Scientists discover orexin neurons sustain motivation in rats

Researchers at Nagoya University in Japan have identified a brain mechanism that helps sustain motivation when challenges increase. Their study, published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) on August 5, 2026, shows that orexin neurons play a crucial role in maintaining motivated behavior.

The findings affect understanding of conditions like depression, addiction, and ADHD, where loss of motivation is common. The research team, led by associate professor Hiroyuki Mizoguchi and professor emeritus Kiyofumi Yamada at the Graduate School of Medicine, focused on orexin neurons, which also regulate sleep, appetite, and energy expenditure.

This discovery is significant because scientists have not fully understood the brain processes behind motivational difficulties. The study provides a potential mechanism by which the brain links reward expectations to the effort required, offering a new target for addressing motivational deficits.

Using genetically modified "orexin-Cre" rats, the team manipulated orexin neurons with chemogenetics and optogenetics. In progressive ratio tests, rats with activated orexin neurons reached higher breakpoints, showing increased willingness to work for food rewards. Conversely, rats with degenerated orexin neurons had lower breakpoints, indicating reduced motivation. Fiber photometry revealed that orexin neuron activity rose during reward anticipation and fell after reward delivery, but remained high when expected rewards were withheld, and intensified with greater effort demands.

Previous research suggested orexin neurons affect motivation, but their specific role was unclear. Earlier studies typically used mice, but rats offer stronger learning abilities for complex tasks. The new rat model overcame technical challenges in targeting these neurons. Optogenetic suppression of orexin neurons reduced motivated behavior, while activation did not further increase motivation, suggesting these neurons are necessary but not sufficient for boosting drive beyond normal levels.

The researchers plan to examine the brain circuits that communicate with orexin neurons. A clearer understanding could lead to new approaches for treating motivational impairments. The study was supported by grants including 22K19749, 23K27360, and 23H02669 from the Japan Society for the Promotion of Science, along with funding from organizations such as the SENSHIN Medical Research Foundation and AMED (JP21wm0425014).