Neuroscientists Discover the Brain Circuity for Persistence

New discovery in mice may one day help those with depression and addiction.

Posted Aug 09, 2019

Source: Gabler-Werbung/Pixabay

Why do some people give up easily and others do not? A common leadership ability among extraordinary achievers—such as CEOs, inventors, astronauts, best-selling authors, successful artists and musicians, popular comedians, media stars, trail-blazing entrepreneurs, ace pilots, Nobel prize winning scientists, and professional athletes—is persistence and motivation—the ability to go the extra mile and not give up easily.

Is there a biological basis to why some are able to persist more than others? A new scientific study published on July 25, 2019, in Cell identifies the molecular underpinnings and brain circuity that constrain motivation when the effort increases to obtain a reward—a new discovery that is the first step towards developing novel treatments for those suffering from addiction, depression, eating disorders, psychiatric disorders, and other mental health conditions.

In a four-year study, researchers from the University of Washington (UW) School of Medicine, and the Washington University School of Medicine, in collaboration with colleagues at other institutions, uncovered what actually happens inside the animal brain at the point of giving up.  

“One of the key aspects of this work is that we identified a previously unknown neuromodulator system that regulates another neuromodulator dopamine,” said Michael Bruchas, the study’s senior author and professor at the University of Washington School of Medicine, and principal faculty member at UW's Center for Neurobiology of Addiction, Pain, and Emotion. “This suggests even more complex relationships with neuropeptide modulators in the brain and monoamine systems like the dopamine and serotonin system.”

To conduct the study, researchers used Pavlovian conditioning on mice. In behavior psychology, Pavlovian conditioning, named after the 1904 Nobel laureate Ivan Petrovich Pavlov, is the method of using a powerful biological reward such as tasty food paired with a predefined stimulus like an image or sound. In this study, the researchers conditioned mice who were food restricted to receive the reward of sugar water when they complete the task of poking their nose in a designated port.

Other techniques the researchers used in the study include optogenetics, chemogenetics, and photometry. The scientists recorded the activity of the brain cells as the mice performed the task. They discovered that a group of brain cells located near the ventral tegmental area (VTA), called the nociceptin neurons, become very active prior to the mice giving up. The nociceptin neurons activity increased as the mice decreased their efforts to obtain the reward of sugar water.

“There are multiple different areas in the brain that kind of coordinate when that tipping point is reached—but I think we’ve demonstrated here that this group of cells, the nociception cells, are definitely a voice that are telling the dopamine cells, and ultimately the animal, to give up,” said co-lead author Christian Pedersen, a fourth-year Ph.D. student in bioengineering at the University of Washington School of Medicine and the UW College of Engineering, in a UW Medicine video report.

“In terms of actually developing medications, and trying to treat psychiatric disease, these nociception cells directly influence dopamine levels in the brain. It’s known that many diseases have to do with dysregulation of dopamine, such as depression is characterized as a reduction of dopamine. This system that we’re reporting can be turned off and on with different medications or drugs to influence how much dopamine is released to reduce the symptoms of psychiatric disorders,” said Pedersen.

“We imagine that it is possible these neurons role in suppression of motivation might be altered in substance use disorder, so that their natural ability to regulate motivation, to seek drugs could be gone,” said Bruchas.

“There is some preliminary evidence published in a recent Science Translational Medicine article that agonists for the receptors (NOPR) that these neurons talk to, can suppress motivation for drugs of abuse," said Bruchas. "We will continue to use various animal models of addiction to pursue this question, and preliminary data suggest that activation of the receptor reduces seeking for drugs like cocaine. We will hopefully present those results at the American College of Neuropsychopharmacology this December in Orlando.”

According to Bruchas, the team is working to further translate their findings into non-human primates and human models by collaborating on a larger project at multiple universities such as Brown, Harvard, and MIT.

“This is one of the first works to really show that these complex molecules known as neuropeptides, can actually influence behavior through the VTA,” said Pedersen. “And that unto itself, is very scientifically important—and also potentially targetable with different medications.”

Copyright © 2019 Cami Rosso All rights reserved.


Parker, Kyle E., Pedersen, Christian E., Gomez, Adrian M., Spangler, Skylar M., Walicki, Marie C., Feng, Shelley Y., Stewart, Sarah L., Otis, James M., Al-Hasani, Ream, McCall, Jordan G., Sakers, Kristina, Bhatti, Dionnet L., Copits, Bryan A., Gereau, Robert W., Jhou, Thomas, Kash, Thomas J., Dougherty, Joseph D., Stuber, Garret D., Bruchas, Michael R. “A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward.” Cell. July 25, 2019.

UW Medicine (2019, July 25). “Researchers discover the science behind giving up [Press Release].” Retrieved from