transporter (Vnut), as essential for regulating mood and motivation in mice. When Vnut was removed from brain cells called astrocytes, the mice displayed higher anxiety, depression-like behavior, and decreased motivation, especially in females.
This effect was linked to reduced dopamine, a key molecule for motivation and positive mood. These findings suggest Vnut plays a vital role in dopamine regulation, with potential implications for understanding mood disorders.
Key Facts:
- Removing Vnut from astrocytes increased anxiety and depressive-like behaviors in mice.
- Female mice lacking Vnut had notably reduced motivation for rewards, a trait associated with depression.
- The effects were linked to lower dopamine levels, key for motivation and emotional regulation.
Source: University of Kentucky
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 in Molecular Psychiatry.
“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 in 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 a 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.
About this neuroscience research news
Author: Sara Macias Palacio
Source: University of Kentucky
Contact: Sara Macias Palacio – University of Kentucky
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward” by Qian Huang et al. Molecular Psychiatry
Abstract
Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward
Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity.
Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP.
Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content.
Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability.
These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens.
Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases.
Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry.
