Loss of motivation is common in conditions such as depression, addiction, and ADHD. Even so, scientists still do not fully understand the brain processes that contribute to these motivational difficulties.

Orexin Neurons and Motivation

The research was led by Hiroyuki Mizoguchi, associate professor, and Kiyofumi Yamada, professor emeritus, at Nagoya University's Graduate School of Medicine. Their team focused on orexin neurons, which help control vital functions including sleep, appetite and energy expenditure.

Previous research has suggested that these neurons may also affect motivation, but their specific contribution has remained uncertain.

To investigate, the scientists studied how changes in orexin neuron activity affected rats seeking food rewards. Earlier studies in this area have generally used mice, but rats have stronger learning abilities and are often better suited to complicated behavioral tasks. Research involving specific neuron types in rats has been more difficult because those cells are harder to target precisely.

The team overcame this obstacle by creating genetically modified "orexin-Cre" rats. This new model allowed the researchers to selectively target and manipulate neurons that produce orexin.

Measuring How Hard Rats Would Work

The researchers first used chemogenetics to activate orexin neurons. They then placed the rats in a progressive ratio test, in which the animals had to make an increasing number of touches to receive each food reward.

The point at which an animal stopped trying (the breakpoint) was used as a measure of motivational strength. Rats whose orexin neurons had been activated reached higher breakpoints, showing that they were willing to perform more work for the reward.

The opposite pattern appeared in rats whose orexin neurons had been selectively degenerated. These animals reached lower breakpoints, indicating that their motivation had weakened.

Brain Activity Rose With Effort

The team next used fiber photometry to monitor orexin neuron activity in real time while the rats waited for and received food.

Activity increased as the animals anticipated the reward, then fell after the food was delivered. When an expected reward did not appear, however, orexin neuron activity remained high.

The response also became stronger as the amount of work required increased. According to the researchers, this pattern may show how the brain connects the expectation of a reward with the effort needed to obtain it.

Suppressing Orexin Reduced Motivation

To determine whether orexin neurons directly influenced behavior, the scientists used optogenetics to control the neurons at the moment the rats expected a reward.

When the researchers suppressed orexin neuron activity using an inhibitory protein, the animals showed less motivated behavior. They took longer to finish tasks that required effort, and their breakpoints decreased.

The team also tried increasing orexin neuron activity at the same moment using an excitatory protein. Although the stimulation successfully activated the cells, it did not cause the rats to work harder or show any further rise in motivation.

These results suggest that orexin neurons are required to maintain motivated behavior, but increasing their activity beyond normal levels may not be enough to produce additional motivation. More research will be needed to determine why the effects are uneven and whether factors such as the duration or pattern of activity influence the outcome.

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."

Understanding Loss of Motivation

Future studies will examine the brain circuits that send information to orexin neurons and receive signals from them. A clearer understanding of how these neurons function could eventually contribute to new ways of addressing motivational deficits, including loss of motivation and difficulty maintaining goal-directed behavior.

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).