Key Brain Protein Tied to Motivation and Mood Identified






A new study has found that a brain protein called vesicular nucleotide transporter (Vnut) plays a key role in controlling mood and motivation in mice. When researchers removed Vnut from brain cells known as astrocytes, the mice showed increased anxiety, signs of depression, and lower motivation—particularly in females.  


The changes were linked to a drop in dopamine, a chemical important for motivation and maintaining a positive mood. These findings highlight Vnut’s importance in regulating dopamine, offering new insights into the possible causes of mood disorders.



Key Facts:  

- Removing Vnut from astrocytes led to increased anxiety and depression-like behaviors in mice.  

- Female mice without Vnut showed a significant drop in motivation for rewards, a common symptom of depression.  

- These behavioral changes were tied to reduced dopamine levels, a critical neurotransmitter for motivation and emotional balance.  

- Researchers at the University of Kentucky contributed to the discovery of this protein’s role in regulating motivation 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 research examines crucial regulators of brain function through multiple mechanisms. Gaining deeper insights could pave the way for new treatments for neurological and psychiatric disorders,” said Weikang Cai, Ph.D., an associate professor in the Department of Molecular and Cellular Biochemistry at the University of Kentucky’s College of Medicine and a faculty member at the Barnstable Brown Diabetes and Obesity Research Center (BBDOC).


Weikang Cai, Ph.D., likewise fills in as the foremost specialist of an award from the Public Organization of Psychological well-being that supported this examination. He teamed up with Qian Huang, Ph.D., an exploration collaborator teacher in the Division of Sub-atomic and Cell Organic chemistry and the main creator of the review.




 

“We found that the deficiency of Vnut in grown-up mice brought about elevated nervousness, burdensome like ways of behaving, and, most outstandingly, decreased inspiration for remunerations — especially in females," said Cai.


During open field tests, the specialists saw that female mice would in general remain close to the walls as opposed to investigating the open region, a way of behaving that signs expanded tension.


"The current review shows that the deficiency of Vnut in astrocytes alone is sufficient to set off burdensome like conduct in mice," said Huang. "Similar systems may likewise assume a part in human discouragement."


The researchers noted key behavioral changes in the mice, including reduced interest and increased immobility during swimming tests, both indicators of depressive-like behavior.  


To assess motivation, the team trained the mice to poke a device with their nose to receive sucrose-infused food pellets—a strong incentive for typical mice. However, the Vnut-deficient mice displayed lower motivation to pursue these rewards.



When the task became more challenging—requiring more nose pokes to obtain food—normal female mice kept working for the reward. In contrast, females lacking Vnut gave up much sooner, indicating reduced motivation, a hallmark symptom of major depression in humans.  


Cai’s team traced this decline in motivation to lower dopamine levels. Dopamine, often called the brain’s “happy” molecule, plays a crucial role in driving motivation and positive behavior in both rodents and humans.



The review's discoveries feature Vnut as a pivotal protein for managing dopamine flagging, temperament, and inspiration. Its misfortune prompts critical conduct impacts, including expanded tension, burdensome like way of behaving, and decreased inspiration for remunerations.


"This disclosure reveals insight into what explicit proteins in specific mind districts mean for feelings and conduct," said Cai. "It opens new roads for future investigation into temperament problems."



Astrocytes are multifunctional glial cells in the central nervous system, essential for regulating metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. A key aspect of their function involves releasing signaling molecules, including ATP, through vesicular exocytosis.  


In this study, the researchers used a specialized genetic mouse model to explore the importance of astrocytic ATP release. Experiments with primary cultured astrocytes revealed that the loss of vesicular nucleotide transporter (Vnut)—the key transporter that loads ATP into secretory vesicles—significantly reduced ATP loading into lysosomes and ATP release. Notably, this disruption occurred without affecting the molecular machinery for exocytosis or the total amount of ATP inside the cells.


Astrocytes are multifunctional glial cells in the focal sensory system, fundamental for controlling digestion, extracellular particle and synapse levels, and synaptic versatility. A vital part of their capability includes delivering flagging particles, including ATP, through vesicular exocytosis.


In this review, the scientists utilized a particular hereditary mouse model to investigate the significance of astrocytic ATP discharge. Explores different avenues regarding essential refined astrocytes uncovered that the deficiency of vesicular nucleotide carrier (Vnut) — the key carrier that heaps ATP into secretory vesicles — fundamentally decreased ATP stacking into lysosomes and ATP discharge. Prominently, this interruption happened without influencing the atomic hardware for exocytosis or the aggregate sum of ATP inside the cells.



The deletion of astrocytic Vnut in adult mice results in heightened anxiety, depressive-like behaviors, and reduced motivation for rewards, particularly in females. Importantly, this change occurs without significant effects on food intake, overall glucose metabolism, cognitive function, or sociability.  


These behavioral changes are linked to notable reductions in basal extracellular dopamine levels in the nucleus accumbens. Furthermore, ex vivo brain slices from these mice demonstrate a pronounced trend toward decreased evoked dopamine release in the nucleus accumbens.


Mechanistically, the observed decrease in dopamine signaling is likely attributed to an increased expression of monoamine oxidases.  


Collectively, these findings highlight the critical role of astrocytic ATP exocytosis in modulating anxiety, depressive-like behaviors, and motivation for rewards by regulating the mesolimbic dopamine circuitry.