Why do some people continue pursuing a goal even when the effort required becomes increasingly difficult? Researchers at Nagoya University in Japan have identified a brain mechanism that may help explain how motivation is sustained. Their study found that orexin neurons play a key role in maintaining and regulating motivated behavior. The findings were published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).
Motivation loss is a common symptom of conditions such as depression, addiction and attention-deficit/hyperactivity disorder (ADHD). However, the brain mechanisms that influence motivation and goal-directed behavior are not yet fully understood.
How Orexin Neurons Influence Motivation
The study was led by Hiroyuki Mizoguchi, associate professor, and Kiyofumi Yamada, professor emeritus, at Nagoya University’s Graduate School of Medicine. The researchers focused on orexin neurons, brain cells that help regulate essential functions such as sleep, appetite and energy expenditure.
Earlier studies suggested that orexin neurons may also play a role in motivation. However, their precise contribution to sustained effort and reward-seeking behavior remained unclear.
To investigate, the research team examined how changes in orexin neuron activity affected rats working to obtain food rewards. Previous studies have often used mice, but rats typically demonstrate stronger learning abilities and are better suited to complex behavioral experiments. Studying specific neuron types in rats has been challenging because these cells are more difficult to target accurately.
To overcome this limitation, the researchers developed genetically modified “orexin-Cre” rats. This model enabled them to selectively identify and manipulate orexin-producing neurons.
Testing How Much Effort Rats Would Make
The researchers first used chemogenetics to activate the rats’ orexin neurons. The animals then completed a progressive ratio test, which required them to make an increasing number of touches to receive each food reward.
The point at which a rat stopped responding, known as the breakpoint, served as a measure of motivation. Rats with activated orexin neurons reached higher breakpoints, indicating that they were willing to work harder for the food reward.
In contrast, rats whose orexin neurons had been selectively degenerated reached lower breakpoints. This result suggested that reduced orexin activity weakened motivated behavior.
Orexin Activity Increased as Effort Rose
The team next used fiber photometry to track orexin neuron activity in real time while the rats anticipated and received food rewards.
Orexin neuron activity increased as the rats expected the reward, then decreased after the food was delivered. When an anticipated reward was withheld, however, activity remained elevated.
The neural response also became stronger when the animals had to perform more work to obtain the reward. According to the researchers, this pattern may explain how the brain links reward expectation with the effort needed to achieve it.
Blocking Orexin Neurons Reduced Motivation
To determine whether orexin neurons directly control motivated behavior, the scientists used optogenetics to manipulate the cells when the rats were expecting a reward.
When the researchers suppressed orexin neuron activity with an inhibitory protein, the rats showed less motivated behavior. They took longer to complete effort-based tasks, and their breakpoints declined.
The team also increased orexin neuron activity at the same point in the task by using an excitatory protein. Although this stimulation successfully activated the neurons, it did not make the rats work harder or produce an additional increase in motivation.
These findings indicate that orexin neurons may be necessary for maintaining motivated behavior, but activating them beyond normal levels may not be sufficient to increase motivation further. Additional research is needed to determine why the effects differ and whether the timing, duration or pattern of orexin activity influences behavior.
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.”
New Clues About Motivation Loss
Future studies will investigate the brain circuits that provide input to orexin neurons and receive signals from them. A better understanding of how these neurons regulate motivation could eventually support new approaches for addressing motivational deficits, including loss of motivation and difficulty sustaining goal-directed behavior.
This research was supported by Grant-in-Aid for Scientific Research [22K19749; 23K27360; and 23H02669 (2023)]; the SENSHIN Medical Research Foundation; the Naito Foundation, Japan; the Takeda Science Foundation, Japan; SRF, Japan; the Asahi Glass Foundation, Japan; the Mishima Kaiun Memorial Foundation, Japan; the Kao Health Science Foundation, Japan; and AMED, Japan (JP21wm0425014).
Source: www.sciencedaily.com