New research is pushing mice to their breaking point to see what our brain does as we give up.

Image credits Lagrevehumaine / Wikimedia.

A group of cells known as nociceptin neurons get busy when we’re giving up, new research shows. True to their name, these neurons release nociceptin, a complex molecule that suppresses dopamine. Dopamine is a neurotransmitter that underpins the brain’s pleasure and reward networks. The findings offer us a fresh take on the processes that govern motivation.

Giveupceptin

“We are taking an entirely new angle on an area of the brain known as VTA [ventral tegmental area],” 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. “The big discovery is that large complex neurotransmitters known as neuropeptides have a very robust effect on animal behavior by acting on the VTA,” said Pedersen.

Nociceptin neurons are located near the VTA, a brain area that houses the hormones that release dopamine during pleasurable activities. This study took four years to complete and, according to the team, is the first one to describe the effects of the nociceptin modulatory system on dopamine neurons. The team hopes their findings will lead to new ways of helping people find motivation when they are depressed or decrease motivation for drug use in substance-abuse disorders.

The team worked with mice that they trained to seek out sucrose (sugar). To do this, the animals had to poke their snout into a port. The team set-up their experiment in such a way that this task was very simple and straight-forward at first: one poke, one reward. Over time, however, it would take exponentially more pokes (two, five, so on) to get the reward — and eventually, the animals just gave up. All the while, the team monitored the mice’s neural activity.

These recordings showed that the nociceptin neurons act as ‘demotivators’ or ‘frustration’ neurons and became most active when mice stopped seeking sucrose — suggesting they put the brakes on motivation.

“We might think of different scenarios where people aren’t motivated like depression and block these neurons and receptors to help them feel better,” says senior author Michael Bruchas, professor of anesthesiology and pain medicine and of pharmacology at the University of Washington School of Medicine.

“That’s what’s powerful about discovering these cells. Neuropsychiatric diseases that impact motivation could be improved.”

The team explains that these neurons exist as a kind of insurance policy for mammals living in the wild. The reward pathways in our brains work to make us mammals maintain homeostasis (i.e. our internal ‘optimal running conditions’). However, in the wild, animals need a safety switch to keep them from pursuing rewards too much, as the environment tends to have limited resources and this pursuit of reward could impact the animal’s survival by expending too much energy, for example. Persistence in seeking uncertain rewards can also be disadvantageous due to risky exposure to predators, the researchers noted.

The paper “A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward” has been published in the journal Cell.