What enables us to sustain effort toward goals, even when the task becomes increasingly difficult? A recent study by researchers at Nagoya University in Japan revealed the underlying brain mechanism, showing that orexin neurons play a crucial role in driving and regulating motivated behavior. The findings were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) .
Motivational deficits, including loss of motivation, are often seen in mental disorders such as depression, addiction and ADHD. However, the brain mechanisms behind these problems remain largely unclear.
The research team, led by Hiroyuki Mizoguchi , associate professor, and Kiyofumi Yamada, professor emeritus, at Nagoya University's Graduate School of Medicine , focused on orexin neurons. These neurons regulate essential physiological functions such as sleep, appetite and energy expenditure. Although recent studies suggest that orexin neurons also influence motivation, their exact role has remained unclear.
This study used rats to examine how changes in orexin neuron activity influence motivation to obtain food rewards. While most previous studies used mice, rats offer superior learning abilities and are better suited for complex behavioral experiments. Because of technical challenges in targeting specific neurons in rats, research in this area has been limited.
To address this limitation, the team developed genetically modified "orexin-Cre" rats, allowing precise targeting and manipulation of orexin-producing neurons. This model was used to investigate how these neurons influence motivation.
First, using chemogenetics, the researchers activated the rats' orexin neurons and had them perform a progressive ratio test where the number of touches required to earn a food reward increased with each trial. The point at which a rat gave up (the breakpoint) measured motivation intensity. Rats with activated orexin neurons showed higher breakpoints, meaning they worked harder for the reward. Conversely, in a model where orexin neurons were selectively degenerated, breakpoints were lower, indicating reduced motivation.
Next, using fiber photometry, the team recorded real-time activity of orexin neurons as the rats anticipated and received their reward. Activity increased before the reward was obtained, decreased once it was received, and remained elevated when an expected reward failed to arrive. Notably, the more effort required, the stronger the orexin neuron activity became. The researchers say this pattern may reflect how the brain links reward expectation to the effort required to pursue them.
To test this causally, the researchers used optogenetics to control orexin neuron activity at the moment a reward was anticipated. When orexin neuron activity was suppressed using an inhibitory protein, the rats' motivated behavior decreased — they took longer to complete effort-based tasks, and their breakpoints dropped. By contrast, when the team attempted to boost orexin neuron activity at that moment using an excitatory protein, no further increase in motivated behavior was observed, even though the stimulation reliably activated the neurons.
In other words, suppressing orexin neurons impaired motivation, but artificially exciting them beyond natural levels did not enhance it. The researchers say this asymmetry suggests orexin neurons are necessary for sustaining motivated behavior, though simply raising their activity may not be sufficient to increase it. Further studies are needed to determine what governs this effect, such as the duration or pattern of orexin neuron activity.
Mizoguchi concluded, "Our study demonstrated significant changes in orexin neuron activity depending on expected rewards and the effort required, suggesting a potential mechanism for translating expectations into sustained action."
Future research will investigate the input and output circuits connected to orexin neurons. A deeper understanding of orexin function may inform new approaches to addressing motivational deficits, including loss of motivation or challenges in sustaining goal-directed behavior.
Publication information:
Yutao Dong, Sheikh Mizanur Rahaman, Wenjun Zhu, Ayumu Inutsuka, Daisuke Ono, Rinako Tanaka, Tetsuo Matsuzaki, Eiji Shibata, Madoka Isobe, Shuntaro Izawa, Akihiro Yamanaka, Kiyofumi Yamada, and Hiroyuki Mizoguchi, 2026. Reward prediction is encoded by orexin neuron activity during motivated behavior, Proceedings of the National Academy of Sciences of the United States of America, DOI: 10.1073/pnas.2520677123
Funding information:
This work was supported by Grant-in-Aid for Scientific Research [22K19749; 23K27360; and 23H02669 (2023)]; SENSHIN Medical Research Foundation; Naito Foundation, Japan; Takeda Science Foundation, Japan; SRF, Japan; Asahi Glass Foundation, Japan; Mishima Kaiun Memorial Foundation, Japan; Kao Health Science Foundation, Japan; and AMED, Japan (JP21wm0425014).
